Patent Publication Number: US-2019194728-A1

Title: Systemic inflammatory and pathogen biomarkers and uses therefor

Description:
FIELD OF THE INVENTION 
     This application claims priority to Australian Provisional Application No. 2016903370 entitled “Systemic inflammatory and pathogen biomarkers and uses therefor” filed 24 Aug. 2016, the contents of which are incorporated herein by reference in their entirety. 
     This invention relates generally to compositions, methods and apparatus for diagnosing and/or monitoring an infection by a bacterium, virus or protozoan by measurement of pathogen-associated and non-infectious systemic inflammation and optionally in combination with detection of a pathogen specific molecule. The invention can be used for diagnosis, including early diagnosis, ruling-out, ruling-in, monitoring, making treatment decisions, or management of subjects suspected of, or having, systemic inflammation. More particularly, the present invention relates to host peripheral blood RNA and protein biomarkers, which are used in combination, and optionally with peripheral blood broad-range pathogen-specific detection assays, that are useful for distinguishing between bacterial, viral, protozoal and non-infectious causes of systemic inflammation. 
     BACKGROUND OF THE INVENTION 
     Fever and clinical signs of systemic inflammation (or SIRS) are commonly seen in patients presenting to medical services; either in general practice clinics, outpatient clinics, emergency rooms, hospital wards or intensive care units (Rangel-Frausto et al. (1995). The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA: the Journal of the American Medical Association, 273(2), 117-123; McGowan et al. (1987). Fever in hospitalized patients. With special reference to the medical service. The American Journal of Medicine, 82(3 Spec No), 580-586; Bor et al. (1988). Fever in hospitalized medical patients: characteristics and significance. Journal of General Internal Medicine, 3(2), 119-125; Finkelstein et al. (2000). Fever in pediatric primary care: occurrence, management, and outcomes. Pediatrics, 105(1 Pt 3), 260-266). 
     When SIRS is the result of a confirmed infectious process it is called infection-positive SIRS (ipSIRS), otherwise known as sepsis. Within this definition lies the following assumptions; the infectious process could be local or generalized; the infection could be bacterial, viral or parasitic; the infectious process could be in an otherwise sterile body compartment. Such a definition has been updated in Levy et al. 2003 (“2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference,” Critical Care Medicine 31, no. 4: 1250-1256) to accommodate clinical and research use of the definition. The revised definition allowed that the infection be in a sterile or non-sterile site (e.g., overgrowth of a pathogen/commensal in the intestine) and that the infection can be either confirmed or suspected. More recently, the definition of sepsis has been updated to be a “life-threatening organ dysfunction caused by a dysregulated host response to infection” (Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA: the Journal of the American Medical Association, 315(8), 801-10). 
     In many instances the use of the terms SIRS and sepsis, their changing definitions, and what clinical conditions they do or do not include, are confusing in clinical situations. Such confusion leads to difficulties in clinical diagnosis and in making decisions on subsequent patient treatment and management. Difficulties in clinical diagnosis are based on the following questions: 1) what constitutes a “suspected” infection given that many body organs/sites are naturally colonized by microbes (e.g.,  Escherichia coli  in the intestines,  Staphylococcus epidermidis  in skin), viruses (e.g., latent viruses such as herpes, resident human rhinovirus in otherwise healthy children) or parasites (e.g.,  Toxoplasma, Giardia ); 2) what constitutes a pathological growth of an organism in a normally non-sterile body site?; 3) what contributions to SIRS are made by a bacterial/viral/parasitic co-infection in a non-sterile body site (e.g., upper respiratory tract), and if such an infection is suspected then should the patient be put on antibiotics, anti-viral or anti-parasitic compounds? 
     Patients with fever and other clinical signs of SIRS need to be carefully assessed, and tested, to determine the cause of the presenting clinical signs as there are many possible differential diagnoses (Munro, N. (2014). Fever in acute and critical care: a diagnostic approach. AACN Adv Crit Care 25: 237-248). Possible, non-limiting, differential diagnoses include infection (bacterial, viral, parasitic), trauma, allergy, drug reaction, autoimmunity, surgery, neutropenia, cancer, metabolic disorders, clotting disorders. 
     Patients with fever and SIRS caused by bacterial infection often require immediate medical attention and it is therefore important to quickly and accurately differentiate such patients. 
     Patients with fever and SIRS caused by viral infection need to be further assessed to determine 1) the degree of systemic inflammation due to viral infection, 2) the degree of involvement of microbes (commensals, microbiome, pathogens) to systemic inflammation 3) contributions that each of viruses, microbes and sterile injury are making to systemic inflammation 4) likelihood of the patient rapidly deteriorating. 
     Patients with fever and SIRS caused by a protozoal infection (e.g., malaria) also need to be further assessed to determine 1) the degree of systemic inflammation due to protozoal infection, 2) the degree of involvement of other microbes (commensals, microbiome, bacterial or viral pathogens) to systemic inflammation 3) contributions that each of protozoans, viruses, microbes and sterile injury are making to systemic inflammation 4) likelihood of the patient rapidly deteriorating. 
     The results of such an assessments aids clinicians in making appropriate management and treatment decisions. Appropriate patient management and treatment decisions leads to lower mortality, shorter hospital stays, less use of medical resources and better patient outcomes. 
     For the purposes of the present disclosure the following definitions are used: Bacterial associated SIRS (BaSIRS) is a condition of a patient with systemic inflammation due to bacterial infection; Viral associated SIRS (VaSIRS) is a condition of a patient with systemic inflammation due to a viral infection; Protozoal associated SIRS (PaSIRS) is a condition of a patient with systemic inflammation due to a protozoal infection; infection-negative SIRS (InSIRS) is a condition of a patient with systemic inflammation due to non-infectious causes. Patients with the conditions BaSIRS, VaSIRS, PaSIRS or InSIRS all have systemic inflammation or SIRS. BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers refer to specific host response biomarkers associated with the conditions of BaSIRS, VaSIRS, PaSIRS and InSIRS, respectively. Bacterial Infection Positive (BIP), Viral Infection Positive (VIP) and Protozoal Infection Positive (PIP) conditions are conditions of patients with detectable bacterial, viral or parasitic molecules respectively. Bacterial Infection Negative (BIN), Viral Infection Negative (VIN) and Protozoal Infection Negative (PIN) conditions are conditions of patients with non-detectable bacterial, viral or parasitic molecules respectively. BIP, VIP and PIP biomarkers refers to biomarkers that are specific to pathogen molecules as determined by the use of bacterial, viral or protozoal molecule detection assays. Collectively, BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers are referred to as “host response specific biomarkers.” BIP, VIP and PIP biomarkers are referred to as “pathogen specific biomarkers”. Patients that present with clinical signs of SIRS can be pathogen specific biomarker positive or negative. Thus, patients can be: BaSIRS/BIP, BaSIRS/BIN, VaSIRS/VIP, VaSIRS/VIN, PaSIRS/PIP, PaSIRS/PIN, InSIRS/BIP, InSIRS/BIN, InSIRS/VIP, InSIRS/VIN, InSIRS/PIP, InSIRS/PIN. Suitably, various biomarkers for each of the conditions can found in higher or lower amounts or be detected or not. The results of host response specific biomarker assays and pathogen specific biomarker assays can be combined creating a BaSIRS, VaSIRS, PaSIRS or InSIRS “indicator”. 
     Whether or not a host responds to a pathogen infection or insult through a SIRS depends largely upon the extent and type of exposure to antigen(s) (PAMPs) or damage associated molecular patterns (DAMPs) (Klimpel G R. Immune Defenses. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (Tex.): University of Texas Medical Branch at Galveston; 1996. Chapter 50). Factors that affect host immune system exposure to PAMPs and DAMPs include; 1) Host immune status, including vaccination, 2). Primary or secondary exposure to the same antigen(s) or antigen class or DAMPs, 3). Stage of infection or insult (early, late, re-activation, recurrence), 4). Infection type (intracellular, cytolytic, persistent, latent, integrated), 5). Mechanism of infection spread within the host (primary hematogenous, secondary hematogenous, local, nervous), 6). Pathogen or insult location (systemic or restricted to mucosal surface or a tissue/organ). 
     There are a limited number of microorganisms (bacteria, yeast, viruses, protozoans) that cause disease in humans and an even fewer number cause the majority of infectious diseases. TABLE 1 lists common bacterial, viral and protozoal pathogens associated with human BaSIRS, VaSIRS and PaSIRS, respectively. Such pathogens have multiple methods of interacting with the host and its cells and if a host mounts a systemic inflammatory response to an infection it means that the immune system has been exposed to sufficient levels of novel pathogen molecules. Representative types of pathogen molecules that can elicit a systemic inflammatory response include proteins, nucleic acids (RNA and/or DNA), lipoproteins, lipoteichoic acid and lipopolysaccharides, many of which can be detected (and typed) circulating in blood at some stage during the disease pathogenesis. 
     Many pathogen molecules are specific to a particular type of pathogen and the host immune system will respond in a specific, adaptive, and usually delayed, manner. However, it is known that there are host receptors, called pattern recognition receptors (PRR), for foreign (microbial, viral, protozoal) antigens (Perry, A. K., Chen, G., Zheng, D., Tang, H., &amp; Cheng, G. (2005). The host type I interferon response to viral and bacterial infections. Cell Research, 15(6), 407-422; Gazzinelli R T, Kalantari P, Fitzgerald K A, Golenbock D T. Innate sensing of malaria parasites. Nat Rev Immunol. 2014 November; 14(11):744-57). PRRs recognise, in a non-specific manner, conserved molecular motifs called Pathogen Associated Molecular Patterns, or PAMPs. The cellular pathways and conserved response to PRR stimulation are well documented and includes the production of Type I interferons (Type I IFNs), tumor necrosis factor (TNF) and interleukins. Whilst different pathogens may use different initial receptors they activate common downstream molecules which ultimately leads to the production of Type I IFNs, IFN and interleukins. The variable downstream effects of these cytokine molecules are dependent upon a number of factors including cell source, concentration, receptor density, receptor avidity and affinity, cell type (Hall, J. C., &amp; Rosen, A. (2010). Type I interferons: crucial participants in disease amplification in autoimmunity. Nature Reviews Rheumatology, 6(1), 40-49; Wajant, H., Pfizenmaier, K., &amp; Scheurich, P. (2003). Tumor necrosis factor signaling. Cell Death and Differentiation, 10(1), 45-65). Accordingly, the host immune system responds to a pathogenic infection in both a generalized (often innate) and specific (often adaptive) manner. 
     The purported “gold standard” of diagnosis for bacterial infection is culture (growth of an organism and partial or complete identification by staining or biochemical or serological assays). Thus, confirmation of a diagnosis of BaSIRS requires isolation and identification of live bacteria from blood or tissue or body fluid samples using culture, but this technique has its limitations (Thierry Calandra and Jonathan Cohen, “The International Sepsis Forum Consensus Conference on Definitions of Infection in the Intensive Care Unit,” Critical Care Medicine 33, no. 7 (July 2005): 1538-1548; R Phillip Dellinger et al., “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008.,” vol. 36, 2008, 296-327, doi:10.1097/01.CCM.0000298158.12101.41). Bacterial culture usually takes a number of days to obtain a positive result and over five days (up to a month) to confirm a negative result. A positive result confirms bacteremia if the sample used was whole blood. However, blood culture is insufficiently reliable with respect to sensitivity, specificity and predictive value, failing to detect a clinically determined ‘bacterial’ cause of fever in 60-80% of patients with suspected primary or secondary bloodstream infection, and in many instances the organism grown is a contaminant (Müller, B., Schuetz, P. &amp; Trampuz, A. Circulating biomarkers as surrogates for bloodstream infections. International Journal of Antimicrobial Agents 30, 16-23 (2007); Jean-Louis Vincent et al., Sepsis in European Intensive Care Units: Results of the SOAP Study, Critical Care Medicine 34, no. 2 (February 2006): 344-353; Brigitte Lamy et al., What Is the Relevance of Obtaining Multiple Blood Samples for Culture? A Comprehensive Model to Optimize the Strategy for Diagnosing Bacteremia, Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America 35, no. 7 (Oct. 1, 2002): 842-850; M D Aronson and D H Bor, Blood Cultures”, Annals of Internal Medicine 106, no. 2 (February 1987): 246-253); Bates, D. W., Goldman, L. &amp; Lee, T. H. Contaminant blood cultures and resource utilization. The true consequences of false-positive results. JAMA 265, 365-369 (1991)). Potential consequences of the diagnostic limitations of bacterial culture in patients suspected of having BaSIRS include; the overuse and misuse of broad-spectrum antibiotics, the development of antimicrobial resistance and  Clostridium difficile  infection, adverse drug reactions, and increased treatment and testing costs. Antimicrobial resistance is becoming a significant problem in critical care patient management, particularly with Gram-negative bacilli (Hotchkiss and Donaldson. 2006, Nature Reviews Immunology 6:813-822; Eber et al., 2010, Arch Intern Med. 170(4):374-353). Recent evidence suggests that indiscriminate use of antibiotics has contributed to resistance and hence guidance on antibiotic treatment duration is now imperative in order to reduce consumption in tertiary care ICU settings (Hanberger et al., 1999, JAMA. 281:61-71). Molecular nucleic acid-based tests have been developed to detect the major sepsis-causing bacterial pathogens in whole blood from patients with suspected sepsis (e.g., SeptiFast® from Roche, Iridica® from Abbott, Sepsis Panel from Biofire (Biomerieux), Prove-it® Sepsis from Mobidiag). Whilst sensitive and specific, such assays have limitations, especially with respect to clinical interpretation of assay results for suspected sepsis patients that are 1) PCR or assay positive and blood culture negative, and 2) PCR or assay negative (Bauer M, Reinhart K (2010) Molecular diagnostics of sepsis—Where are we today? International Journal of Medical Microbiology 300: 411-413). Thus, blood culture, at least in the minds of clinicians, remains the gold standard for diagnosis of sepsis (BaSIRS) because the results of molecular pathogen detection assays are difficult to interpret in isolation. 
     Currently, diagnosis of viral conditions is challenging. In general, the conventional method for diagnosing viral infection is cell culture and isolation (growth of virus in cell culture, observation of cytopathic effect (CPE) or hemadsorption (HAD), and partial or complete identification by staining or biochemical or immunoassay (e.g., immunofluorescence)) (Hsiung, G. D. 1984. Diagnostic virology: from animals to automation. Yale J. Biol. Med. 57:727-733; Leland D S, Ginocchio C C (2007) Role of Cell Culture for Virus Detection in the Age of Technology. Clinical Microbiology Reviews 20: 49-78). This method has limitations in that it requires; appropriate transport of the clinical sample in an appropriate virus-preservation medium, an initial strong suspicion of what the infecting virus might be (to select a suitable cell line that will grow the suspected virus), a laboratory having suitable expertise, equipment and cell lines, and, once these conditions are all in place, a lengthy incubation period (days to weeks) to grow the virus. The process is laborious and expensive. 
     With respect to improving the diagnosis of viral conditions, and more recently, sensitive and specific assays such as those using monoclonal antibodies or nucleic acid amplification have become available and are now widely available and used in diagnostic laboratories. Amplification of viral DNA and RNA (e.g., PCR) and viral antigen detection are fast and do not require the lengthy incubation period needed for viral isolation in cell cultures, may involve less technical expertise, and are sensitive enough to be useful for viruses that do not proliferate in standard cell cultures. Molecular detection of viral DNA and RNA also has its limitations in that an initial strong suspicion of what the infecting virus might be is also required (to use specific PCR primers and probes, for example), the method detects both live and dead virus, and most molecular tests are designed to detect only one type of virus and, as such, will only detect one type of virus. By way of example, it has been shown that mixed respiratory infections occur in up to 15% of immunocompetent children and that such mixed infections lead to an increase in disease severity (Waner, J. L. 1994. Mixed viral infections: detection and management. Clin. Microbiol. Rev. 7:143-151). A PCR designed to only one type of virus will not detect a mixed infection if the primers and probes are not specific to all viruses present in the clinical specimen. To cover the possibility of a mixed infection, as well as to cover multiple possible viral causes or strains, there are some commercially available assays capable of detecting more than one virus and/or strain at a time (e.g., BioMerieux, BioFire, FilmArray®, Respiratory Panel; Luminex, xTAG® Respiratory Viral Panel). Such an approach is especially useful in confirming an infective agent if clinical signs are pathognomonic or if a particular body system is affected (e.g., respiratory tract or gastrointestinal tract). Further, there are techniques that allow for amplification of viral DNA of unknown sequence which could be useful in situations where the clinical signs are generalized, for viruses with high mutation rates, for new and emerging viruses, or for detecting biological weapons of man-made nature (Clem et al. (2007) Virus detection and identification using random multiplex (RT)-PCR with 3′-locked random primers. Virol J 4: 65; Liang et al. (1992) Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257(5072):967-971; Nie X et al. (2001) A novel usage of random primers for multiplex RT-PCR detection of virus and viroid in aphids, leaves, and tubers. J Virol Methods 91(1):37-49; Ralph et al. (1993) RNA fingerprinting using arbitrarily primed PCR identifies differentially regulated RNAs in mink lung (Mv1Lu) cells growth arrested by transforming growth factor beta 1. Proc Natl Acad Sci USA 90(22):10710-10714.). Further, a microarray has been designed to detect every known virus for which there is DNA sequence information in GenBank (called “Virochip”) (Greninger, A. L., Chen, E. C., Sittler, T., Scheinerman, A., Roubinian, N., Yu, G., et al. (2010). A metagenomic analysis of pandemic influenza A (2009 H1N1) infection in patients from North America. PLoS ONE, 5(10), e13381; Chiu C Y, Greninger A L, Kanada K, Kwok T, Fischer K F, et al. (2008) Identification of cardioviruses related to Theiler&#39;s murine encephalomyelitis virus in human infections. Proc Natl Acad Sci USA 105: 14124-14129). The use of such a microarray for diagnostic purposes in human patients presenting with clinical signs of SIRS is perhaps superfluous since there is only a limited number of human viruses that are known to cause SIRS (see TABLES 1 and 2). However, a more directed microarray using just those human viruses that are known to cause SIRS could be used for the purpose outlined in this patent. 
     It has been shown that the use of molecular detection methods, compared to conventional detection methods, in patients with lower respiratory tract infections did not significantly change the treatment regimen but led to an overall increase in cost of patient management (Oosterheert J J, van Loon A M, Schuurman R, Hoepelman A I M, Hak E, et al. (2005) Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection. Clinical Infectious Diseases 41: 1438-1444). Thus, the availability of faster and more sensitive molecular detection assays for pathogens does not necessarily positively impact clinical decision making, patient outcome, antibiotic use, adoption or hospital econometrics. Further, pathogen detection assays for viruses have limitations in that the results are often difficult to interpret in a clinical context when used in isolation. Thus, the diagnosis of a viral infection, and if a virus is isolated or identified whether it is pathogenic or not, cannot always be made simply by determining the presence of such an organism in a host sample. 
     In some instances, detection of host antibodies to an infecting virus remains the diagnostic gold standard, because either the virus cannot be grown, or the presence of virus in a biological fluid is transient (e.g., arboviral infections) and therefore cannot be detected at times when the patient is symptomatic. Antibody detection also has limitations including: it usually takes at least 10 days for a host to generate detectable and specific immunoglobulin G antibodies in a primary infection, by which time the clinical signs have often abated; anti-viral antibodies following a primary infection can persist for a long period making it difficult to interpret the timing of an infection relapse for viruses that show latency; a specific test must be ordered to detect a specific virus. These limitations make it difficult to determine when the host was infected, whether high antibody titers to a particular virus means that a particular virus is the causative agent of the presenting clinical signs, and which test to order. In some instances the ratio of IgM to IgG antibodies can be used to determine the recency of virus infection. IgM is usually produced early in the immune response and is non-specific, whereas IgG is produced later in the immune response and is specific. Examples of the use of this approach include the diagnosis of hepatitis E (Tripathy et al. (2012). Cytokine Profiles, CTL Response and T Cell Frequencies in the Peripheral Blood of Acute Patients and Individuals Recovered from Hepatitis E Infection. PLoS ONE, 7(2), e31822), dengue (SA-Ngasang et al. (2005). Specific IgM and IgG responses in primary and secondary dengue virus infections determined by enzyme-linked immunosorbent assay. Epidemiology and Infection, 134(04), 820), and Epstein-Barr Virus (Hess, R. D. (2004). Routine Epstein-Barr Virus Diagnostics from the Laboratory Perspective: Still Challenging after 35 Years. Journal of Clinical Microbiology, 42(8), 3381-3387). The IgM/IgG ratio approach also suffers from the limitation that the clinician must know which specific test to order a priori. 
     Parasitic diseases place a heavy burden on human health worldwide with the majority of people affected living in developing countries. However, protozoan parasites are the most common parasitic infection and affect humans irrespective of whether they live in a first or third world country as more and more people become immunocompromised as a result of human immunodeficiency virus (HIV) infection, organ transplant or chemotherapy (Stark D, Barratt J L N, van Hal S, Marriott D, Harkness J, et al. (2009) Clinical Significance of Enteric Protozoa in the Immunosuppressed Human Population. Clinical Microbiology Reviews 22: 634-650). Common and well-known protozoan human pathogens include  Plasmodium  (malaria),  Leishmania  (leishmaniasis),  Trypanosoma  (sleeping sickness and Chagas disease),  Cryptosporidium, Giardia, Toxoplasma, Babesia, Balantidium  and  Entamoeba . Common and well-known protozoan human pathogens that can be found in peripheral blood (causing a parasitemia) include  Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae, Plasmodium vivax, Leishmania donovani, Trypanosoma brucei, Trypanosoma cruzi, Toxoplasma gondii  and  Babesia microti . Diagnosis of protozoal infections is achieved by pathogen detection using a variety of methods including light microscopy, or antigen or nucleic acid detection using different techniques such as tissue biopsy and histology, fecal or blood smears and staining, ELISA, lateral flow immunochromatography, and nucleic acid amplification. These methods of diagnosis have limitations including the fact that they often require special stains and skilled personnel, the sample taken has to have the parasite present, and often the parasite is opportunistic, meaning that many people are carriers of such parasites and do not show clinical signs until their immune system is compromised. As a result, such pathogen detection assays for protozoan parasites are difficult to interpret in a clinical context when used in isolation. 
     Diagnosis of non-infectious SIRS is often by default—that is, elimination of an infection as a cause of SIRS. 
     Thus, the diagnosis of a bacterial, viral or parasitic infection, and if an organism is isolated or identified, whether it is pathogenic or not, cannot always be made simply by determining the presence of such an organism in a host sample. 
     In the absence of a gold standard assay for diagnosis of a condition a combination of tests or parameters, or the use of a group of experts, can be used (Hui, S. L. and X. H. Zhou (1998). Evaluation of diagnostic tests without gold standards. Statistical Methods in Medical Research 7(4), 354-370; Zhang, B., Chen, Z. &amp; Albert, P. S. Estimating diagnostic accuracy of raters without a gold standard by exploiting a group of experts. Biometrics 68, 1294-1302 (2012); Reitsma, J. B., Rutjes, A. W. S., Khan, K. S., Coomarasamy, A. &amp; Bossuyt, P. M. A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard. J Clin Epidemiol 62, 797-806 (2009)). In the absence of a gold standard test for BaSIRS a clinical diagnosis is provided by the physician(s) at the time the patient presents and in the absence of any results from diagnostic tests. This is done in the interests of rapid treatment and positive patient outcomes. Such an approach has proven to be reasonably reliable (AUC ˜0.88) in children but only with respect to differentiating between patients ultimately shown to be blood culture positive and those that were judged to be unlikely to have an infection at the time antibiotics were administered (Fischer, J. E. et al. Quantifying uncertainty: physicians&#39; estimates of infection in critically ill neonates and children. Clin. Infect. Dis. 38, 1383-1390 (2004)). In Fischer et al., (2004), 54% of critically ill children were put on antibiotics during their hospital stay, of which only 14% and 16% had proven systemic bacterial infection or localized infection respectively. In this study, 53% of antibiotic treatment courses for critically ill children were for those that had an unlikely infection and 38% were antibiotic treatment courses for critically ill children as a rule-out treatment episode. Clearly, pediatric physicians err on the side of caution with respect to treating critically ill patients by placing all suspected BaSIRS patients on antibiotics—38% of all antibiotics used in critically ill children are used on the basis of ruling out BaSIRS, that is, are used as a precaution. The risks of not correctly diagnosing BaSIRS are profound (Dellinger, R. P. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. in Crit. Care Med. 36, 296-327 (2008)). Thus, making a diagnosis of BaSIRS (ruling in) carries much less clinical risk than making a diagnosis of InSIRS (ruling out BaSIRS and VaSIRS and PaSIRS). 
     Therefore, with respect to correctly diagnosing BaSIRS, blood culture has unacceptably low negative predictive value (NPV), or unacceptably high false negative levels. With respect to correctly diagnosing BaSIRS, clinical diagnosis has unacceptably low positive predictive value (PPV), or unacceptably high false positive levels. In the latter instance the consequence is that many patients are unnecessarily prescribed antibiotics because of 1) the clinical risk of misdiagnosing BaSIRS, 2) the lack of a gold standard diagnostic test, and 3) the fact that blood culture results take too long to provide results that are clinically actionable. 
     Diagnosis of a viral infection, including VaSIRS, is often done based on presenting clinical signs only. The reasons for this are; most viral infections are not life-threatening, there are few therapeutic interventions available, many viral infections cause the same clinical signs, and most diagnostic assays take too long and are too expensive. The consequence is that many VaSIRS patients are unnecessarily prescribed antibiotics because of the clinical risk of misdiagnosing BaSIRS. 
     Diagnosis of a parasitic infection, including PaSIRS, is based on presenting clinical signs, detection of the parasite and, in areas with low parasite prevalence, exclusion of more common bacterial and viral causes. The consequence is that many PaSIRS patients are misdiagnosed, diagnosed late in the course of disease progression, or unnecessarily prescribed antibiotics because of the clinical risk of misdiagnosing BaSIRS. 
     Alternative diagnostic approaches to BaSIRS have been investigated including determination of host response using biomarkers (Michael Bauer and Konrad Reinhart, “Molecular Diagnostics of Sepsis—Where Are We Today?” International Journal of Medical Microbiology 300, no. 6 (Aug. 1, 2010): 411-413, doi:10.1016/j.ijmm.2010.04.006; John C Marshall and Konrad Reinhart, “Biomarkers of Sepsis,” Critical Care Medicine 37, no. 7 (July 2009): 2290-2298, doi:10.1097/CCM.0b013e3181a02afc.). A systematic literature search identified nearly 180 molecules as potential biomarkers of sepsis of which 20% have been assessed in appropriately designed sepsis studies including C-reactive protein (CRP), procalcitonin (PCT), and IL6 (Reinhart, K., Bauer, M., Riedemann, N. C. &amp; Hartog, C. S. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers. Clinical Microbiology Reviews 25, 609-634 (2012)). 
     Alternative diagnostic approaches to VaSIRS have been investigated including determination of host response using biomarkers to specific viruses (Huang Y, Zaas A K, Rao A, Dobigeon N, Woolf P J, et al. (2011) Temporal Dynamics of Host Molecular Responses Differentiate Symptomatic and Asymptomatic Influenza A Infection. PLoS Genet 7: e1002234; Wang Y, Dennehy P H, Keyserling H L, Tang K, Gentsch J R, et al. (2007) Rotavirus Infection Alters Peripheral T-Cell Homeostasis in Children with Acute Diarrhea. Journal of Virology 81: 3904-3912), and in one instance a common signature to a number of respiratory viruses has been published in two separate scientific papers (Zaas A K, Chen M, Varkey J, Veldman T, Hero A O III, et al. (2009) Gene Expression Signatures Diagnose Influenza and Other Symptomatic Respiratory Viral Infections in Humans. Cell Host &amp; Microbe 6: 207-217; Tsalik, E. L., Henao, R., Nichols, M., Burke, T., Ko, E. R., McClain, M. T., et al. (2016). Host gene expression classifiers diagnose acute respiratory illness etiology. Science Translational Medicine, 8(322), 322ra11-322ra11). 
     Alternative diagnostic approaches to PaSIRS have been investigated including determination of host response using biomarkers (Ockenhouse C F, Hu W C, Kester K E, Cummings J F, Stewart A, et al. (2006) Common and Divergent Immune Response Signaling Pathways Discovered in Peripheral Blood Mononuclear Cell Gene Expression Patterns in Presymptomatic and Clinically Apparent Malaria. Infection and Immunity 74: 5561-5573; Chaussabel D, Semnani R T, McDowell M A, Sacks D et al. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 2003 Jul. 15; 102(2):672-81). 
     The acute management plans for patients with BaSIRS, VaSIRS, PaSIRS and InSIRS are different. For best patient outcomes, it is important that those patients who have a suspected infection, or are at high risk of infection, are identified early and graded and monitored in order to initiate evidence-based and goal-orientated medical therapy, including early use of antibiotics, anti-viral or anti-parasitic therapies. An assay that is reliable, fast, and able to determine the presence or absence of a pathogen infection in patients with systemic inflammation will assist clinicians in making appropriate patient management and treatment decisions. In a background of high prevalence of systemic inflammation and unreliable pathogen detection assays, what is needed is a diagnostic assay that combines specific detection of systemic inflammation biomarkers with broad-range pathogen detection assays so that patients presenting with clinical signs of systemic inflammation can be confidently categorized into InSIRS, BaSIRS, VaSIRS and PaSIRS. Patients negative for both pathogen associated SIRS and pathogen detection assays can be “ruled out” as having an infection. Such an assay would have high negative predictive value for systemic pathogen infection which would have high clinical utility by allowing clinicians to confidently withhold therapies, in particular antibiotics. Patients positive for both pathogen associated SIRS and pathogen detection assays can be “ruled in” as having a particular type of infection (or mixed infection). Such an assay would have high positive predictive value for systemic pathogen infection allowing clinicians to confidently manage and treat patients. 
     Testing for microbes, viruses and parasites requires that clinical samples be taken from patients. Examples of clinical samples include; blood, plasma, serum, cerebrospinal fluid (CSF), stool, urine, tissue, pus, saliva, semen, skin, other body fluids. Examples of clinical sampling methods include; venipuncture, biopsy, scrapings, aspirate, lavage, collection of body fluids and stools into sterile containers. Most clinical sampling methods are invasive (physically or on privacy), or painful, or laborious, or require multiple samplings, or, in some instances, dangerous (e.g., large CSF volumes in neonates). The taking of blood via venipuncture is perhaps the least invasive method of clinical sampling and, in the case of BaSIRS, VaSIRS, PaSIRS and InSIRS, the most relevant. As such, in a background of high prevalence of SIRS, what is needed is a diagnostic assay, based on the use of a peripheral blood sample, with a high predictive value for BaSIRS so that clinicians can confidently rule out, or rule in, a bacterial cause of SIRS. 
     Therefore, a need exists for better ways of differentiating patients presenting with systemic inflammation to permit early diagnosis, ruling out or ruling in infection, monitoring, and making better treatment and management decisions. 
     SUMMARY OF THE INVENTION 
     In work leading up to the present invention, it was determined that derived biomarker values that are indicative of a ratio of measured biomarkers values (e.g., biomarker levels) provide significantly more diagnostic power than measured biomarker values alone for assessing the likelihood that a particular condition, or degree thereof, is present or absent in a subject (see, WO 2015/117204). The present inventors have now determined that the vast majority of derived biomarker values in peripheral blood cells are shared between patients within different SIRS subgroups (e.g., BaSIRS, VaSIRS, PaSIRS and InSIRS), which suggests, therefore, that there are numerous biochemical pathways that are common to SIRS conditions of different etiology. Accordingly, it was reasoned that it would be necessary to subtract biomarker combinations corresponding to these derived biomarker values (also referred to herein as “derived biomarkers”) from the pool of biomarker combinations to identify derived biomarkers with improved specificity to a particular SIRS condition. Of note, it was also found that exclusion of derived biomarkers belonging to any one particular SIRS subgroup (e.g., PaSIRS) from the pool of derived biomarkers markedly changed the biomarker combinations resulting from the analysis and undermined their specificity for diagnosing individual SIRS conditions. 
     The present inventors have also determined that derived biomarker values in peripheral blood cells can vary between subjects with different non-SIRS inflammatory conditions including autoimmunity, asthma, stress, anaphylaxis, trauma and obesity, and between subjects of different age, gender and race. This suggests, therefore, that the corresponding derived biomarkers also need to be subtracted from the pool of derived biomarkers to identify biomarker combinations with improved specificity to a SIRS condition of specified etiology. 
     The present invention is also predicated in part on the identification of derived biomarkers with remarkable specificity to systemic inflammations caused by a range of different viral infections across different mammals (humans, macaques, chimpanzees, pigs, rats, mice). Because such derived biomarkers are specific to systemic inflammations associated with a variety of different types of viruses covering examples from each of the Baltimore classification groups (I-VII), they are considered to be “pan-viral” inflammatory derived biomarkers. To ensure that the derived biomarkers described herein are truly pan-viral and also specific to a viral infection, the following procedures and methods were deliberately performed: 1). A mixture of both DNA and RNA viruses were included in the “discovery” core datasets—only those derived biomarkers with strong performance across all of these datasets were selected for further analysis, 2). A wide range of virus families, including both DNA and RNA viruses, were included in the various “validation” datasets, 3). A wide range of virus families causing a variety of clinical signs were included in the various datasets, 4). Viruses covering all of the Baltimore Classification categories were included in the various datasets, 5). Viruses and samples covering a variety of stage of infection, infection type, mechanism of spread and location were included in the various datasets, 6). Controlled and time-course datasets were selected to cover more than one species of mammal (humans, macaques, chimpanzees, pigs, mice), 7). In time-course studies samples early in the infection process were chosen, prior to peak clinical signs, to limit the possibility of a bacterial co-infection, 8). Derived biomarkers shared with other inflammatory conditions were subtracted (e.g., derived biomarkers for BaSIRS, PaSIRS and InSIRS, as well as derived biomarkers for autoimmunity, asthma, bacterial infections, sarcoidosis, stress, anaphylaxis, trauma, age, obesity, gender and race), 9). Validation was performed in both adults and children with a variety of viral conditions. Following the stringent selection process only those derived biomarkers with an AUC greater than existing virus assays and clinical judgment were selected to ensure clinical utility. 
     The present inventors further propose that the host response specific derived biomarkers for BaSIRS, VaSIRS, PaSIRS and InSIRS disclosed herein can be used advantageously with pathogen specific biomarkers to augment the diagnosis of the etiological basis of systemic inflammation including determining whether systemic inflammation in a patient is due to a bacterial, viral, or protozoal infection, or due to some other non-infectious cause. The use of a combination of host response derived biomarkers and pathogen-specific biomarkers provides a more definitive diagnosis, especially the ability to either rule out or rule in a particular condition in patients with systemic inflammation, especially in situations where pathogen detection assay results are suspected of being either falsely positive or negative. 
     Based on the above determinations, the present inventors have developed various methods, apparatus, compositions, and kits, which take advantage of derived biomarkers, and optionally in combination with pathogen-specific detection assays, to determine the etiology, presence, absence or degree of a SIRS condition of a specified etiology (e.g., BaSIRS, VaSIRS, PaSIRS or InSIRS) in subjects presenting with fever or clinical signs of systemic inflammation. In certain embodiments, these methods, apparatus, compositions, and kits represent a significant advance over prior art processes and products, which have not been able to: 1) distinguish the various etiologies of systemic inflammation; and/or 2) determine the contribution of a particular type of infection (if any) to the presenting clinical signs and pathology; and/or 3) determine if an isolated or detected microorganism is a true pathogen, a commensal, a normal component of the microbiome, a contaminant, or an incidental finding. Such a combination of information provides strong positive and negative predictive power, which in turn provides clinicians with the ability to make better informed management and treatment decisions. 
     Accordingly, in one aspect, the present invention provides methods for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values and a plurality of VaSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value and at least one VaSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, and each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers; and (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS. Typically, in any of the aspects or embodiments described herein, the subject has at least one clinical sign (e.g., 1, 2, 3, 4, 5 or more) of SIRS. 
     Suitably, in any aspect or embodiments disclosed herein, the BaSIRS derived biomarker combination and the VaSIRS derived biomarker combination are not derived biomarker combinations for any one or more inflammatory conditions selected from autoimmunity, asthma, stress, anaphylaxis, trauma and obesity. Alternatively, or in addition, the derived BaSIRS biomarkers and derived VaSIRS biomarkers are not derived biomarkers for any one or more of age, gender and race. 
     In any of the aspects or embodiments disclosed herein, the methods may further comprise: (a) determining a plurality of pathogen specific biomarker values including at least one bacterial biomarker value and at least one viral biomarker value, the least one bacterial biomarker value being indicative of a value measured for a corresponding bacterial biomarker in the sample, the least one viral biomarker value being indicative of a value measured for a corresponding viral biomarker in the sample; and (b) determining the indicator using the host response specific derived biomarker values in combination with the pathogen specific biomarker values. Suitably, in some of these aspects or embodiments, the indicator is also used to rule in or rule out a SIRS condition of a particular etiology. For example, if the plurality of host response specific derived biomarker values indicates the likely presence of a pathogen-associated SIRS condition (e.g., BaSIRS, VaSIRS or InSIRS) in the subject and the pathogen specific biomarker value(s) indicate(s) the likely presence of a pathogen (e.g., bacterium, virus, protozoan) associated with the pathogen-associated SIRS condition in the subject, then the indicator determined using the combination of host response specific derived biomarker values and pathogen specific biomarker value(s) can be used to rule in the pathogen-associated SIRS condition. Alternatively, if the plurality of host response specific derived biomarker values indicates the likely absence of a pathogen-associated SIRS condition (e.g., BaSIRS, VaSIRS or InSIRS) in the subject and the pathogen specific biomarker value(s) indicate(s) the likely absence of a pathogen (e.g., bacterium, virus, protozoan) associated with the pathogen-associated SIRS condition in the subject, then the indicator determined using the combination of host response specific derived biomarker values and pathogen specific biomarker value(s) can be used to rule out the pathogen-associated SIRS condition. 
     Suitably, in any of the aspects or embodiments disclosed herein, each BaSIRS derived biomarker value is determined using a pair of the BaSIRS biomarker values, and is indicative of a ratio of levels of a corresponding pair of BaSIRS biomarkers. Alternatively, or in addition, each VaSIRS derived biomarker value is determined using a pair of the VaSIRS biomarker values, and is indicative of a ratio of levels of a corresponding pair of VaSIRS biomarkers. 
     In some embodiments, the plurality of host response specific biomarker values further includes a plurality of PaSIRS biomarker values, the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample, and the plurality of host response specific derived biomarker values further includes at least one PaSIRS derived biomarker value, and the methods further comprise: determining each PaSIRS derived biomarker value using at least a subset of the plurality of PaSIRS biomarker values, the PaSIRS derived biomarker value being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers; and determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS. 
     Suitably, in any of the aspects or embodiments disclosed herein, each PaSIRS derived biomarker value is determined using a pair of the PaSIRS biomarker values, and is indicative of a ratio of levels of a corresponding pair of PaSIRS biomarkers. 
     In a related aspect, the present invention provides methods for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS or PaSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values, and a plurality of PaSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value, and at least one PaSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, and each derived PaSIRS biomarker value being determined using at least a subset of the plurality of PaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers; and (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS. 
     In some embodiments, the methods further comprise: (a) determining a plurality of pathogen specific biomarker values including at least one bacterial biomarker value, at least one viral biomarker value and at least one protozoal biomarker value, the at least one bacterial biomarker value being indicative of a value measured for a corresponding bacterial biomarker in the sample, the least one viral biomarker value being indicative of a value measured for a corresponding viral biomarker in the sample, and the least one protozoal biomarker value being indicative of a value measured for a corresponding protozoal biomarker in the sample; and (b) determining the indicator using the host response specific derived biomarker values in combination with the pathogen specific biomarker values. 
     In some embodiments of any of the aspects disclosed herein, the plurality of host response specific biomarker values further includes a plurality of InSIRS biomarker values, the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample, and the plurality of host response specific derived biomarker values further includes at least one InSIRS derived biomarker value, and the methods further comprise: determining each InSIRS derived biomarker value using at least a subset of the plurality of InSIRS biomarker values, the InSIRS derived biomarker value being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; and determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of InSIRS biomarkers forms a InSIRS derived biomarker combination which is not a derived marker combination for BaSIRS, VaSIRS or PaSIRS. 
     Accordingly, in a related aspect, the present invention provides methods for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values, and a plurality of InSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value, and at least one InSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, and each derived InSIRS biomarker value being determined using at least a subset of the plurality of InSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; and (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of InSIRS biomarkers forms an InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS. 
     In still another related aspect, the present invention provides methods for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values, a plurality of PaSIRS biomarker values, and a plurality of InSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample, the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value, at least one PaSIRS derived biomarker value, and at least one InSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, each derived PaSIRS biomarker value being determined using at least a subset of the plurality of PaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers, and each derived InSIRS biomarker value being determined using at least a subset of the plurality of InSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; and (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, and wherein the at least a subset of InSIRS biomarkers forms an InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS. 
     Suitably, in any of the embodiments or aspects disclosed herein, the indicator is determined by combining a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, etc.) of derived biomarker values. For example, the methods may comprise combining the derived biomarker values using a combining function, wherein the combining function is at least one of: an additive model; a linear model; a support vector machine; a neural network model; a random forest model; a regression model; a genetic algorithm; an annealing algorithm; a weighted sum; a nearest neighbor model; and a probabilistic model. 
     Exemplary BaSIRS derived biomarker combinations can be selected from TABLE A. 
     
       
         
           
               
             
               
                 TABLE A 
               
               
                   
               
               
                 BaSIRS Derived Biomarkers 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 PDGFC:KLRF1 
                 GAS7:GAB2 
                 PDGFC:LPIN2 
                 GALNT2:IK 
               
               
                 TMEM165:PARP8 
                 PDGFC:INPP5D 
                 TSPO:NLRP1 
                 CD82:JARID2 
               
               
                 ITGA7:KLRF1 
                 ST3GAL2:PRKD2 
                 PCOLCE2:NMUR1 
                 PDGFC:ICK 
               
               
                 CR1:GAB2 
                 HK3:INPP5D 
                 FAM129A:GAB2 
                 GALNT2:SAP130 
               
               
                 PCOLCE2:KLRF1 
                 ENTPD7:KLRD1 
                 ALPL:NLRP1 
                 PDGFC:FBXO28 
               
               
                 ITGA7:INPP5D 
                 PDGFC:SIDT1 
                 TSPO:ZFP36L2 
                 TSPO:GAB2 
               
               
                 GALNT2:CCNK 
                 PDGFC:SPIN1 
                 ALPL:ZFP36L2 
                 COX15:INPP5D 
               
               
                 PDGFC:KLRD1 
                 PCOLCE2:YPEL1 
                 PCOLCE2:FOXJ3 
                 ITGA7:LAG3 
               
               
                 PDGFC:CCNK 
                 PDGFC:SYTL2 
                 PDGFC:KIAA0355 
                 TSPO:CAMK1D 
               
               
                 CR1:ADAM19 
                 PDGFC:TGFBR3 
                 PDGFC:KIAA0907 
                 OPLAH:POGZ 
               
               
                 ITGA7:CCNK 
                 IGFBP7:KLRF1 
                 GAS7:DOCK5 
                 ALPL:RNASE6 
               
               
                 PCOLCE2:PRSS23 
                 PCOLCE2:RUNX2 
                 CD82:CNNM3 
                 RAB32:NLRP1 
               
               
                 TMEM165:PRPF38B 
                 SMPDL3A:KLRD1 
                 GAS7:EXTL3 
                 TLR5:SEMA4D 
               
               
                 PDGFC:PHF3 
                 GALNT2:KLRF1 
                 TSPO:RNASE6 
                 IMPDH1:NLRP1 
               
               
                 GAS7:NLRP1 
                 PDGFC:YPEL1 
                 ALPL:MME 
                 ALPL:CAMK1D 
               
               
                 PCOLCE2:KLRD1 
                 HK3:DENND3 
                 HK3:TLE3 
                 TSPO:NFIC 
               
               
                 GALNT2:KLRD1 
                 PDGFC:CBLL1 
                 MCTP1:PARP8 
                 GAS7:HAL 
               
               
                 KIAA0101:IL2RB 
                 OPLAH:KLRD1 
                 TSPO:HCLS1 
                 PDGFC:NCOA6 
               
               
                 CR1:HAL 
                 OPLAH:ZHX2 
                 TSPO:CASS4 
                 PDGFC:PIK3C2A 
               
               
                 PDGFC:RFC1 
                 PDGFC:RYK 
                 GAS7:RBM23 
                 TSPO:ADAM19 
               
               
                 ENTPD7:KLRF1 
                 PDGFC:IKZF5 
                 GAS7:EPHB4 
                 CD82:NOV 
               
               
                 PDGFC:GRK5 
                 GALNT2:INPP5D 
                 PDGFC:RBM15 
                 PDGFC:PDS5B 
               
               
                 PCOLCE2:PYHIN1 
                 PDGFC:GCC2 
                 ADM:CLEC7A 
                 FIG4:INPP5D 
               
               
                 GAS7:PRKDC 
                 PDGFC:MBIP 
                 PDGFC:LEPROTL1 
                 TSPO:NOV 
               
               
                 GAS7:CAMK1D 
                 COX15:UTRN 
                 PDGFC:NPAT 
               
               
                 MGAM:MME 
                 SMPDL3A:QRICH1 
                 TSPO:PLA2G7 
               
               
                   
               
            
           
         
       
     
     In specific embodiments, a single BaSIRS derived biomarker combination (e.g., any one from TABLE A) is used for determining the indicator. In other embodiments, two BaSIRS derived biomarker combinations (e.g., any two from TABLE A) are used for determining the indicator. In still other embodiments, three BaSIRS derived biomarker combinations (e.g., any three from TABLE A) are used for determining the indicator. In still other embodiments, four BaSIRS derived biomarker combinations (e.g., any four from TABLE A) are used for determining the indicator. 
     In representative examples of this type, the methods comprise: (a) determining a single BaSIRS derived biomarker value using a pair of BaSIRS biomarker values, the single BaSIRS derived biomarker value being indicative of a ratio of levels of first and second BaSIRS biomarkers; and (b) determining the indicator using the single derived BaSIRS biomarker value. 
     In other representative examples of this type, the methods comprise: (a) determining a first BaSIRS derived biomarker value using a first pair of BaSIRS biomarker values, the first BaSIRS derived biomarker value being indicative of a ratio of levels of first and second BaSIRS biomarkers; (b) determining a second BaSIRS derived biomarker value using a second pair of BaSIRS biomarker values, the second BaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth BaSIRS biomarkers; and (c) determining the indicator by combining the first and second derived BaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In still other representative examples of this type, the methods comprise: (a) determining a first BaSIRS derived biomarker value using a first pair of BaSIRS biomarker values, the first BaSIRS derived biomarker value being indicative of a ratio of levels of first and second BaSIRS biomarkers; (b) determining a second BaSIRS derived biomarker value using a second pair of BaSIRS biomarker values, the second BaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth BaSIRS biomarkers; (c) determining a third BaSIRS derived biomarker value using a third pair of BaSIRS biomarker values, the third BaSIRS derived biomarker value being indicative of a ratio of levels of fifth and fourth BaSIRS biomarkers; and (d) determining the indicator by combining the first and sixth derived BaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In certain embodiments, individual BaSIRS derived biomarker combinations are selected from TSPO:HCLS1, OPLAH:ZHX2, TSPO:RNASE6; GAS7:CAMK1D, ST3GAL2:PRKD2, PCOLCE2:NMUR1 and CR1:HAL. In preferred embodiments, individual BaSIRS derived biomarker combinations are selected from OPLAH:ZHX2 and TSPO:HCLS1. 
     The bacterium associated with the BaSIRS is suitably selected from any Gram positive or Gram negative bacterial species which is capable of inducing at least one of the clinical signs of SIRS. 
     Typical VaSIRS derived biomarker combinations are suitably selected from TABLE B. 
     
       
         
           
               
             
               
                 TABLE B 
               
               
                   
               
               
                 VaSIRS Derived Biomarker 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 IFI6:IL16 
                 OASL:SERTAD2 
                 OASL:KIAA0247 
                 OASL:TOPORS 
               
               
                 OASL:NR3C1 
                 OASL:LPAR2 
                 OASL:ARHGAP26 
                 EIF2AK2:IL16 
               
               
                 OASL:EMR2 
                 OASL:ITGAX 
                 OASL:LYN 
                 OASL:NCOA1 
               
               
                 OASL:SORL1 
                 OASL:TGFBR2 
                 OASL:PCBP2 
                 OASL:PTGER4 
               
               
                 OASL:TLR2 
                 OASL:ARHGAP25 
                 OASL:XPO6 
                 OASL:GNAQ 
               
               
                 OASL:PACSIN2 
                 OASL:GNA12 
                 OASL:ATP6V1B2 
                 OASL:GSK3B 
               
               
                 OASL:LILRA2 
                 OASL:NUMB 
                 OASL:CSF2RB 
                 OASL:IL6R 
               
               
                 OASL:PTPRE 
                 OASL:CREBBP 
                 OASL:GYPC 
                 OASL:MAPK14 
               
               
                 OASL:RPS6KA1 
                 OASL:PINK1 
                 OASL:IL4R 
                 USP18:TGFBR2 
               
               
                 OASL:CASC3 
                 OASL:PITPNA 
                 OASL:MMP25 
                 ISG15:LTB 
               
               
                 OASL:VEZF1 
                 OASL:SEMA4D 
                 OASL:PSEN1 
                 OASL:INPP5D 
               
               
                 OASL:CRLF3 
                 OASL:TGFBI 
                 OASL:SH2B3 
                 OASL:MED13 
               
               
                 OASL:NDEL1 
                 OASL:APLP2 
                 OASL:STAT5A 
                 OASL:MORC3 
               
               
                 OASL:RASSF2 
                 OASL:CCNG2 
                 ISG15:IL16 
                 OASL:PTAFR 
               
               
                 OASL:TLE4 
                 OASL:MKRN1 
                 MX1:LEF1 
                 OASL:RBM23 
               
               
                 OASL:CD97 
                 OASL:RGS14 
                 OASL:CAMK2G 
                 OASL:SNN 
               
               
                 OASL:CEP68 
                 OASL:LYST 
                 OASL:ETS2 
                 OASL:ST13 
               
               
                 OASL:RXRA 
                 OASL:TNRC6B 
                 OASL:POLB 
                 OASL:TFEB 
               
               
                 OASL:SP3 
                 OASL:TYROBP 
                 OASL:STK38L 
                 OASL:ZFYVE16 
               
               
                 OASL:ABLIM1 
                 OASL:WDR37 
                 OASL:TFE3 
                 EIF2AK2:SATB1 
               
               
                 OASL:AOAH 
                 OASL:WDR47 
                 OASL:ICAM3 
                 OASL:ABAT 
               
               
                 OASL:MBP 
                 UBE2L6:IL16 
                 OASL:ITGB2 
                 OASL:ABI1 
               
               
                 OASL:NLRP1 
                 OASL:BTG1 
                 OASL:PISD 
                 OASL:ACVR1B 
               
               
                 OASL:PBX3 
                 OASL:CD93 
                 OASL:PLXNC1 
                 OASL:GPSM3 
               
               
                 OASL:PTPN6 
                 OASL:DCP2 
                 OASL:SNX27 
                 OASL:MPPE1 
               
               
                 OASL:RYBP 
                 OASL:FYB 
                 OASL:TNIP1 
                 OASL:PTEN 
               
               
                 OASL:IL13RA1 
                 OASL:MAML1 
                 OASL:ZMIZ1 
                 OASL:SEC62 
               
               
                 OASL:LCP2 
                 OASL:SNRK 
                 OASL:FOXO3 
                 IFI6:MYC 
               
               
                 OASL:LRP10 
                 OASL:USP4 
                 OASL:IL10RB 
                 IFI6:PCF11 
               
               
                 OASL:SYPL1 
                 OASL:YTHDF3 
                 OASL:MAP3K5 
                 OASL:AIF1 
               
               
                 OASL:VAMP3 
                 OASL:CEP170 
                 OASL:POLD4 
                 OASL:CSNK1D 
               
               
                 IFI44:LTB 
                 OASL:PLEKHO2 
                 OASL:ARAP1 
                 OASL:GABARAP 
               
               
                 OASL:ARHGEF2 
                 OASL:SMAD4 
                 OASL:CTBP2 
                 OASL:HAL 
               
               
                 OASL:CTDSP2 
                 OASL:ST3GAL1 
                 OASL:DGKA 
                 OASL:LAPTM5 
               
               
                 OASL:LST1 
                 OASL:ZNF292 
                 OASL:NFYA 
                 OASL:XPC 
               
               
                 OASL:MAPK1 
                 IFI44:IL4R 
                 OASL:PCNX 
                 USP18:NFKB1 
               
               
                 OASL:N4BP1 
                 OASL:HPCAL1 
                 OASL:PFDN5 
                 OASL:ACAP2 
               
               
                 OASL:STAT5B 
                 OASL:IGSF6 
                 OASL:R3HDM2 
                 OASL:CLEC4A 
               
               
                 IFI44:ABLIM1 
                 OASL:MTMR3 
                 OASL:STX6 
                 OASL:HIP1 
               
               
                 IFI44:IL6ST 
                 OASL:PHF20 
                 EIF2AK2:SYPL1 
                 OASL:PIAS1 
               
               
                 OASL:BACH1 
                 OASL:PPARD 
                 ISG15:ABLIM1 
                 OASL:PPP3R1 
               
               
                 OASL:KLF7 
                 OASL:PPP4R1 
                 OASL:FOXJ2 
                 OASL:RALB 
               
               
                 OASL:PRMT2 
                 OASL:RBMS1 
                 OASL:IQSEC1 
                 OASL:RGS19 
               
               
                 OASL:HCK 
                 OASL:RHOG 
                 OASL:LRMP 
                 OASL:TRIOBP 
               
               
                 OASL:ITPKB 
                 OASL:TIAM1 
                 OASL:NAB1 
                 EIF2AK2:PDE3B 
               
               
                 OASL:MAP4K4 
                 USP18:IL16 
                 OASL:RAB31 
                 OASL:NCOA4 
               
               
                 OASL:PPM1F 
                 OASL:CBX7 
                 OASL:WASF2 
                 OASL:RARA 
               
               
                 OASL:RAB14 
                 OASL:RAF1 
                 OASL:ZNF274 
                 OASL:RPS6KA3 
               
               
                 IFI6:ABLIM1 
                 OASL:SERINC5 
                 OAS2:LEF1 
                 OASL:SIRPA 
               
               
                 OAS2:FAIM3 
                 OASL:UBQLN2 
                 OASL:BRD1 
                 OASL:TLE3 
               
               
                 OASL:TNFRSF1A 
                 USP18:CHMP7 
                 DHX58:IL16 
                 OASL:SLCO3A1 
               
               
                 DDX60:TGFBR2 
                 USP18:NECAP2 
                 ISG15:IL4R 
                 OASL:ZDHHC17 
               
               
                 OASL:FLOT2 
                 OASL:CAP1 
                 OASL:BRD4 
                 USP18:FOXO1 
               
               
                 OASL:FNBP1 
                 OASL:HPS1 
                 OASL:CCNT2 
                 OASL:ASAP1 
               
               
                 OASL:MAP3K3 
                 OASL:IL1RAP 
                 OASL:FGR 
                 OASL:BAZ2B 
               
               
                 OASL:STX10 
                 OASL:MEF2A 
                 OASL:ITSN2 
                 OASL:FAM65B 
               
               
                 OASL:ZDHHC18 
                 OASL:RNF19B 
                 OASL:LYL1 
                 OASL:HHEX 
               
               
                 OASL:ZNF143 
                 OASL:TMEM127 
                 OASL:PHF3 
                 OASL:MAX 
               
               
                 TAP1:TGFBR2 
                 USP18:IL27RA 
                 OASL:PSAP 
                 OASL:PHF2 
               
               
                 OAS2:ABLIM1 
                 OASL:CDIPT 
                 OASL:STX3 
                 OASL:RNF130 
               
               
                 OASL:ARRB2 
                 OASL:CREB1 
                 OASL:TNK2 
                 OASL:SOS2 
               
               
                 OASL:IKBKB 
                 OASL:GPS2 
                 EIF2AK2:ZNF274 
                 OASL:STAM2 
               
               
                 OASL:KBTBD2 
                 OASL:NDE1 
                 OASL:ACAA1 
                 OASL:ZFC3H1 
               
               
                 OASL:PHC2 
                 OASL:RAB11FIP1 
                 OASL:CHD3 
                 IFI44:CYLD 
               
               
                 OASL:PUM2 
                 USP18:ABLIM1 
                 OASL:FRY 
                 IFIH1:CRLF3 
               
               
                 OASL:SSFA2 
                 EIF2AK2:TNRC6B 
                 OASL:GRB2 
                 OASL:BANP 
               
               
                 IFI44:MYC 
                 OASL:FAM134A 
                 OASL:MAP3K11 
                 OASL:CCND3 
               
               
                 OASL:ABHD2 
                 OASL:FCGRT 
                 OASL:NEK7 
                 OASL:DGCR2 
               
               
                 OASL:CYLD 
                 OASL:LPIN2 
                 OASL:PPP2R5A 
                 OASL:USP15 
               
               
                 OASL:MAST3 
                 OASL:PECAM1 
                 USP18:ST13 
                 USP18:EIF3H 
               
               
                 OASL:UBN1 
                 OASL:WBP2 
                 XAF1:LEF1 
                 OASL:LAT2 
               
               
                 IFI6:IL6ST 
                 OASL:ZNF148 
                 OASL:CASP8 
                 OASL:ZYX 
               
               
                 IFIH1:TGFBR2 
                 OASL:RTN3 
                 OASL:PCF11 
                 USP18:CAMK1D 
               
               
                 OASL:CNPY3 
                 OASL:TYK2 
                 OASL:PRKCD 
                 ZBP1:NDE1 
               
               
                 OASL:KIAA0232 
                 USP18:LTB 
                 OASL:PSTPIP1 
               
               
                   
               
            
           
         
       
     
     In specific embodiments, a single VaSIRS derived biomarker combination (e.g., any one from TABLE B) is used for determining the indicator. In other embodiments, two VaSIRS derived biomarker combinations (e.g., any two from TABLE B) are used for determining the indicator. In still other embodiments, three VaSIRS derived biomarker combinations (e.g., any three from TABLE B) are used for determining the indicator. In still other embodiments, four VaSIRS derived biomarker combinations (e.g., any four from TABLE B) are used for determining the indicator. 
     In non-limiting examples of this type, the methods comprise: (a) determining a single VaSIRS derived biomarker value using a pair of VaSIRS biomarker values, the single VaSIRS derived biomarker value being indicative of a ratio of levels of first and second VaSIRS biomarkers; and (b) determining the indicator using the single derived VaSIRS biomarker value. 
     In other non-limiting examples of this type, the methods comprise: (a) determining a first VaSIRS derived biomarker value using a first pair of VaSIRS biomarker values, the first VaSIRS derived biomarker value being indicative of a ratio of levels of first and second VaSIRS biomarkers; (b) determining a second VaSIRS derived biomarker value using a second pair of VaSIRS biomarker values, the second VaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth VaSIRS biomarkers; and (c) determining the indicator by combining the first and second derived VaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In still other non-limiting examples of this type, the methods comprise: (a) determining a first VaSIRS derived biomarker value using a first pair of VaSIRS biomarker values, the first VaSIRS derived biomarker value being indicative of a ratio of levels of first and second VaSIRS biomarkers; (b) determining a second VaSIRS derived biomarker value using a second pair of VaSIRS biomarker values, the second VaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth VaSIRS biomarkers; (c) determining a third VaSIRS derived biomarker value using a third pair of VaSIRS biomarker values, the third VaSIRS derived biomarker value being indicative of a ratio of levels of fifth and fourth VaSIRS biomarkers; and (d) determining the indicator by combining the first and sixth derived VaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In certain embodiments, individual VaSIRS derived biomarker combinations are selected from ISG15:IL16, OASL:ADGRE5, TAP1:TGFBR2, IFIH1:CRLF3, IFI44:IL4R, EIF2AK2:SYPL1, OAS2:LEF1, STAT1:PCBP2 and IFI6:IL6ST. In preferred embodiments, individual VaSIRS derived biomarker combinations are selected from ISG15:IL16 and OASL:ADGRE5. 
     The virus associated with the VaSIRS is suitably selected from any one of Baltimore virus classification Groups I, II, III, IV, V, VI and VII, which is capable of inducing at least one of the clinical signs of SIRS. 
     Exemplary PaSIRS derived biomarker combinations are suitably selected from TABLE C. 
     
       
         
           
               
             
               
                 TABLE C 
               
               
                   
               
               
                 PaSIRS Derived Biomarker 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 RPL9:WARS 
                 PREPL:WARS 
                 SEH1L:WARS 
                 EXOSC10:MYD88 
               
               
                 RPL9:CSTB 
                 TCF4:LAP3 
                 EXOSC10:UBE2L6 
                 LY9:WARS 
               
               
                 NUP160:WARS 
                 ZBED5:WARS 
                 TTC17:LAP3 
                 IMP3:CSTB 
               
               
                 IMP3:ATOX1 
                 TCF4:POMP 
                 SUCLG2:CEBPB 
                 RPL15:CEBPB 
               
               
                 RPS4X:WARS 
                 NUP160:SQRDL 
                 EXOSC10:G6PD 
                 ARHGAP17:ATOX1 
               
               
                 TCF4:CEBPB 
                 TRIT1:WARS 
                 CEP192:WARS 
                 TTC17:MYD88 
               
               
                 IMP3:LAP3 
                 ZBED5:CEBPB 
                 NUP160:CD63 
                 EXOSC10:TCIRG1 
               
               
                 EXOSC10:WARS 
                 IMP3:WARS 
                 TMEM50B:WARS 
                 ZMYND11:CEBPB 
               
               
                 TTC17:WARS 
                 RPS4X:SQRDL 
                 EXOSC10:LDHA 
                 CEP192:TANK 
               
               
                 TCF4:WARS 
                 NUP160:POMP 
                 ARID1A:CSTB 
                 IMP3:UBE2L6 
               
               
                 METAP1:WARS 
                 EXOSC10:LAP3 
                 SUCLG2:WARS 
                 RPS4X:CD63 
               
               
                 FNTA:POMP 
                 RPS4X:GNG5 
                 ARID1A:CEBPB 
                 RPL9:CD63 
               
               
                 TCF4:TANK 
                 TOP2B:WARS 
                 FBXO11:TANK 
                 ARID1A:UBE2L6 
               
               
                 TOP2B:CEBPB 
                 RPL9:POMP 
                 SUCLG2:SH3GLB1 
                 TCF4:UBE2L6 
               
               
                 AHCTF1:CEBPB 
                 EXOSC10:ATOX1 
                 TTC17:G6PD 
                 ARID1A:WARS 
               
               
                 RPS4X:MYD88 
                 TTC17:TANK 
                 IMP3:PCMT1 
                 CAMK2G:G6PD 
               
               
                 IMP3:CEBPB 
                 EXOSC10:CEBPB 
                 ARID1A:LAP3 
                 RPS4X:SH3GLB1 
               
               
                 RPL9:CEBPB 
                 NOSIP:CEBPB 
                 IMP3:SQRDL 
                 RPL9:TANK 
               
               
                 RPS4X:CEBPB 
                 RPL22:CEBPB 
                 TCF4:ATOX1 
                 IMP3:TANK 
               
               
                 TTC17:CEBPB 
                 TTC17:ATP2A2 
                 IMP3:SH3GLB1 
                 ZBED5:SH3GLB1 
               
               
                 TMEM50B:CEBPB 
                 ZMYND11:CSTB 
                 RPS4X:SERPINB1 
                 ZMYND11:SH3GLB1 
               
               
                 RPS4X:POMP 
                 FNTA:SH3GLB1 
                 FBXO11:RALB 
                 RPS14:CD63 
               
               
                 TOP2B:POMP 
                 ARID1A:TAP1 
                 TMEM50B:SQRDL 
                 CAMK2G:SQRDL 
               
               
                 METAP1:POMP 
                 NOSIP:WARS 
                 CSNK1G2:CEBPB 
                 ARIH2:CEBPB 
               
               
                 EXOSC10:CSTB 
                 RPS4X:UPP1 
                 RPL15:SH3GLB1 
                 ARID1A:NFIL3 
               
               
                 ZNF266:CEBPB 
                 CNOT7:CEBPB 
                 BCL11A:G6PD 
                 IMP3:POMP 
               
               
                 TTC17:ATOX1 
                 ARHGAP17:WARS 
                 ZBED5:SQRDL 
                 EXOSC10:ENO1 
               
               
                 CSNK1G2:G6PD 
                 UFM1:WARS 
                 ARID1A:SERPINB1 
                 PREPL:SH3GLB1 
               
               
                 SETX:CEBPB 
                 PREPL:SQRDL 
                 RPS14:SH3GLB1 
                 TTC17:BCL6 
               
               
                 ARHGAP17:CEBPB 
                 IMP3:TAP1 
                 EXOSC10:TAP1 
                 ZMYND11:POMP 
               
               
                 ZMYND11:WARS 
                 ARID1A:PCMT1 
                 BCL11A:CEBPB 
                 IMP3:RIT1 
               
               
                 IMP3:UPP1 
                 SUCLG2:SQRDL 
                 ADSL:ATOX1 
                 CAMK2G:CD63 
               
               
                 EXOSC10:IRF1 
                 RPL22:SH3GLB1 
                 TCF4:FCER1G 
                 IL10RA:CEBPB 
               
               
                 UFM1:CEBPB 
                 BCL11A:WARS 
                 LY9:SH3GLB1 
                 FNTA:TCIRG1 
               
               
                 ARID1A:LDHA 
                 CNOT7:WARS 
                 IMP3:GNG5 
                 CAMK2G:TCIRG1 
               
               
                 RPL9:ATOX1 
                 ZBED5:TCIRG1 
                 SERTAD2:CEBPB 
                 EXOSC10:PCMT1 
               
               
                 TTC17:GNG5 
                 EXOSC10:SQRDL 
                 AHCTF1:MYD88 
                 RPS14:SQRDL 
               
               
                 EXOSC10:POMP 
                 AHCTF1:GNG5 
                 ARID1A:ENO1 
                 IMP3:PGD 
               
               
                 ARID1A:ATOX1 
                 ZMYND11:FCER1G 
                 EXOSC10:UPP1 
                 ZBED5:TNIP1 
               
               
                 RPL9:SH3GLB1 
                 TOP2B:ENO1 
                 CEP192:CSTB 
                 CHN2:WARS 
               
               
                 LY9:CEBPB 
                 IMP3:IRF1 
                 LY9:SQRDL 
                 IMP3:TCIRG1 
               
               
                 RPS14:WARS 
                 CEP192:TAP1 
                 LY9:TNIP1 
                 AHCTF1:SQRDL 
               
               
                 FNTA:SQRDL 
                 RPL9:MYD88 
                 CNOT7:G6PD 
                 CLIP4:WARS 
               
               
                 APEX1:CD63 
                 RPL22:GNG5 
                 ARID1A:PLSCR1 
                 NOSIP:POMP 
               
               
                 SETX:WARS 
                 FNTA:MYD88 
                 CEP192:ATOX1 
                 RPL22:SQRDL 
               
               
                 IMP3:TNIP1 
                 TCF4:GNG5 
                 IMP3:ENO1 
                 IMP3:VAMP3 
               
               
                 FNTA:CD63 
                 EXOSC10:TANK 
                 ARID1A:IRF1 
                 TTC17:TIMP2 
               
               
                 TTC17:TCIRG1 
                 MLLT10:WARS 
                 EXOSC10:GNG5 
                 TTC17:SQRDL 
               
               
                 EXOSC10:SH3GLB1 
                 TTC17:POMP 
                 LY9:ATOX1 
                 ARID1A:CD63 
               
               
                 RPS4X:FCER1G 
                 TCF4:MYD88 
                 FBXO11:CEBPB 
                 FNTA:LAP3 
               
               
                 RPS4X:PGD 
                 IMP3:MYD88 
                 RPL9:SLAMF7 
                 BCL11A:LAP3 
               
               
                 CAMK2G:CEBPB 
                 TOP2B:CD63 
                 RPL9:TNIP1 
                 IMP3:FCER1G 
               
               
                 ZMYND11:G6PD 
                 CEP192:RALB 
                 PREPL:CD63 
                 CEP192:TNIP1 
               
               
                 FNTA:CEBPB 
                 NUP160:PGD 
                 ARHGAP17:SQRDL 
                 ZMYND11:SQRDL 
               
               
                 ZMYND11:CD63 
                 RPL9:SQRDL 
                 ZBED5:POMP 
                 ZMYND11:GNG5 
               
               
                 TCF4:RALB 
                 CEP192:PCMT1 
                 RPS4X:TSPO 
                 ARID1A:SLAMF7 
               
               
                 ARHGAP17:LAP3 
                 TCF4:SQRDL 
                 IMP3:G6PD 
                 ARID1A:TCIRG1 
               
               
                 IMP3:CD63 
                 RPL9:GNG5 
                 CEP192:POMP 
                 ARID1A:TNIP1 
               
               
                 ZMYND11:C3AR1 
                 EXOSC10:CD63 
                 TMEM50B:CD63 
                 ZMYND11:PGD 
               
               
                 AHCTF1:WARS 
                 TCF4:SH3GLB1 
                 ZMYND11:ENO1 
                 CSNK1G2:TCIRG1 
               
               
                 RPS4X:ENO1 
                 ADSL:WARS 
                 CEP192:LAP3 
                 TTC17:CD63 
               
               
                 CEP192:PLSCR1 
                 TTC17:SH3GLB1 
                 RPL9:UPP1 
                 NUP160:RTN4 
               
               
                 EXOSC9:POMP 
                 ARID1A:SQRDL 
                 TCF4:SERPINB1 
                 RPL15:SQRDL 
               
               
                 FNTA:GNG5 
                 ARID1A:G6PD 
                 AHCTF1:PLAUR 
                 TTC17:UPP1 
               
               
                 CEP192:IRF1 
                 AHCTF1:TANK 
                 RPL22:WARS 
                 CAMK2G:FCER1G 
               
               
                 CEP192:CEBPB 
                 EXOSC2:CEBPB 
                 EXOSC2:POMP 
                 CEP192:TCIRG1 
               
               
                 IRF8:CEBPB 
                 CNOT7:CSTB 
                 AHCTF1:UPP1 
                 TTC17:SERPINB1 
               
               
                 CEP192:G6PD 
                 ARID1A:PGD 
                 IMP3:RALB 
                 EXOSC2:UPP1 
               
               
                 FBXO11:UPP1 
                 ARID1A:STAT3 
                 ADK:SH3GLB1 
                 IMP3:TSPO 
               
               
                 ARIH2:TCIRG1 
                 NOSIP:TCIRG1 
                 SUCLG2:CD63 
                 BCL11A:TNIP1 
               
               
                 PCID2:WARS 
                 RPL9:FCER1G 
                 FNTA:WARS 
                 ADSL:ENO1 
               
               
                 CAMK2G:PGD 
                 ARID1A:TRPC4AP 
                 EXOSC10:TUBA1B 
                 NOSIP:SQRDL 
               
               
                 EXOSC10:FLII 
                 ARID1A:SH3GLB1 
                 IMP3:PCBP1 
                 SERBP1:SH3GLB1 
               
               
                 RPL15:CD63 
                 CEP192:RAB27A 
                 ARID1A:GRINA 
                 ARID1A:NFKBIA 
               
               
                 RPL22:CD63 
                 EXOSC10:FCER1G 
                 TTC17:PGD 
                 RPL9:ENO1 
               
               
                 CNOT7:SQRDL 
                 SETX:SQRDL 
                 ARID1A:TANK 
                 ARID1A:RAB27A 
               
               
                 FBXO11:SQRDL 
                 CEP192:MYD88 
                 CSNK1G2:FLII 
                 RPL15:WARS 
               
               
                 TCF4:UPP1 
                 ARID1A:BCL6 
                 CEP192:STAT3 
                 BCL11A:CSTB 
               
               
                 PCID2:CEBPB 
                 EXOSC2:CD63 
                 AHCTF1:SH3GLB1 
               
               
                   
               
            
           
         
       
     
     In specific embodiments, a single PaSIRS derived biomarker combination (e.g., any one from TABLE C) is used for determining the indicator. In other embodiments, two PaSIRS derived biomarker combinations (e.g., any two from TABLE C) are used for determining the indicator. In still other embodiments, three PaSIRS derived biomarker combinations (e.g., any three from TABLE C) are used for determining the indicator. In still other embodiments, four PaSIRS derived biomarker combinations (e.g., any four from TABLE C) are used for determining the indicator. 
     In illustrative examples of this type, the methods comprise: (a) determining a single PaSIRS derived biomarker value using a pair of PaSIRS biomarker values, the single PaSIRS derived biomarker value being indicative of a ratio of levels of first and second PaSIRS biomarkers; and (b) determining the indicator using the single derived PaSIRS biomarker value. 
     In other illustrative examples of this type, the methods comprise: (a) determining a first PaSIRS derived biomarker value using a first pair of PaSIRS biomarker values, the first PaSIRS derived biomarker value being indicative of a ratio of levels of first and second PaSIRS biomarkers; (b) determining a second PaSIRS derived biomarker value using a second pair of PaSIRS biomarker values, the second PaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth PaSIRS biomarkers; and (c) determining the indicator by combining the first and second derived PaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In still other illustrative examples of this type, the methods comprise: (a) determining a first PaSIRS derived biomarker value using a first pair of PaSIRS biomarker values, the first PaSIRS derived biomarker value being indicative of a ratio of levels of first and second PaSIRS biomarkers; (b) determining a second PaSIRS derived biomarker value using a second pair of PaSIRS biomarker values, the second PaSIRS derived biomarker value being indicative of a ratio of levels of third and fourth PaSIRS biomarkers; (c) determining a third PaSIRS derived biomarker value using a third pair of PaSIRS biomarker values, the third PaSIRS derived biomarker value being indicative of a ratio of levels of fifth and fourth PaSIRS biomarkers; and (d) determining the indicator by combining the first and sixth derived PaSIRS biomarker values, using for example a combining function as disclosed herein. 
     In certain embodiments, individual PaSIRS derived biomarker combinations are suitably selected from TTC17:G6PD, HERC6:LAP3 and NUP160:TPP1. 
     The protozoan associated with the PaSIRS is suitably selected from any of the following protozoal genera, which are capable of inducing at least one of the clinical signs of SIRS; for example,  Toxoplasma, Babesia, Plasmodium, Trypanosoma, Giardia, Entamoeba, Cryptosporidium, Balantidium  and  Leishmania.    
     Typical InSIRS derived biomarker combinations can be selected from TABLE D. 
     
       
         
           
               
             
               
                 TABLE D 
               
               
                   
               
               
                 InSIRS Derived Biomarker 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 TNFSF8:VEZT 
                 TNFSF8:CDK6 
                 TNFSF8:SLC35A3 
                 TNFSF8:YEATS4 
               
               
                 TNFSF8:HEATR1 
                 TNFSF8:MANEA 
                 ADAM19:TMEM87A 
                 TNFSF8:CLUAP1 
               
               
                 TNFSF8:THOC2 
                 TNFSF8:CKAP2 
                 TNFSF8:LANCL1 
                 TNFSF8:LARP4 
               
               
                 TNFSF8:NIP7 
                 TNFSF8:ZNF507 
                 ADAM19:ERCC4 
                 TNFSF8:SLC35D1 
               
               
                 TNFSF8:MLLT10 
                 TNFSF8:GGPS1 
                 TNFSF8:CD28 
                 SYNE2:RBM26 
               
               
                 TNFSF8:EIF5B 
                 TNFSF8:XPO4 
                 ADAM19:MLLT10 
                 TNFSF8:CD40LG 
               
               
                 TNFSF8:LRRC8D 
                 TNFSF8:PHC3 
                 TNFSF8:IQCB1 
                 VNN3:CYSLTR1 
               
               
                 TNFSF8:RNMT 
                 TNFSF8:ASCC3 
                 TNFSF8:FASTKD2 
                 TNFSF8:SYT11 
               
               
                 STK17B:ARL6IP5 
                 TNFSF8:NOL10 
                 TNFSF8:RDX 
                 TNFSF8:RIOK2 
               
               
                 ENTPD1:ARL6IP5 
                 TNFSF8:ANK3 
                 TNFSF8:MTO1 
                 TNFSF8:BZW2 
               
               
                 TNFSF8:CD84 
                 TNFSF8:SMC3 
                 IQSEC1:MACF1 
                 TNFSF8:LARP1 
               
               
                 TNFSF8:PWP1 
                 TNFSF8:REPS1 
                 TNFSF8:SMC6 
                 ADAM19:SYT11 
               
               
                 TNFSF8:IPO7 
                 TNFSF8:C14orf1 
                 TNFSF8:NEK1 
                 TNFSF8:NCBP1 
               
               
                 ADAM19:EXOC7 
                 TNFSF8:FUT8 
                 TNFSF8:ZNF562 
                 ADAM19:MACF1 
               
               
                 TNFSF8:ARHGAP5 
                 TNFSF8:VPS13A 
                 TNFSF8:PEX1 
                 TNFSF8:NOL8 
               
               
                 TNFSF8:RMND1 
                 TNFSF8:RAD50 
                 ADAM19:SIDT2 
                 TNFSF8:KIAA0391 
               
               
                 TNFSF8:IDE 
                 TNFSF8:ESF1 
                 TNFSF8:METTL5 
               
               
                 TNFSF8:TBCE 
                 TNFSF8:MRPS10 
                 CYP4F3:TRAPPC2 
               
               
                 TNFSF8:G3BP1 
                 CDA:EFHD2 
                 TNFSF8:KRIT1 
               
               
                   
               
            
           
         
       
     
     In specific embodiments, a single InSIRS derived biomarker combination (e.g., any one from TABLE D) is used for determining the indicator. In other embodiments, two InSIRS derived biomarker combinations (e.g., any two from TABLE D) are used for determining the indicator. In still other embodiments, three InSIRS derived biomarker combinations (e.g., any three from TABLE D) are used for determining the indicator. In still other embodiments, four InSIRS derived biomarker combinations (e.g., any four from TABLE D) are used for determining the indicator. 
     In representative examples of this type, the methods comprise: (a) determining a single InSIRS derived biomarker value using a pair of InSIRS biomarker values, the single InSIRS derived biomarker value being indicative of a ratio of levels of first and second InSIRS biomarkers; and (b) determining the indicator using the single derived InSIRS biomarker value. 
     In other representative examples of this type, the methods comprise: (a) determining a first InSIRS derived biomarker value using a first pair of InSIRS biomarker values, the first InSIRS derived biomarker value being indicative of a ratio of levels of first and second InSIRS biomarkers; (b) determining a second InSIRS derived biomarker value using a second pair of InSIRS biomarker values, the second InSIRS derived biomarker value being indicative of a ratio of levels of third and fourth InSIRS biomarkers; and (c) determining the indicator by combining the first and second derived InSIRS biomarker values, using for example a combining function as disclosed herein. 
     In still other representative examples of this type, the methods comprise: (a) determining a first InSIRS derived biomarker value using a first pair of InSIRS biomarker values, the first InSIRS derived biomarker value being indicative of a ratio of levels of first and second InSIRS biomarkers; (b) determining a second InSIRS derived biomarker value using a second pair of InSIRS biomarker values, the second InSIRS derived biomarker value being indicative of a ratio of levels of third and fourth InSIRS biomarkers; (c) determining a third InSIRS derived biomarker value using a third pair of InSIRS biomarker values, the third InSIRS derived biomarker value being indicative of a ratio of levels of fifth and fourth InSIRS biomarkers; and (d) determining the indicator by combining the first and sixth derived InSIRS biomarker values, using for example a combining function as disclosed herein. 
     In certain embodiments, individual InSIRS derived biomarker combinations are suitably selected from ENTPD1:ARL6IP5, TNFSF8:HEATR1, ADAM19:POLR2A, SYNE2:VPS13C, TNFSF8:NIP7, CDA:EFHD2, ADAM19:MLLT10, PTGS1:ENTPD1, ADAM19:EXOC7 and CDA:PTGS1. In preferred embodiments, individual InSIRS derived biomarker combinations are suitably selected from ENTPD1:ARL6IP5 and TNFSF8:HEATR1. 
     Numerous non-infectious conditions are capable of inducing at least one of the clinical signs of SIRS, non-limiting examples of which include cancer, pancreatitis, surgery, embolism, aneurysm, autoimmune disease, sarcoidosis, trauma, asthma, allergic reaction, burn, haemorrhage, ischaemia/reperfusion, adverse drug response, stress, tissue damage/inflammation, foreign body response, obesity, coronary artery disease, anxiety, age. 
     Another aspect of the present invention provides apparatus for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS. This apparatus generally comprises at least one electronic processing device that: 
     determines a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values and a plurality of VaSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample; 
     determines a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value and at least one VaSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, and each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers; and 
     determines the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS. 
     In some embodiments, the at least one processing device: 
     (a) determines a plurality of pathogen specific biomarker values including at least one bacterial biomarker value and at least one viral biomarker value, the least one bacterial biomarker value being indicative of a value measured for a corresponding bacterial biomarker in the sample, the least one viral biomarker value being indicative of a value measured for a corresponding viral biomarker in the sample; and 
     (b) determines the indicator using the host response specific derived biomarker values in combination with the pathogen specific biomarker values. 
     In some embodiments, the plurality of host response specific biomarker values determined by the least one electronic processing device further include a plurality of PaSIRS biomarker values, the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample, and the plurality of host response specific derived biomarker values further includes at least one PaSIRS derived biomarker value, and the least one electronic processing device further: 
     determines each PaSIRS derived biomarker value using at least a subset of the plurality of PaSIRS biomarker values, the PaSIRS derived biomarker value being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers; and 
     determines the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS. 
     In some embodiments, the least one electronic processing device: 
     (a) determines a plurality of pathogen specific biomarker values including at least one bacterial biomarker value, at least one viral biomarker value and at least one protozoal biomarker value, the at least one bacterial biomarker value being indicative of a value measured for a corresponding bacterial biomarker in the sample, the least one viral biomarker value being indicative of a value measured for a corresponding viral biomarker in the sample, and the least one protozoal biomarker value being indicative of a value measured for a corresponding protozoal biomarker in the sample; and 
     (b) determines the indicator using the host response specific derived biomarker values in combination with the pathogen specific biomarker values. 
     In some embodiments, the plurality of host response specific biomarker values determined by the least one electronic processing device further include a plurality of InSIRS biomarker values, the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample, and the plurality of host response specific derived biomarker values further includes at least one InSIRS derived biomarker value, and the least one electronic processing device further: 
     determines each InSIRS derived biomarker value using at least a subset of the plurality of InSIRS biomarker values, the InSIRS derived biomarker value being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; and 
     determines the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of InSIRS biomarkers forms a InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS. 
     In yet another aspect, the present invention provides compositions for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS. These compositions generally comprise, consist or consist essentially of: (1) a pair of BaSIRS biomarker cDNAs, and for each BaSIRS biomarker cDNA at least one oligonucleotide primer that hybridizes to the BaSIRS biomarker cDNA, and/or at least one oligonucleotide probe that hybridizes to the BaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, and (2) a pair of VaSIRS biomarker cDNAs, and for each VaSIRS biomarker cDNA at least one oligonucleotide primer that hybridizes to the VaSIRS biomarker cDNA, and/or at least one oligonucleotide probe that hybridizes to the VaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the pair of BaSIRS biomarker cDNAs forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the pair of VaSIRS biomarker cDNAs forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, wherein the BaSIRS derived biomarker combination is selected from the BaSIRS derived biomarker combinations set out in TABLE A, and wherein the VaSIRS derived biomarker combination is selected from the VaSIRS derived biomarker combinations set out in TABLE B. 
     In some embodiments, the compositions further comprise (a) a pair of PaSIRS biomarker cDNAs, and for each PaSIRS biomarker cDNA at least one oligonucleotide primer that hybridizes to the PaSIRS biomarker cDNA, and/or at least one oligonucleotide probe that hybridizes to the PaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the pair of PaSIRS biomarker cDNAs forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, and wherein the PaSIRS derived biomarker combination is selected from the PaSIRS derived biomarker combinations set out in TABLE C. 
     Alternatively, or in addition, the compositions may further comprise (b) a pair of InSIRS biomarker cDNAs, and for each InSIRS biomarker cDNA at least one oligonucleotide primer that hybridizes to the InSIRS biomarker cDNA, and/or at least one oligonucleotide probe that hybridizes to the InSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the pair of InSIRS biomarker cDNAs forms an InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS, and wherein the InSIRS derived biomarker combination is selected from the InSIRS derived biomarker combinations set out in TABLE D. 
     Suitably, in any of the embodiments or aspects disclosed herein, the compositions further comprise a DNA polymerase. The DNA polymerase may be a thermostable DNA polymerase. 
     In any of the embodiments or aspects disclosed herein, the compositions suitably comprise for each cDNA a pair of forward and reverse oligonucleotide primers that hybridize to opposite complementary strands of the cDNA and that permit nucleic acid amplification of at least a portion of the cDNA to produce an amplicon. In representative examples of these embodiments, the compositions may further comprise for each cDNA an oligonucleotide probe that comprises a heterologous label and hybridizes to the amplicon. 
     In certain embodiments, the components of an individual composition are comprised in a mixture. 
     Suitably, the compositions comprise a population of cDNAs corresponding to mRNA derived from a cell or cell population from a patient sample. In preferred embodiments, the population of cDNAs represents whole leukocyte cDNA (e.g., whole peripheral blood leukocyte cDNA) with a cDNA expression profile characteristic of a subject with a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS, wherein the cDNA expression profile comprises at least one pair of biomarkers (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50 or more pairs of biomarkers), wherein a respective pair of biomarkers comprises a first biomarker and a second biomarker, wherein the first biomarker is expressed at a higher level in leukocytes (e.g., whole peripheral blood leukocytes) from a subject with the SIRS condition than in leukocytes (e.g., whole peripheral blood leukocytes) from a healthy subject or from a subject without the SIRS condition (e.g., the first biomarker is expressed in leukocytes from a subject with the SIRS condition at a level that is at least 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, or 5000% of the level of the first biomarker in leukocytes from a healthy subject or from a subject without the SIRS condition), wherein the second biomarker is expressed at about the same or at a lower level in leukocytes (e.g., whole peripheral blood leukocytes) from a subject with the SIRS condition than in leukocytes (e.g., whole peripheral blood leukocytes) from a healthy subject or from a subject without the SIRS condition (e.g., the second biomarker is expressed in leukocytes from a subject with the SIRS condition at a level that is no more than 105%, 104%, 103%, 102%, 100%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, 0.005%, 0.001% of the level of the second biomarker in leukocytes from a healthy subject or from a subject without the SIRS condition) and wherein the first biomarker is a first mentioned or ‘numerator’ biomarker of a respective pair of biomarkers in any one of TABLES A, B, C or D, and the second biomarker represents a second mentioned or ‘denominator’ biomarker of the respective pair of biomarkers. 
     In some embodiments, the sample is a body fluid, including blood, urine, plasma, serum, urine, secretion or excretion. In some embodiments, the cell population is from blood, suitably peripheral blood. In specific embodiments, the sample comprises blood, suitably peripheral blood. Suitably, the cell or cell population is a cell or cell population of the immune system, suitably a leukocyte or leukocyte population. 
     Suitably, in any of the embodiments or aspects disclosed herein, the compositions may further comprise a pathogen nucleic acid and at least one oligonucleotide primer that hybridizes to the pathogen nucleic acid, and/or at least one oligonucleotide probe that hybridizes to the pathogen nucleic acid, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label. Suitably the pathogen from which the pathogen nucleic acid is selected is from a bacterium, a virus and a protozoan. The pathogen nucleic acid is suitably derived from a patient sample, suitably a body fluid, illustrative examples of which include blood, urine, plasma, serum, urine, secretion or excretion. In specific embodiments, the sample comprises blood, suitably peripheral blood. 
     Still another aspect of the present invention provides kits for determining an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS. The kits generally comprise, consist or consist essentially of: (1) for each of a pair of BaSIRS biomarker cDNAs at least one oligonucleotide primer and/or at least one oligonucleotide probe that hybridizes to the BaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label; and (2) for each of a pair of VaSIRS biomarker cDNA at least one oligonucleotide primer and/or at least one oligonucleotide probe that hybridizes to the VaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprise(s) a heterologous label, wherein the pair of BaSIRS biomarker cDNAs forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the pair of VaSIRS biomarker cDNAs forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, wherein the BaSIRS derived biomarker combination is selected from the BaSIRS derived biomarker combinations set out in TABLE A, and wherein the VaSIRS derived biomarker combination is selected from the VaSIRS derived biomarker combinations set out in TABLE B. 
     In some embodiments, the kits further comprise (a) for each of a pair of PaSIRS biomarker cDNAs at least one oligonucleotide primer and/or at least one oligonucleotide probe that hybridizes to the PaSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the pair of PaSIRS biomarker cDNAs forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, and wherein the PaSIRS derived biomarker combination is selected from the PaSIRS derived biomarker combinations set out in TABLE C. 
     Alternatively, or in addition, the kits may further comprise (b) for each of a pair of InSIRS biomarker cDNAs at least one oligonucleotide primer and/or at least one oligonucleotide probe that hybridizes to the InSIRS biomarker cDNA, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label, wherein the pair of InSIRS biomarker cDNAs forms an InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS, and wherein the InSIRS derived biomarker combination is selected from the InSIRS derived biomarker combinations set out in TABLE D. 
     Suitably, in any of the embodiments or aspects disclosed herein, the kits may further comprise at least one oligonucleotide primer that hybridizes to a pathogen nucleic acid, and/or at least one oligonucleotide probe that hybridizes to the pathogen nucleic acid, wherein the at least one oligonucleotide primer and/or the at least one oligonucleotide probe comprises a heterologous label. 
     In any of the embodiments or aspects disclosed herein, the kits may further comprise a DNA polymerase. Suitably, the DNA polymerase is a thermostable DNA polymerase. 
     In any of the embodiments or aspects disclosed herein, the kits suitably comprise for each cDNA a pair of forward and reverse oligonucleotide primers that permit nucleic acid amplification of at least a portion of the cDNA to produce an amplicon. In representative examples of these embodiments, the kits may further comprise for each cDNA an oligonucleotide probe that comprises a heterologous label and hybridizes to the amplicon. 
     In specific embodiments, the components of the kits when used to determine the indicator are combined to form a mixture. 
     The kits may further comprise one or more reagents for preparing mRNA from a cell or cell population from a patient sample (e.g., a body fluid such as blood, urine, plasma, serum, urine, secretion or excretion). In representative examples of this type, the kits comprise a reagent for preparing cDNA from the mRNA. 
     In a further aspect, the present invention provides methods for treating a subject with a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: exposing the subject to a treatment regimen for treating the SIRS condition based on an indicator obtained from an indicator-determining method, wherein the indicator is indicative of the presence, absence or degree of the SIRS condition in the subject, and wherein the indicator-determining method is as broadly described above and elsewhere herein. In some embodiments, the methods further comprise taking a sample from the subject and determining an indicator indicative of the likelihood of the presence, absence or degree of the SIRS condition using the indicator-determining method. In other embodiments, the methods further comprise sending a sample taken from the subject to a laboratory at which the indicator is determined according to the indicator-determining method. In these embodiments, the methods suitably further comprise receiving the indicator from the laboratory. 
     In a related aspect, the present invention provides methods for managing a subject with a specific SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: exposing the subject to a treatment regimen for the specific SIRS condition and avoiding exposing the subject to a treatment regimen for a SIRS condition other than the specific SIRS condition, based on an indicator obtained from an indicator-determining method, wherein the indicator is indicative of the presence, absence or degree of the SIRS condition in the subject, and wherein the indicator-determining method is an indicator-determining method as broadly described above and elsewhere herein. In some embodiments, the methods further comprise taking a sample from the subject and determining an indicator indicative of the likelihood of the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS, or InSIRS using the indicator-determining method. In other embodiments, the methods further comprise sending a sample taken from the subject to a laboratory at which the indicator is determined according to the indicator-determining method. In these embodiments, the methods suitably further comprise receiving the indicator from the laboratory. 
     In a further aspect, the present invention provides methods of monitoring the efficacy of a treatment regimen in a subject with a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS, wherein the treatment regimen is monitored for efficacy towards a desired health state (e.g., absence of the SIRS condition). These methods generally comprise, consist or consist essentially of: (1) obtaining a biomarker profile of a sample taken from the subject after treatment of the subject with the treatment regimen, wherein the sample biomarker profile comprises (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an infection positive SIRS condition (“IpSIRS”), a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) comparing the sample biomarker profile to a reference biomarker profile that is correlated with a presence, absence or degree of the SIRS condition to thereby determine whether the treatment regimen is effective for changing the health status of the subject to the desired health state. 
     In a related aspect, the present invention provides methods of monitoring the efficacy of a treatment regimen in a subject towards a desired health state (e.g., absence of BaSIRS, VaSIRS, PaSIRS, or InSIRS). These methods generally comprise, consist or consist essentially of: (1) determining an indicator according to an indicator-determining method as broadly described above and elsewhere herein based on a sample taken from the subject after treatment of the subject with the treatment regimen; and (2) assessing the likelihood of the subject having a presence, absence or degree of a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS using the indicator to thereby determine whether the treatment regimen is effective for changing the health status of the subject to the desired health state. In some embodiments, the indicator is determined using a plurality of host response specific derived biomarker values. In other embodiments, the indicator is determined using a plurality of host response specific derived biomarker values and a plurality of pathogen specific biomarker values. 
     Another aspect of the present invention provides methods of correlating a biomarker profile with an effective treatment regimen for a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a biomarker profile of a sample taken from a subject with the SIRS condition and for whom an effective treatment has been identified, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) correlating the biomarker profile so determined with an effective treatment regimen for the SIRS condition. 
     In yet another aspect, the present invention provides methods of determining whether a treatment regimen is effective for treating a subject with a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a post-treatment biomarker profile of a sample taken from the subject after treatment with a treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) determining a post-treatment indicator using the post-treatment biomarker profile, wherein the post-treatment indicator is at least partially indicative of the presence, absence or degree of the SIRS condition, wherein the post-treatment indicator indicates whether the treatment regimen is effective for treating the SIRS condition in the subject on the basis that post-treatment indicator indicates the presence of a healthy condition or the presence of the SIRS condition of a lower degree relative to the degree of the SIRS condition in the subject before treatment with the treatment regimen. 
     A further aspect of the present invention provides methods of correlating a biomarker profile with a positive or negative response to a treatment regimen for treating a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) determining a biomarker profile of a sample taken from a subject with the SIRS condition following commencement of the treatment regimen, wherein the reference biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) correlating the sample biomarker profile with a positive or negative response to the treatment regimen. 
     Another aspect of the present invention provides methods of determining a positive or negative response to a treatment regimen by a subject with a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) correlating a reference biomarker profile with a positive or negative response to the treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; (2) detecting a biomarker profile of a sample taken from the subject, wherein the sample biomarker profile comprises (i) a plurality of host response specific derived biomarker values for each of the plurality of derived biomarkers in the reference biomarker profile, and optionally (ii) a pathogen specific biomarker value for the pathogen biomarker in the reference biomarker profile, wherein the sample biomarker profile indicates whether the subject is responding positively or negatively to the treatment regimen. 
     Still another aspect of the present invention provides methods of determining a positive or negative response to a treatment regimen by a subject with a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS. These methods generally comprise, consist or consist essentially of: (1) obtaining a biomarker profile of a sample taken from the subject following commencement of the treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition, wherein the sample biomarker profile is correlated with a positive or negative response to the treatment regimen; and (2) and determining whether the subject is responding positively or negatively to the treatment regimen. 
     Yet other aspects of the present invention contemplate the use of the indicator-determining methods as broadly described above and elsewhere herein in methods for correlating a biomarker profile with an effective treatment regimen for a SIRS condition selected from BaSIRS and VaSIRS and optionally one of PaSIRS or InSIRS, or for determining whether a treatment regimen is effective for treating a subject with the SIRS condition, or for correlating a biomarker profile with a positive or negative response to a treatment regimen, or for determining a positive or negative response to a treatment regimen by a subject with the SIRS condition. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1 : Plot of the performance (AUC) of the best BaSIRS derived biomarkers following a greedy search. The best derived biomarker identified was TSPO:HCLS1 with an AUC of 0.84. The addition of further derived biomarkers adds incrementally to the overall AUC. The addition of further derived biomarkers beyond the first two was considered to add noise and difficulty in translating to a commercial format. 
         FIG. 2 : Performance (AUC) of the final BaSIRS signature, represented as bar graphs, in the various datasets used, including in the “discovery” (training), “validation” and “control” datasets. The signature was developed to provide strong AUC in BaSIRS datasets and weak AUC in datasets containing samples derived from subjects with SIRS unrelated to bacterial infection. 
         FIG. 3 : Performance of the final BaSIRS signature (OPLAH:ZHX2 and TSPO:HCLS1), represented as box and whisker plots, in the discovery datasets. Good separation in all datasets can be seen between Control (non-BaSIRS) and Case (BaSIRS) subjects. 
         FIG. 4 : Performance of the final BaSIRS signature (OPLAH:ZHX2 and TSPO:HCLS1) represented as box and whisker plots, in the validation datasets. Good separation in all datasets can be seen between Control (non-BaSIRS) and Case (BaSIRS) subjects. 
         FIG. 5 : Performance of the final BaSIRS signature (OPLAH:ZHX2 and TSPO:HCLS1) represented as box and whisker plots, in the control datasets. Poor separation in all datasets can be seen between Control (healthy or SIRS other than BaSIRS) and Case (SIRS other than BaSIRS) subjects. 
         FIG. 6 : Plot of the performance (AUC) of the best VaSIRS derived biomarkers following a greedy search. The best derived biomarker identified was ISG15:IL16 with an AUC of 0.92. The addition of further derived biomarkers adds incrementally to the overall AUC. The addition of further derived biomarkers beyond the first two was considered to add noise and difficulty in translating to a commercial format. 
         FIG. 7 : Box and whisker plots demonstrating performance (AUC=0.962) of the final VaSIRS signature (ISG15:IL16 and OASL:ADGRE5 in the right hand plot) in pediatric patients in intensive care with systemic inflammation. This figure shows the performance of the components of the pan-viral signature, and in combination (ISG15:IL16 and OASL:ADGRE5), in three pediatric patient cohorts from a study consisting of 12 sterile systemic inflammation (InSIRS, “control”), 28 bacterial systemic inflammation (“sepsis”), 6 viral systemic inflammation (“viral”). The study was called GAPPSS. ADGRE5 is also called CD97. 
         FIG. 8 : Box and whisker plots showing the performance of the final VaSIRS signature (ISG15:IL16 and OASL:ADGRE5) for 624 patients admitted to intensive care with suspected sepsis (MARS clinical trial). Patients are grouped based on retrospective physician diagnosis and whether a pathogenic organism was isolated (bacteria, mixed condition, virus) or not (healthy, SIRS). Good separation of those patients retrospectively diagnosed with a viral condition, and for which a virus was isolated, can be seen when using the final VaSIRS signature in this large patient cohort. 
         FIG. 9 : Box and whisker plots showing the performance of the final VaSIRS signature (ISG15:IL16 and OASL:ADGRE5) for patients presenting to a clinic with acute clinical signs associated with Human Immunodeficiency Virus (HIV) (GSE29429). Comparison was made between two groups of subjects, including 17 healthy controls and 30 patients infected with HIV. The Area Under Curve (AUC) was 0.91. 
         FIG. 10 : Box and whisker plots using the final VaSIRS signature in a time course study in a limited number of piglets deliberately infected (Day 0) with porcine circovirus and followed for 29 days. Blood samples were taken prior to inoculation (Day 0) and on Days 7, 14, 21 and 29 (GSE14790). The alternate and correlated biomarker N4BP1 was substituted for OASL because this latter biomarker is not found in pigs. Areas Under Curve (AUCs) were 0.812, 1.00, 1.00 and 1.00 for Days 0 vs 7, 0 vs 14, 0 vs 21 and 0 vs 29, respectively. 
         FIG. 11 : Use of the final VaSIRS signature in children with acute mild (n=9), moderate (n=9) or severe (n=8) Respiratory Syncytial Virus (RSV) infection, and upon 4-6 weeks of recovery for those children that had acute moderate and severe infection shows good separation between those with acute infection versus those in recovery. Little difference was found between patients with RSV infection of varying severity. 
         FIG. 12 : Time course study of the use of the final VaSIRS signature in cynomologus macaques (n=15) infected with aerosolized Marburg virus (Filoviridae, Group V). In this study 15 Marburg virus-infected macaques (1000 pfu) were studied over a nine-day period with three animals sacrificed at each two-day interval. Cytokine and gene expression analyzes revealed similar peaks by Day 7 to that of SeptiCyte VIRUS score. The first major elevation in VaSIRS signature can be seen on Day 3 post-exposure which correlates to the first detectable presence of viral antigen in regional lymph nodes and precedes first detectable viremia (Day 4) and elevated body temperature (Day 5). (original study published by Lin, K. L., Twenhafel, N. A., Connor, J. H., Cashman, K. A., Shamblin, J. D., Donnelly, G. C., et al. (2015). Temporal Characterization of Marburg Virus Angola Infection following Aerosol Challenge in Rhesus Macaques. Journal of Virology, 89(19), 9875-9885.) 
         FIG. 13 : Use of VaSIRS signature over time using liver biopsies from chimpanzees intravenously inoculated (Week 0) with either Hepatitis C Virus (HCV, n=3) or Hepatitis E Virus (HEV, n=4). Samples were grouped based on the independent detection of viremia, including; first positive week (and the second positive week for HCV), the peak positive week, the last positive week, the first negative week and the fourth negative week. The temporal gene expression responses for each virus (each Baltimore Group IV viruses) is different. The VaSIRS signature using liver tissue largely reflected viremia detected in plasma using virus-specific RT-PCR assays, the peak of which preceded both the antibody response and peak liver histological activity index (HAI, Ishtak activity) by 1-4 weeks for both viruses. (original study published by Yu, C., Boon, D., McDonald, S. L., Myers, T. G., Tomioka, K., Nguyen, H., et al. (2010). Pathogenesis of Hepatitis E Virus and Hepatitis C Virus in Chimpanzees: Similarities and Differences. Journal of Virology, 84(21), 11264-11278.) 
         FIG. 14 : Plot of the performance (AUC) of the best PaSIRS derived biomarkers following a greedy search. The performance of these same derived biomarkers is also shown in a merged control dataset (lower line). The best derived biomarker identified was TTC17:G6PD with an AUC of 0.96. The addition of further derived biomarkers adds incrementally to the overall AUC. The addition of further derived biomarkers beyond the first three was considered to add noise and difficulty in translating to a commercial format. 
         FIG. 15 : Box and whisker plots of the performance of the combination of the derived biomarkers TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 for sixteen non-protozoal datasets (top two rows) and four protozoal datasets. The overall AUC across these datasets for this single derived biomarker was 0.99. 
         FIG. 16 : Box and whisker plots of the performance of the derived biomarkers TTC17/G6PD and HERC6/LAP3 and NUP160/TPP1 for Clinical (protozoal) and Control (non-protozoal) datasets. The Clinical dataset consists of five merged datasets (GSE34404, 64610, 33811, 15221 and 5418), and the Control dataset consists of 16 merged datasets, including four viral (GSE40366, 41752, 51808, 52428), eight SIRS (GSE19301, 38485, 46743, 64813, 17755, 47655, 29532, 61672), three Triage (GSE11908, 33341, 25504) and one healthy (GSE35846). Each merged dataset contains those subjects (or patients) with the condition under study (Case) and those subjects without the condition (Control). Good separation can be observed between the Case and Control in the Clinical (protozoal) dataset whilst there is poor separation between Case and Control in the Control dataset. Such performance indicates specificity of the derived biomarkers. 
         FIG. 17 : Box and whisker plots demonstrating the performance of the final PaSIRS signature TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 in the dataset GSE43661. Macrophages from three donors were cultured and either infected with  Leishmania major  (Case) or mock infected (Control). Samples were taken at time point 0 and at 3, 6, 12 and 24 hours. The value of the derived biomarkers changes over time in both infected and mock-infected samples and the largest difference between these two cohorts can be seen at time points 3 and 6 hours post-infection. 
         FIG. 18 : Box and whisker plot showing the performance of the final PaSIRS signature TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 in the dataset GSE23750. Intestinal biopsies were taken from eight patients with  Entamoeba histolytica  infection on Day 1 and on Day 60 following treatment. A difference between the two time points can be observed but it is not large, perhaps because the sample was an intestinal biopsy rather than peripheral blood. 
         FIG. 19 : Box and whisker plot showing the performance of the final PaSIRS signature TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 in dataset GSE7047. Cultured (in vitro) HeLa cells were either infected or not with  Trypanosoma cruzi . Three replicates were performed. A large difference can be observed in the value obtained for this combination of derived biomarkers between infected and uninfected HeLa cells. 
         FIG. 20 : Box and whisker plot showing the performance of the final PaSIRS signature TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 in dataset GSE50957. Five people on malaria prophylaxis were infected with  Plasmodium falciparum  through the bites of infected mosquitos and blood samples were taken pre- and post-infection. Blood samples from two healthy controls were also included in the study. Despite the subjects being on malaria prophylaxis a large difference can be observed between samples taken pre- and post-infection. 
         FIG. 21 : Box and whisker plot showing the performance of the final PaSIRS signature TTC17/G6PD, HERC6/LAP3 and NUP160/TPP1 in dataset GSE52166 which is a larger study of the same design as GSE50957 but involving more patients (n=54, samples taken pre- and post-infection). Despite the subjects being on malaria prophylaxis a difference, albeit less dramatic than for GSE50957, can be observed between samples taken pre- and post-infection. 
         FIG. 22 : Plot of the performance (AUC) of the best inSIRS derived biomarkers following a greedy search. The best derived biomarker identified was ENTPD1:ARL6IP5 with an AUC of 0.898. The addition of further derived biomarkers adds incrementally to the overall AUC. The addition of further derived biomarkers beyond the first two was considered to add noise and difficulty in translating to a commercial format. 
         FIG. 23 : Box and whisker plots showing the performance of the inSIRS signature (ENTPD1/ARL6IP5; TNFSF8/HEATR1) using controls datasets (infectious SIRS; GSE datasets 11909 (mixed conditions including autoimmunity vs infection positive), 19301 (asthma exacerbation vs quiescent), 38485 (schizophrenia vs healthy), 41752 (Lassa virus infection vs healthy), 42834 (tuberculosis vs healthy), 51808 (Dengue virus infection vs healthy), 52428 (influenza virus infection vs healthy), 61672 (anxiety vs not) and 64813 (post-traumatic stress syndrome vs pre-stress). 
         FIG. 24 : Box and whisker plots showing the performance of the inSIRS signature (ENTPD1/ARL6IP5; TNFSF8/HEATR1) using discovery datasets, including GAPPSS (sepsis and surgical SIRS in children), GSE17755 (autoimmune disease vs infected), GSE36809 (trauma with and without sepsis), GSE47655 (anaphylaxis), GSE63990 (acute respiratory infection) and 74224 (sepsis and SIRS in adults). 
         FIG. 25 : Box and whisker plots showing the performance of the inSIRS signature (ENTPD1/ARL6IP5; TNFSF8/HEATR1) using a separate set of samples (validation) from the datasets, including GAPPSS (sepsis and surgical SIRS in children), GSE17755 (autoimmune disease vs infected), GSE36809 (trauma, with or without sepsis), GSE47655 (anaphylaxis), GSE63990 (acute respiratory infection) and 74224 (sepsis and SIRS in adults). 
         FIG. 26 : Multi-dimensional scaling plot using random forest and BaSIRS and VaSIRS derived biomarkers on data associated with GSE63990. Good separation of patients with acute respiratory inflammation into those patients with bacterial and viral infections and non-infectious illness can be observed when using BaSIRS and VaSIRS derived biomarkers. It can be seen that some patients with acute respiratory inflammation due to a bacterial infection (as diagnosed by a clinician) cluster with those patients with a viral infection (as determined using multi-dimensional scaling) and vice versa. 
         FIG. 27 : Example patient report for the host response specific biomarkers for a bacterial infection (alone)—called SeptiCyte MICROBE. 
         FIG. 28 : Example patient report for the host response specific biomarkers for a viral infection (alone)—called SeptiCyte VIRUS. 
         FIG. 29 : Example patient report for the host response specific biomarkers for a protozoal infection (alone)—called SeptiCyte PROTOZOAN. 
         FIG. 30 : Example patient report for the host response specific biomarkers for bacterial, viral, protozoal and infection negative systemic inflammation combined—called SeptiCyte SPECTRUM. In this instance the patient has a predominant bacterial host response. 
         FIG. 31 : Example patient report for the host response specific biomarkers for bacterial, viral, protozoal and infection negative systemic inflammation combined—called SeptiCyte SPECTRUM. In this instance the patient has a predominant viral host response. 
         FIG. 32 : Example patient report for the host response specific biomarkers for bacterial, viral, protozoal and infection negative systemic inflammation combined—called SeptiCyte SPECTRUM. In this instance the patient has a predominant protozoal host response. 
         FIG. 33 : Example patient report for the host response specific biomarkers for bacterial, viral, protozoal and infection negative systemic inflammation combined—called SeptiCyte SPECTRUM. In this instance the patient has a predominant non-infectious host response. 
         FIG. 34 : Plot of BaSIRS signature results (Y axis, host response) versus bacterial pathogen detection results (X axis, pathogen molecule) for intensive care patients with retrospectively diagnosed “sepsis” (ipSIRS), “SIRS” (InSIRS) or “indeterminate” (three clinicians could not decide on a diagnosis). The Y axis is designated as “SeptiScore”, which is a probability of BaSIRS, and the X axis is in RT-PCR cycle time (Ct), which is a measurement of bacterial DNA in whole blood. Each dot represents a patient blood sample that has been tested and those that are circled (on the right hand side) are the only samples that were found to be blood culture positive. Such samples also have low Ct values, indicating that bacterial DNA could be detected at high levels, and high SeptiScores, indicating a strong specific host response to bacterial infection. 
         FIG. 35 : Plot of VaSIRS signature and viral pathogen results for intensive care patients included in the MARS study. Those patients that were viral pathogen positive are circled (with varying sized circles for different virus types). In particular, those patients positive for influenza and RSV virus antigens are also strongly positive for VaSIRS signature. 
         FIG. 36 . A plot of scores obtained for SeptiCyte™ VIRUS and SeptiCyte™ MICROBE for pediatric patients participating in a clinical trial that presented with clinical signs of SIRS. Some patients (n=28) were retrospectively diagnosed as having sepsis (nine were also positive on PCR for a viral infection), some (n=6) were retrospectively diagnosed as having a viral infection (three were also diagnosed as having confirmed or suspected sepsis), and some were retrospectively diagnosed as having systemic inflammation but no infection (n=12). Good separation can be seen between those patients having InSIRS (“Control”) compared to other causes of SIRS. However, separation between those patients with BaSIRS and VaSIRS is less clear, suggesting that, for at least some patients, inflammation due to multiple pathogen types can exist at the same time. Further, viral infection may lead to bacterial infection, or bacterial infection may lead to viral infection. 
         FIG. 37 : Box and whisker plots demonstrating the performance, as measured by probability (Y axis), of each of the PaSIRS (“Protozoal”), BaSIRS (“Bacterial”), VaSIRS (“Viral”) and InSIRS (“SIRS”) final signatures in eight individual and independent GEO datasets covering a range of conditions including patients with sepsis, influenza, malaria, non-infectious systemic inflammation, and healthy subjects. The probabilities demonstrate that each systemic inflammatory signature is specific for its intended target condition. Combined probabilities were determined by mapping each score onto a sigmoidal curve via the logit function. Probabilities were then calculated using a LOO-CV approach. 
     
    
    
     BRIEF DESCRIPTION OF THE TABLES 
     TABLE 1: Representative key human pathogens that are known to cause systemic inflammation and bacteremia, fungemia, viremia or protozoan parasitemia. 
     TABLE 2: Common human viruses that cause SIRS as part of their pathogenesis and for which there are specific anti-viral treatments. 
     TABLES 3: BaSIRS biomarker details including; Sequence identification number, gene symbol and Ensembl transcript ID. 
     TABLE 4: BaSIRS biomarker details including; Sequence identification number, gene symbol and GenBank accession. 
     TABLE 5: VaSIRS biomarker details including; Sequence identification number, gene symbol and Ensembl transcript ID. 
     TABLE 6: VaSIRS biomarker details including; Sequence identification number, gene symbol and GenBank accession. 
     TABLE 7: PaSIRS biomarker details including; Sequence identification number, gene symbol and Ensembl transcript ID. 
     TABLE 8: PaSIRS biomarker details including; Sequence identification number, gene symbol and GenBank accession. 
     TABLE 9: PaSIRS biomarker details including; Sequence identification number, gene symbol and Ensembl transcript ID. 
     TABLE 10: PaSIRS biomarker details including; Sequence identification number, gene symbol and GenBank accession. 
     TABLE 11: Exemplary  Escherichia coli  DNA sequence including Single Nucleotide Polymorphisms (SNPs) at positions 396 and 398 (bolded). 
     TABLE 12: Description of datasets and number of samples used as part of discovery of derived biomarkers for BaSIRS. The total number of genes that were able to be used across all of these datasets was 3698. All useable samples in these datasets were randomly divided into BaSIRS discovery and validation (see TABLE 10) sets. 
     TABLE 13: Description of datasets and number of samples used as part of validation of derived biomarkers for BaSIRS. 
     TABLE 14: Description of control datasets and number of samples used for subtraction from the derived biomarkers for BaSIRS. The subtraction process ensured that the BaSIRS derived biomarkers were specific. 
     TABLE 15: Performance (as measured by AUC) of the final BaSIRS signature in each of the Discovery, Validation and Control datasets. 
     TABLE 16: Performance (as meassured by AUC) of the top 102 BaSIRS derived biomarkers in each of the BaSIRS validation datasets. Only those derived biomarkers with a mean AUC&gt;0.85 were used in a greedy search to identify the best combination of derived biomarkers. 
     TABLE 17: Details of Gene Expression Omnibus (GEO) datasets used for discovery of viral derived biomarkers. 
     TABLE 18: Details of Gene Expression Omnibus (GEO) datasets used for validation of viral derived biomarkers. 
     TABLE 19: Description of control datasets used for subtraction from the derived biomarkers for VaSIRS. The subtraction process ensured that the VaSIRS derived biomarkers were specific. 
     TABLE 20: List of derived VaSIRS biomarkers with an of AUC&gt;0.8 in at least 11 of 14 viral datasets. 
     TABLE 21: Details of Gene Expression Omnibus (GEO) datasets used for discovery of protozoal derived biomarkers. 
     TABLE 22: Description of the GEO datasets used for validation of the protozoal derived biomarkers. 
     TABLE 23: Description of control datasets used for subtraction from the derived biomarkers for PaSIRS. The subtraction process ensured that the PaSIRS derived biomarkers were specific. 
     TABLE 24: Description of datasets used for discovery, validation and subtraction from the derived biomarkers for InSIRS. The subtraction process ensured that the InSIRS derived biomarkers were specific. 
     TABLE 25: Derived biomarkers grouped (A, B, C, D) based on correlation to each of the biomarkers in the final BaSIRS signature (OPLAH, ZHX2, TSPO, HCLS1). 
     TABLE 26: Derived biomarkers grouped (A, B, C, D) based on correlation to each of the biomarkers in the final VaSIRS signature (ISG15, IL16, OASL, ADGRE5). 
     TABLE 27: Derived biomarkers grouped (A, B, C, D) based on correlation to each of the biomarkers in the final PaSIRS signature (TTC17, G6PD, HERC6, LAP3, NUP160, TPP1). 
     TABLE 28: Derived biomarkers grouped (A, B, C, D) based on correlation to each of the biomarkers in the final inSIRS signature (ARL6IP5, ENTPD1, HEATR1, TNFSF8). 
     TABLE 29: Top performing (based on AUC) BaSIRS derived biomarkers following a greedy search on a combined dataset. The top derived biomarker was TSPO:HCLS1 with an AUC of 0.838. Incremental AUC increases can be made with the addition of further derived biomarkers as indicated. 
     TABLE 30: BaSIRS numerators and denominators appearing more than once in derived biomarkers with a mean AUC&gt;0.85 in the validation datasets. 
     TABLE 31: Top performing (based on AUC) VaSIRS derived biomarkers following a greedy search on a combined dataset. The top derived biomarker was ISG15:IL16 with an AUC of 0.92. Incremental AUC increases can be made with the addition of further derived biomarkers as indicated. 
     TABLE 32: VaSIRS numerators and denominators appearing more than twice in the 473 derived biomarkers with a mean AUC&gt;0.80 in at least 11 of 14 viral datasets. 
     TABLE 33: Top performing (based on AUC) PaSIRS derived biomarkers following a greedy search on a combined dataset. The top derived biomarker was TTC17:G6PD with an AUC of 0.96. Incremental AUC increases can be made with the addition of further derived biomarkers as indicated. 
     TABLE 34: PaSIRS numerators and denominators appearing more than twice in the 523 derived biomarkers with a mean AUC&gt;0.75 in the validation datasets. 
     TABLE 35: TABLE of individual performance, in descending AUC, of the 523 PaSIRS derived biomarkers with an average AUC&gt;0.75 across each of five protozoal datasets. 
     TABLE 36: Top performing (based on AUC) InSIRS derived biomarkers following a greedy search on a combined dataset. The top derived biomarker was ENTPD1:ARL6IP5 with an AUC of 0.898. Incremental AUC increases can be made with the addition of further derived biomarkers as indicated. 
     TABLE 37: inSIRS numerators and denominators appearing more than twice in the 164 derived biomarkers with a mean AUC&gt;0.82 in the validation datasets. 
     TABLE 38: TABLE of individual performance, in descending AUC, of 164 inSIRS derived biomarkers with an average AUC&gt;0.82 across each of six non-infectious systemic inflammation datasets. 
     TABLE 39: Interpretation of results obtained when using a combination of BaSIRS and bacterial detection. 
     TABLE 40: Interpretation of results obtained when using a combination of VaSIRS and virus detection. 
     TABLE 41: Interpretation of results obtained when using a combination of PaSIRS and protozoan detection. 
     DETAILED DESCRIPTION OF THE INVENTION 
     1. Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below. 
     The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. 
     As used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or). 
     The term “biomarker” broadly refers to any detectable compound, such as a protein, a peptide, a proteoglycan, a glycoprotein, a lipoprotein, a carbohydrate, a lipid, a nucleic acid (e.g., DNA, such as cDNA or amplified DNA, or RNA, such as mRNA), an organic or inorganic chemical, a natural or synthetic polymer, a small molecule (e.g., a metabolite), or a discriminating molecule or discriminating fragment of any of the foregoing, that is present in or derived from a sample, typically a biological sample. “Derived from” as used in this context refers to a compound that, when detected, is indicative of a particular molecule being present in the sample. For example, detection of a particular cDNA can be indicative of the presence of a particular RNA transcript in the sample. As another example, detection of or binding to a particular antibody can be indicative of the presence of a particular antigen (e.g., protein) in the sample. Here, a discriminating molecule or fragment is a molecule or fragment that, when detected, indicates presence or abundance of an above-identified compound. A biomarker can, for example, be isolated from a sample, directly measured in a sample, or detected in or determined to be in a sample. A biomarker can, for example, be functional, partially functional, or non-functional. In specific embodiments, the “biomarkers” include “host response biomarkers”, and “pathogen biomarkers”, which are described in more detail below. A biomarker is considered to be informative for a SIRS condition as disclosed herein if a measurable aspect of the biomarker is associated with the presence of the SIRS condition in a subject in comparison to a predetermined value or a reference profile from a control population. Such a measurable aspect may include, for example, the presence, absence, or level of the biomarker in the sample, and/or its presence or level as a part of a profile of more than one biomarker, for example as part of a combination with one or more other biomarkers, including as part of a derived biomarker combination as described herein. 
     The term “biomarker value” refers to a value measured or derived for at least one corresponding biomarker of a subject and which is typically at least partially indicative of a level of a biomarker in a sample taken from the subject. Thus, the biomarker values could be measured biomarker values, which are values of biomarkers measured for the subject. These values may be quantitative or qualitative. Fo example, a measured biomarker value may refer to the presence or absence of a biomarker or may refer to a level of a biomarker, in a sample. The measured biomarker values can be values relating to raw or normalized biomarker levels (e.g., a raw, non-normalized biomarker level, or a normalized biomarker levels that is determined relative to an internal or external control biomarker level) and to mathematically transformed biomarker levels (e.g., a logarithmic representation of a biomarker level such as amplification amount, cycle time, etc.). Alternatively, the biomarker values could be derived biomarker values, which are values that have been derived from one or more measured biomarker values, for example by applying a function to the one or more measured biomarker values. Biomarker values can be of any appropriate form depending on the manner in which the values are determined. For example, the biomarker values could be determined using high-throughput technologies such as mass spectrometry, sequencing platforms, array and hybridization platforms, immunoassays, flow cytometry, or any combination of such technologies and in one preferred example, the biomarker values relate to a level of activity or abundance of an expression product or other measurable molecule, quantified using a technique such as PCR, sequencing or the like. In this case, the biomarker values can be in the form of amplification amounts, or cycle times, which are a logarithmic representation of the levels of the biomarker within a sample and which thus correspond to mathematical transformations of raw or normalized biomarker levels, as will be appreciated by persons skilled in the art and as will be described in more detail below. Thus, in situations in which mathematically transformed biomarker values are used as measured biomarker values, the expression “derived biomarker value being indicative of a ratio of levels of a plurality of biomarkers” and the like does not necessarily mean that the derived biomarker value is one that results from a division of one measured biomarker value by another measured biomarker value. Instead, the measured biomarker values can be combined using any suitable function, whereby the resulting derived biomarker value is one that corresponds to or reflects a ratio of non-normalized (e.g., raw) or normalized biomarker levels. 
     The term “biomarker profile” refers to one or a plurality of one or more types of biomarkers (e.g., an mRNA molecule, a cDNA molecule and/or a protein, lipopolysaccharide, etc.), or an indication thereof, together with a feature, such as a measurable aspect (e.g., biomarker value that is measured or derived), of the biomarker(s). A biomarker profile may comprise a single biomarker level that correlates with the presence, absence or degree of a condition (e.g., BaSIRS or VaSIRS, or PaSIRS or InSIRS). Alternatively, a biomarker profile may comprise at least two such biomarkers or indications thereof, where the biomarkers can be in the same or different classes, such as, for example, a nucleic acid and a polypeptide. Thus, a biomarker profile may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more biomarkers or indications thereof. In some embodiments, a biomarker profile comprises hundreds, or even thousands, of biomarkers or indications thereof. A biomarker profile can further comprise one or more controls or internal standards. In certain embodiments, the biomarker profile comprises at least one biomarker, or indication thereof, that serves as an internal standard. In other embodiments, a biomarker profile comprises an indication of one or more types of biomarkers. The term “indication” as used herein in this context merely refers to a situation where the biomarker profile contains symbols, data, abbreviations or other similar indicia for a biomarker, rather than the biomarker molecular entity itself. The term “biomarker profile” is also used herein to refer to a biomarker value or combination of at least two biomarker values, wherein individual biomarker values correspond to values of biomarkers that can be measured or derived from one or more subjects, which combination is characteristic of a discrete condition, stage of condition, subtype of condition. The term “profile biomarkers” is used to refer to a subset of the biomarkers that have been identified for use in a biomarker profile that can be used in performing a clinical assessment, such as to rule in or rule out a specific condition, different stages or severity of conditions, or subtypes of different conditions. The number of profile biomarkers will vary, but is typically of the order of 10 or less. 
     The terms “complementary” and “complementarity” refer to polynucleotides (i.e., a sequence of nucleotides) related by the base-pairing rules. For example, the sequence “A-G-T,” is complementary to the sequence “T-C-A.” Complementarity may be “partial,” in which only some of the nucleic acids&#39; bases are matched according to the base pairing rules. Or, there may be “complete” or “total” complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. 
     Throughout this specification, unless the context requires otherwise, the words “comprise,” “comprises” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. Thus, use of the term “comprising” and the like indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of” is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements. 
     The term “correlating” refers to determining a relationship between one type of data with another or with a state. 
     The term “degree” of BaSIRS, VaSIRS, PaSIRS, or InSIRS, as used herein, refers to the seriousness, severity, stage or state of a BaSIRS, VaSIRS, PaSIRS, or InSIRS. For example, a BaSIRS, VaSIRS, PaSIRS, or InSIRS may be characterized as mild, moderate or severe. A person of skill in the art would be able to determine or assess the degree of a particular BaSIRS, VaSIRS, PaSIRS, or InSIRS. For example, the degree of a BaSIRS, VaSIRS, PaSIRS, or InSIRS may be determined by comparing the likelihood or length of survival of a subject having a BaSIRS, VaSIRS, PaSIRS, or InSIRS with the likelihood or length of survival in other subjects having BaSIRS, VaSIRS, PaSIRS, or InSIRS. In other embodiments, the degree of a BaSIRS, VaSIRS, PaSIRS, or InSIRS may be determined by comparing the clinical signs of a subject having a condition with the degree of the clinical signs in other subjects having BaSIRS, VaSIRS, PaSIRS, or InSIRS. 
     As used herein, the terms “diagnosis”, “diagnosing” and the like are used interchangeably herein to encompass determining the likelihood that a subject will develop a condition, or the existence or nature of a condition in a subject. These terms also encompass determining the severity of disease or episode of disease, as well as in the context of rational therapy, in which the diagnosis guides therapy, including initial selection of therapy, modification of therapy (e.g., adjustment of dose or dosage regimen), and the like. By “likelihood” is meant a measure of whether a subject with particular measured or derived biomarker values actually has a condition (or not) based on a given mathematical model. An increased likelihood for example may be relative or absolute and may be expressed qualitatively or quantitatively. For instance, an increased likelihood may be determined simply by determining the subject&#39;s measured, derived or indicator biomarker values for at least two BaSIRS, VaSIRS, PaSIRS, or InSIRS biomarkers in combination with at least one pathogen specific biomarker and placing the subject in an “increased likelihood” category, based upon previous population studies. The term “likelihood” is also used interchangeably herein with the term “probability”. The term “risk” relates to the possibility or probability of a particular event occurring at some point in the future. “Risk stratification” refers to an arraying of known clinical risk factors to allow physicians to classify patients into a low, moderate, high or highest risk of developing a particular disease or condition. 
     The term “gene”, as used herein, refers to a stretch of nucleic acid that codes for a polypeptide or for an RNA chain that has a function. While it is the exon region of a gene that is transcribed to form mRNA, the term “gene” also includes regulatory regions such as promoters and enhancers that govern expression of the exon region. 
     By “high density acid arrays” and the like is meant those arrays that contain at least 400 different features (e.g., probes) per cm 2 . 
     The term “indicator” as used herein refers to a result or representation of a result, including any information, number, ratio, signal, sign, mark, or note by which a skilled artisan can estimate and/or determine a likelihood or risk of whether or not a subject is suffering from a given disease or condition. In the case of the present invention, the “indicator” may optionally be used together with other clinical characteristics, to arrive at a diagnosis (that is, the occurrence or nonoccurrence) of BaSIRS, VaSIRS, PaSIRS, or InSIRS in a subject. That such an indicator is “determined” is not meant to imply that the indicator is 100% accurate. The skilled clinician may use the indicator together with other clinical indicia to arrive at a diagnosis. 
     The term “immobilized” means that a molecular species of interest is fixed to a solid support, suitably by covalent linkage. This covalent linkage can be achieved by different means depending on the molecular nature of the molecular species. Moreover, the molecular species may be also fixed on the solid support by electrostatic forces, hydrophobic or hydrophilic interactions or Van-der-Waals forces. The above described physico-chemical interactions typically occur in interactions between molecules. In particular embodiments, all that is required is that the molecules (e.g., nucleic acids or polypeptides) remain immobilized or attached to a support under conditions in which it is intended to use the support, for example in applications requiring nucleic acid amplification and/or sequencing or in in antibody-binding assays. For example, oligonucleotides or primers are immobilized such that a 3′ end is available for enzymatic extension and/or at least a portion of the sequence is capable of hybridizing to a complementary sequence. In some embodiments, immobilization can occur via hybridization to a surface attached primer, in which case the immobilized primer or oligonucleotide may be in the 3′-5′ orientation. In other embodiments, immobilization can occur by means other than base-pairing hybridization, such as the covalent attachment. 
     The term “immune system”, as used herein, refers to cells, molecular components and mechanisms, including antigen-specific and non-specific categories of the adaptive and innate immune systems, respectively, that provide a defense against damage and insults resulting from a viral infection. The term “innate immune system” refers to a host&#39;s non-specific reaction to insult to include antigen-nonspecific defense cells, molecular components and mechanisms that come into action immediately or within several hours after exposure to almost any insult or antigen. Elements of the innate immunity include for example phagocytic cells (monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes such as neutrophils, reticuloendothelial cells such as Kupffer cells, and microglia), cells that release inflammatory mediators (basophils, mast cells and eosinophils), natural killer cells (NK cells) and physical barriers and molecules such as keratin, mucous, secretions, complement proteins, immunoglobulin M (IgM), acute phase proteins, fibrinogen and molecules of the clotting cascade, and cytokines. Effector compounds of the innate immune system include chemicals such as lysozymes, IgM, mucous and chemoattractants (e.g., cytokines or histamine), complement and clotting proteins. The term “adaptive immune system” refers to antigen-specific cells, molecular components and mechanisms that emerge over several days, and react with and remove a specific antigen. The adaptive immune system develops throughout a host&#39;s lifetime. The adaptive immune system is based on leukocytes, and is divided into two major sections: the humoral immune system, which acts mainly via immunoglobulins produced by B cells, and the cell-mediated immune system, which functions mainly via T cells. 
     Reference herein to “immuno-interactive” includes reference to any interaction, reaction, or other form of association between molecules and in particular where one of the molecules is, or mimics, a component of the immune system. 
     The term “level” as used herein encompasses the absolute amount of a biomarker as referred to herein, the relative amount or concentration of the biomarker as well as any value or parameter which correlates thereto or can be derived therefrom. For example, the level can be a copy number, weight, moles, abundance, concentration such as μg/L or a relative amount such as 1.0, 1.5, 2.0, 2.5, 3, 5, 10, 15, 20, 25, 30, 40, 60, 80 or 100 times a reference or control level. Optionally, the term level includes the level of a biomarker normalized to an internal normalization control, such as the expression of a housekeeping gene. 
     The term “microarray” refers to an arrangement of hybridizable array elements, e.g., probes (including primers), ligands, biomarker nucleic acid sequence or protein sequences on a substrate. 
     By monitoring the “progression” of a SIRS condition over time, is meant that changes in the severity (e.g., worsening or improvement) of the SIRS condition or particular aspects of the SIRS condition are monitored over time. 
     The term “nucleic acid” or “polynucleotide” as used herein includes RNA, mRNA, miRNA, cRNA, cDNA mtDNA, or DNA. The term typically refers to a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide. The term includes single and double stranded forms of DNA or RNA. 
     By “obtained” is meant to come into possession. Samples so obtained include, for example, nucleic acid extracts or polypeptide extracts isolated or derived from a particular source. For instance, the extract may be isolated directly from a biological fluid or tissue of a subject. 
     The term “pathogen biomarker” refers to any bacterial, viral or protozoan molecule. The pathogen molecules can be nucleic acid, protein, carbohydrate, lipid, metabolite or combinations of such molecules. 
     As used herein, the term “positive response” means that the result of a treatment regimen includes some clinically significant benefit, such as the prevention, or reduction of severity, of symptoms, or a slowing of the progression of the condition. By contrast, the term “negative response” means that a treatment regimen provides no clinically significant benefit, such as the prevention, or reduction of severity, of symptoms, or increases the rate of progression of the condition. 
     “Protein”, “polypeptide” and “peptide” are used interchangeably herein to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. 
     By “primer” is meant an oligonucleotide which, when paired with a strand of DNA, is capable of initiating the synthesis of a primer extension product in the presence of a suitable polymerizing agent. The primer is preferably single-stranded for maximum efficiency in amplification but can alternatively be double-stranded. A primer must be sufficiently long to prime the synthesis of extension products in the presence of the polymerization agent. The length of the primer depends on many factors, including application, temperature to be employed, template reaction conditions, other reagents, and source of primers. For example, depending on the complexity of the target sequence, the primer may be at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 50, 75, 100, 150, 200, 300, 400, 500, to one base shorter in length than the template sequence at the 3′ end of the primer to allow extension of a nucleic acid chain, though the 5′ end of the primer may extend in length beyond the 3′ end of the template sequence. In certain embodiments, primers can be large polynucleotides, such as from about 35 nucleotides to several kilobases or more. Primers can be selected to be “substantially complementary” to the sequence on the template to which it is designed to hybridize and serve as a site for the initiation of synthesis. By “substantially complementary”, it is meant that the primer is sufficiently complementary to hybridize with a target polynucleotide. Desirably, the primer contains no mismatches with the template to which it is designed to hybridize but this is not essential. For example, non-complementary nucleotide residues can be attached to the 5′ end of the primer, with the remainder of the primer sequence being complementary to the template. Alternatively, non-complementary nucleotide residues or a stretch of non-complementary nucleotide residues can be interspersed into a primer, provided that the primer sequence has sufficient complementarity with the sequence of the template to hybridize therewith and thereby form a template for synthesis of the extension product of the primer. 
     As used herein, the term “probe” refers to a molecule that binds to a specific sequence or sub-sequence or other moiety of another molecule. Unless otherwise indicated, the term “probe” typically refers to a nucleic acid probe that binds to another nucleic acid, also referred to herein as a “target polynucleotide”, through complementary base pairing. Probes can bind target polynucleotides lacking complete sequence complementarity with the probe, depending on the stringency of the hybridization conditions. Probes can be labeled directly or indirectly and include primers within their scope. 
     The term “sample” as used herein includes any biological specimen that may be extracted, untreated, treated, diluted or concentrated from a subject. Samples may include, without limitation, biological fluids, exudates such as whole blood, serum, red blood cells, white blood cells, plasma, saliva, urine, stool (i.e., faeces), tears, sweat, phlegm, sebum, nipple aspirate, ductal lavage, bronchial, pharyngeal or nasal lavage or swab, tumor exudates, synovial fluid, ascitic fluid, peritoneal fluid, amniotic fluid, cerebrospinal fluid, lymph, fine needle aspirate, amniotic fluid, any other bodily fluid, cell lysates, cellular secretion products, inflammation fluid, semen and vaginal secretions. Samples may include tissue samples and biopsies, tissue homogenates, washes, swabs and the like. Advantageous samples may include ones comprising any one or more biomarkers as taught herein in detectable quantities. Suitably, the sample is readily obtainable by minimally invasive methods, allowing the removal or isolation of the sample from the subject. In certain embodiments, the sample contains blood, especially peripheral blood, or a fraction or extract thereof. Typically, the sample comprises blood cells such as mature, immature or developing leukocytes, including lymphocytes, polymorphonuclear leukocytes, neutrophils, monocytes, reticulocytes, basophils, coelomocytes, hemocytes, eosinophils, megakaryocytes, macrophages, dendritic cells natural killer cells, or fraction of such cells (e.g., a nucleic acid or protein fraction). In specific embodiments, the sample comprises leukocytes including peripheral blood mononuclear cells (PBMC). 
     The term “solid support” as used herein refers to a solid inert surface or body to which a molecular species, such as a nucleic acid and polypeptides can be immobilized. Non-limiting examples of solid supports include glass surfaces, plastic surfaces, latex, dextran, polystyrene surfaces, polypropylene surfaces, polyacrylamide gels, gold surfaces, and silicon wafers. In some embodiments, the solid supports are in the form of membranes, chips or particles. For example, the solid support may be a glass surface (e.g., a planar surface of a flow cell channel). In some embodiments, the solid support may comprise an inert substrate or matrix which has been “functionalized”, such as by applying a layer or coating of an intermediate material comprising reactive groups which permit covalent attachment to molecules such as polynucleotides. By way of non-limiting example, such supports can include polyacrylamide hydrogels supported on an inert substrate such as glass. The molecules (e.g., polynucleotides) can be directly covalently attached to the intermediate material (e.g., a hydrogel) but the intermediate material can itself be non-covalently attached to the substrate or matrix (e.g., a glass substrate). The support can include a plurality of particles or beads each having a different attached molecular species. 
     As used herein, the term SIRS (“systemic inflammatory response syndrome”) refers to a clinical response arising from a non-specific insult with two or more of the following measureable clinical characteristics; a body temperature greater than 38° C. or less than 36° C., a heart rate greater than 90 beats per minute, a respiratory rate greater than 20 per minute, a white blood cell count (total leukocytes) greater than 12,000 per mm 3  or less than 4,000 per mm 3 , or a band neutrophil percentage greater than 10%. From an immunological perspective, it may be seen as representing a systemic response to insult (e.g., major surgery) or systemic inflammation. As used herein, “VaSIRS” includes any one or more (e.g., 1, 2, 3, 4, 5) of the clinical responses noted above but with underlying viral infection etiology. Confirmation of infection can be determined using any suitable procedure known in the art, illustrative examples of which include nucleic acid detection (e.g., polymerase chain reaction (PCR), immunological detection (e.g., ELISA), isolation of virus from infected cells, cell lysis and imaging techniques such as electron microscopy. From an immunological perspective, VaSIRS may be seen as a systemic response to viral infection, whether it is a local, peripheral or systemic infection. 
     The terms “subject”, “individual” and “patient” are used interchangeably herein to refer to an animal subject, particularly a vertebrate subject, and even more particularly a mammalian subject. Suitable vertebrate animals that fall within the scope of the invention include, but are not restricted to, any member of the phylum Chordata, subphylum vertebrata including primates, rodents (e.g., mice rats, guinea pigs), lagomorphs (e.g., rabbits, hares), bovines (e.g., cattle), ovines (e.g., sheep), caprines (e.g., goats), porcines (e.g., pigs), equines (e.g., horses), canines (e.g., dogs), felines (e.g., cats), avians (e.g., chickens, turkeys, ducks, geese, companion birds such as  canaries , budgerigars etc.), marine mammals (e.g., dolphins, whales), reptiles (snakes, frogs, lizards, etc.), and fish. A preferred subject is a primate (e.g., a human, ape, monkey, chimpanzee). The subject suitably has at least one (e.g., 1, 2, 3, 4, 5 or more) clinical sign of SIRS. 
     As used herein, the term “treatment regimen” refers to prophylactic and/or therapeutic (i.e., after onset of a specified condition) treatments, unless the context specifically indicates otherwise. The term “treatment regimen” encompasses natural substances and pharmaceutical agents (i.e., “drugs”) as well as any other treatment regimen including but not limited to dietary treatments, physical therapy or exercise regimens, surgical interventions, and combinations thereof. 
     It will be appreciated that the terms used herein and associated definitions are used for the purpose of explanation only and are not intended to be limiting. 
     2. Pan-Bacterial, Pan-Viral, Pan-Protozoal and Infection-Negative SIRS Biomarkers and their Use for Identifying Subjects with BaSIRS, VaSIRS, PaSIRS or InSIRS 
     The present invention concerns methods, apparatus, compositions and kits for identifying subjects with BaSIRS, VaSIRS, PaSIRS or InSIRS. In particular, BaSIRS, VaSIRS, PaSIRS, or InSIRS biomarkers and BIP, VIP and PIP biomarkers are disclosed for use alone or in combination in these modalities to assess the likelihood of the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in subjects. The methods, apparatus, compositions and kits of the invention are useful for early detection of BaSIRS, VaSIRS, PaSIRS or InSIRS, thus allowing better treatment interventions for subjects with symptoms of SIRS that stem at least in part from a bacterial, viral, protozoal infection or non-infectious causes. 
     The present inventors have determined that certain expression products are commonly, specifically and differentially expressed in humans, including cells of the immune system, during systemic inflammations with a range of bacterial etiologies underscoring the conserved nature of the host response to a BaSIRS. The results presented herein provide clear evidence that a unique biologically-relevant biomarker profile predicts BaSIRS with a remarkable degree of accuracy. This “pan-bacterial” systemic inflammation biomarker profile was validated in independently derived external datasets and publicly available datasets (see, TABLES 11 and 12 for the BaSIRS datasets used) and used to distinguish BaSIRS from other SIRS conditions including VaSIRS, PaSIRS and InSIRS (including autoimmune disease associated SIRS (ADaSIRS), cancer associated SIRS (CaSIRS) and trauma associated SIRS (TaSIRS)). 
     The present inventors have also determined that certain expression products are commonly, specifically and differentially expressed in humans, macaques, chimpanzees, mice, rats and pigs during systemic inflammations with a range of viral etiologies (e.g., Baltimore virus classification Groups I, II, III, IV, V, VI and VII), underscoring the conserved nature of the host response to a VaSIRS. The results presented herein provide clear evidence that a unique biologically-relevant biomarker profile predicts VaSIRS with a remarkable degree of accuracy. This “pan-viral” systemic inflammation biomarker profile was validated in independently derived external datasets and publicly available datasets (see, TABLES 16 and 17 for the VaSIRS datasets used) and used to distinguish VaSIRS from other SIRS conditions including BaSIRS, PaSIRS and InSIRS (including autoimmune disease associated SIRS (ADaSIRS), cancer associated SIRS (CaSIRS) and trauma associated SIRS (TaSIRS)). 
     It has also been determined that certain expression products are commonly, specifically and differentially expressed in humans during systemic inflammations with a range of protozoan etiologies ( Plasmodium, Leishmania, Trypanosoma, Entamoeba ) underscoring the conserved nature of the host response to a PaSIRS. The results presented herein provide clear evidence that a unique biologically-relevant biomarker profile predicts PaSIRS with a remarkable degree of accuracy. This “pan-protozoal” systemic inflammation biomarker profile was validated in publicly available datasets (see, TABLES 20 and 21 for the PaSIRS datasets used) and used to distinguish PaSIRS from other SIRS conditions including BaSIRS, VaSIRS and InSIRS (including autoimmune disease associated SIRS (ADaSIRS), cancer associated SIRS (CaSIRS) and trauma associated SIRS (TaSIRS)). 
     Additionally, it has been determined that certain expression products are commonly, specifically and differentially expressed in humans during systemic inflammations with a range of non-infectious etiologies underscoring the conserved nature of the host response of InSIRS. The results presented herein provide clear evidence that a unique biologically-relevant biomarker profile predicts InSIRS with a remarkable degree of accuracy. This infection-negative systemic inflammation biomarker profile was validated in publicly available datasets (see, TABLE 23 for the InSIRS datasets used) and used to distinguish InSIRS from other SIRS conditions including bacterial associated SIRS (BaSIRS), virus associated SIRS (VaSIRS) and protozoal associated SIRS (PaSIRS). 
     Overall, these findings provide compelling evidence that the expression products disclosed herein can function as biomarkers, respectively, for BaSIRS, VaSIRS, PaSIRS and InSIRS and may serve as useful diagnostic tools for triaging treatment decisions for SIRS-affected subjects. In this regard, it is proposed that the methods, apparatus, compositions and kits disclosed herein that are based on these biomarkers may serve in point-of-care diagnostics that allow for rapid and inexpensive screening for, and differentiation of, BaSIRS, VaSIRS, PaSIRS and InSIRS, which may result in significant cost savings to the medical system as SIRS-affected subjects can be exposed to therapeutic agents that are suitable for treating the etiology (e.g., bacterial, viral, protozoan or non-infectious) of their SIRS condition as opposed to therapeutic agents for SIRS conditions with other etiologies. 
     The present inventors have also identified, and designed assays for, common nucleic acid molecules in bacteria and protozoans and identified assays for detection of viruses at the genus level. For bacteria, the invention arises from the discovery that limited numbers of bacterial DNA Single Nucleotide Polymorphisms (SNPs) (SNP biomarkers) can be used to sensitively detect, quantify and broadly categorize bacterial DNA in the presence of host mammalian DNA. Further, the inventors have designed a simple, multiplexed nucleic acid amplification assay that can detect a limited number of human key protozoal pathogens that cause parasitemia. Further, multiplex assays that simultaneously detect the presence of a number of different, but limited, important human pathogenic virus genera are commercially available or have been reported in the scientific literature. 
     Thus, specific expression products are disclosed herein as host response specific biomarkers that provide a means for identifying BaSIRS, VaSIRS, PaSIRS or InSIRS and/or for distinguishing these systemic inflammatory conditions from each other for a subject with BaSIRS, VaSIRS, PaSIRS or InSIRS. Evaluation of these BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers through analysis of their levels in a subject or in a sample taken from a subject provides a measured or derived biomarker value for determinating an indicator that can be used for assessing the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject. 
     Further, specific nucleic acids are disclosed herein as pathogen specific biomarkers, including bacterial SNP biomarkers, or conserved protozoal DNA sequence biomarkers, or conserved viral DNA sequence biomarkers, that provide a means for identifying bacterial infection positive (BIP), viral infection positive (VIP) or protozoal infection positive (PIP) samples and/or for distinguishing these three infection-positive conditions from each other and other infection-negative conditions. Evaluation of these nucleic acid biomarkers through analysis of their levels in a subject or in a sample taken from a subject provides a measured or derived biomarker value for determinating an indicator that can be used for assessing the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject. 
     Additionally, unique combinations of host response specific biomarkers for identifying BaSIRS, VaSIRS, PaSIRS or InSIRS, and optionally pathogen specific biomarkers for identifying BIP, VIP or PIP, are disclosed that provide a means of more accurately identifying, compared to their use in isolation, BaSIRS, VaSIRS, PaSIRS or InSIRS and/or for distinguishing these systemic inflammatory conditions from each other. In certain embodiments, the host response specific and pathogen specific biomarker combinations are evaluated through analysis of their combined levels in a subject or in a sample taken from a subject, to thereby determine an indicator that is useful for assessing the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject. 
     Accordingly, biomarker values can be measured biomarker raw data values, which are values of biomarkers measured for the subject, or alternatively could be derived biomarker values, which are values that have been derived from one or more measured biomarker values, for example by applying a function to the measured biomarker values. As used herein, biomarkers values to which a function has been applied are referred to as “derived biomarkers values” and the biomarkers to which the derived biomarker values correspond are referred to herein as “derived biomarkers”. As used herein, host response specific derived biomarker values and pathogen specific biomarker values to which a combining function has been applied are referred to as “compound biomarker values” and the biomarkers to which the compound biomarker values correspond are referred to herein as “compound biomarkers”. 
     The biomarker values may be determined in any one of a number of ways. An exemplary method of determining biomarker values is described by the present inventors in WO 2015/117204, which is incorporated herein by reference in its entirety. In one example, the process of determining biomarker values can include measuring the biomarker values, for example by performing tests on the subject or on sample(s) taken from the subject. More typically however, the step of determining the biomarker values includes having an electronic processing device receive or otherwise obtain biomarker values that have been previously measured or derived. This could include for example, retrieving the biomarker values from a data store such as a remote database, obtaining biomarker values that have been manually inputted using an input device, or the like. The biomarker values are combined by the electronic processing device, for example by adding, multiplying, subtracting, or dividing biomarker values, to provide one or more derived biomarker values. In its simplest form, a single derived biomarker value may represent an indicator value that is at least partially indicative of an indicator representing a presence, absence or degree of a condition. Alternatively, a plurality of derived biomarker values may be combined using a combining function to provide an indicator value. in other embodiments, at least one derived biomarker value is combined with one or more biomarker values to provide a compound biomarker value representing an indicator value. The combining step is performed so that multiple biomarker values that are measured or derived can be combined into a single indicator value, providing a more useful and straightforward mechanism for allowing the indicator to be interpreted and hence used in diagnosing the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in the subject. 
     Accordingly, an indicator is determined using a combination of the plurality of biomarker values, the indicator being at least partially indicative of the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS. Assuming the method is performed using an electronic processing device, an indication of the indicator is optionally displayed or otherwise provided to the user. In this regard, the indication could be a graphical or alphanumeric representation of an indicator value. Alternatively however, the indication could be the result of a comparison of the indicator value to predefined thresholds or ranges, or alternatively could be an indication of the presence, absence, degree of BaSIRS, VaSIRS, PaSIRS or InSIRS, derived using the indicator. 
     In some embodiments in which a plurality of host response specific biomarkers and derived biomarker values are used, in order to ensure that an effective diagnosis can be determined, at least two of the biomarkers have a mutual correlation in respect of BaSIRS, VaSIRS, PaSIRS or InSIRS that lies within a mutual correlation range, the mutual correlation range being between ±0.9. This requirement means that the two biomarkers are not entirely correlated in respect of each other when considered in the context of the BaSIRS, VaSIRS, PaSIRS or InSIRS being diagnosed. In other words, at least two of the biomarkers in the combination respond differently as the condition changes, which adds significantly to their ability when combined to discriminate between at least two conditions, to diagnose the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in or of the subject. Representative biomarker combinations, which are also referred to herein as “derived biomarker combinations”, which meet these criteria, are listed in TABLES A to D. 
     Typically, the requirement that host response specific biomarkers have a low mutual correlation means that the biomarkers may relate to different biological attributes or domains such as, but not limited, to different molecular functions, different biological processes and different cellular components. Illustrative examples of molecular function include addition of, or removal of, one of more of the following moieties to, or from, a protein, polypeptide, peptide, nucleic acid (e.g., DNA, RNA): linear, branched, saturated or unsaturated alkyl (e.g., C 1 -C 24  alkyl); phosphate; ubiquitin; acyl; fatty acid, lipid, phospholipid; nucleotide base; hydroxyl and the like. Molecular functions also include signaling pathways, including without limitation, receptor signaling pathways and nuclear signaling pathways. Non-limiting examples of molecular functions also include cleavage of a nucleic acid, peptide, polypeptide or protein at one or more sites; polymerization of a nucleic acid, peptide, polypeptide or protein; translocation through a cell membrane (e.g., outer cell membrane; nuclear membrane); translocation into or out of a cell organelle (e.g., Golgi apparatus, lysosome, endoplasmic reticulum, nucleus, mitochondria); receptor binding, receptor signaling, membrane channel binding, membrane channel influx or efflux; and the like. 
     Illustrative examples of biological processes include: stages of the cell cycle such as meiosis, mitosis, cell division, prophase, metaphase, anaphase, telophase and interphase, stages of cell differentiation; apoptosis; necrosis; chemotaxis; immune responses including adaptive and innate immune responses, pro-inflammatory immune responses, autoimmune responses, tolerogenic responses and the like. Other illustrative examples of biological processes include generating or breaking down adenosine triphosphate (ATP), saccharides, polysaccharides, fatty acids, lipids, phospholipids, sphingolipids, glycolipids, cholesterol, nucleotides, nucleic acids, membranes (e.g., cell plasma membrane, nuclear membrane), amino acids, peptides, polypeptides, proteins and the like. Representative examples of cellular components include organelles, membranes, as for example noted above, and others. 
     It will be understood that the use of host response specific biomarkers that have different biological attributes or domains provides further information than if the biomarkers were related to the same or common biological attributes or domains. In this regard, it will be appreciated if the at least two biomarkers are highly correlated to each other, the use of both biomarkers would add little diagnostic improvement compared to the use of a single one of the biomarkers. Accordingly, an indicator-determining method of the present invention in which a plurality of biomarkers and biomarker values are used preferably employ biomarkers that are not well correlated with each other, thereby ensuring that the inclusion of each biomarker in the method adds significantly to the discriminative ability of the indicator. 
     Further, it will be understood that the use of a combination of host response specific biomarkers that have a low mutual correlation with pathogen specific biomarkers adds significantly to the positive and negative discriminative ability of the biomarker indicator. Accordingly, an indicator-determining method of the present invention in which a plurality of biomarkers and biomarker values are used preferably employ host response biomarkers that are not well correlated with each other in combination with pathogen specific biomarkers, thereby ensuring that the inclusion of each biomarker in the method adds significantly to the discriminative ability of the indicator. 
     Despite this, in order to ensure that the indicator can accurately be used in performing the discrimination between at least two conditions (e.g., BaSIRS, VaSIRS, PaSIRS or InSIRS) or the diagnosis of the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS, the indicator has a performance value that is greater than or equal to a performance threshold. The performance threshold may be of any suitable form but is to be typically indicative of an explained variance of at least 0.3, or an equivalent value of another performance measure. 
     Suitably, a combination of biomarkers is employed, which includes (1) host response specific biomarkers having a mutual correlation between ±0.9 and which combination provides an explained variance of at least 0.3, and; (2) pathogen specific biomarkers. In specific embodiments, host response specific biomarkers are used in combination with pathogen specific biomarkers when greater discriminatory power (positive or negative predictive value) is required. Also, this typically allows an indicator to be defined that is suitable for ensuring that an accurate discrimination and/or diagnosis can be obtained whilst minimizing the number of biomarkers that are required. Typically the mutual correlation range is one of ±0.8; ±0.7; ±0.6; ±0.5; ±0.4; ±0.3; ±0.2; and, ±0.1. Typically each BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker has a condition correlation with the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS that lies outside a condition correlation range, the condition correlation range being between ±0.3 and more typically ±0.9; ±0.8; ±0.7; ±0.6; ±0.5; and, ±0.4. Typically the performance threshold is indicative of an explained variance of at least one of 0.4; 0.5; 0.6; 0.7; 0.8; and 0.9. 
     It will be understood that in this context, the biomarkers used within the above-described method can define a biomarker profile for BaSIRS, VaSIRS, PaSIRS or InSIRS, which includes a minimal number of biomarkers, whilst maintaining sufficient performance to allow the biomarker profile to be used in making a clinically relevant diagnosis or differentiation. Minimizing the number of biomarkers used minimizes the costs associated with performing diagnostic tests and in the case of nucleic acid expression products, allows the test to be performed utilizing relatively straightforward techniques such as nucleic acid array, and polymerase chain reaction (PCR) processes, or the like, allowing the test to be performed rapidly in a clinical environment. 
     Furthermore, producing a single indicator value allows the results of the test to be easily interpreted by a clinician or other medical practitioner, so that test can be used for reliable diagnosis in a clinical environment. 
     Processes for generating suitable host response biomarker profiles are described for example in WO 2015/117204, which uses the term “biomarker signature” in place of “biomarker profile” as defined herein. It will be understood, therefore, that terms “biomarker profile” and “biomarker signature” are equivalent in scope. The biomarker profile-generating processes disclosed in WO 2015/117204 provide mechanisms for selecting a combination of biomarkers, and more typically derived biomarkers, that can be used to form a biomarker profile, which in turn can be used in diagnosing the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS. In this regard, the biomarker profile defines the biomarkers that should be measured (i.e., the profile biomarkers), how derived biomarker values should be determined for measured biomarker values, and then how biomarker values should be subsequently combined to generate an indicator value. The biomarker profile can also specify defined indicator value ranges that indicate a particular presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS. 
     Processes for generating suitable pathogen specific biomarkers for bacteria are described for example in WO 2014/190394. The bacterial pathogen specific biomarkers disclosed in WO 2014/190394 provide mechanisms for selecting a combination of biomarkers that can be used to form a biomarker profile, which in turn can be used in diagnosing the presence, absence or degree of BIP, and for broadly categorizing the type of bacteria detected (if detected). Processes for generating suitable pathogen specific biomarkers for viruses are described herein and in the scientific literature. The virus pathogen specific biomarkers disclosed herein provide mechanisms for selecting a combination of biomarkers that can be used to form a biomarker profile, which in turn can be used in diagnosing the presence, absence or degree of VIP, and for broadly categorizing the type of viruses(s) detected (if detected) and for determining the presence, absence or degree of VIP that can be treated using currently available anti-viral therapies. Processes for generating suitable pathogen specific biomarkers for protozoans are described herein. The protozoan antigen specific biomarkers disclosed herein provide mechanisms for selecting a combination of biomarkers that can be used to form a biomarker profile, which in turn can be used in diagnosing the presence, absence or degree of PIP, and for broadly categorizing the type of protozoan detected (if detected). 
     Using the above-described methods a number of host response specific biomarkers have been identified that are particularly useful for assessing a likelihood that a subject has a presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject. Further, using the above-described methods a number of pathogen specific biomarkers have been identified that are particularly useful when combined with host response specific biomarkers for assessing a likelihood that a subject has a presence, absence or degree of bacterial, viral or protozoal infection in a subject. Combinations of host response specific biomarkers and pathogen-specific biomarkers are referred to herein as “compound biomarkers”. As used herein, the term “compound biomarkers” refers to a combination of host response specific biomarkers and at least one pathogen specific biomarker. Generally a host response specific biomarker is a biomarker of the host&#39;s immune system, which is altered, or whose level of expression is altered, as part of an inflammatory response to damage or insult resulting from a bacterial, viral or protozoal infection. A pathogen specific biomarker is a molecule or group of molecules of a pathogen, which is specific to a particular category, genus or type of bacteria, virus or protozoan. Compound biomarkers for BaSIRS, VaSIRS, PaSIRS or InSIRS are suitably a combination of both expression products of host genes (also referred to interchangeably herein as “BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker genes”) and pathogen specific biomarkers, including polynucleotide, polypeptide, carbohydrate, lipid, lipopolysaccharide, metabolite. As used herein, polynucleotide expression products of BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker genes are referred to herein as “BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polynucleotides.” Polypeptide expression products of the BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker genes are referred to herein as “BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polypeptides.” 
     BaSIRS biomarkers are suitably selected from expression products of any one or more of the following BaSIRS genes: ADAM19, ADM, ALPL, CAMK1D, CASS4, CBLL1, CCNK, CD82, CLEC7A, CNNM3, COX15, CR1, DENND3, DOCK5, ENTPD7, EPHB4, EXTL3, FAM129A, FBXO28,  FIG. 4 , FOXJ3, GAB2, GALNT2, GAS7, GCC2, GRK5, HAL, HCLS1, HK3, ICK, IGFBP7, IK, IKZF5, IL2RB, IMPDH1, INPP5D, ITGA7, JARID2, KIAA0101, KIAA0355, KIAA0907, KLRD1, KLRF1, LAG3, LEPROTL1, LPIN2, MBIP, MCTP1, MGAM, MME, NCOA6, NFIC, NLRP1, NMUR1, NOV, NPAT, OPLAH, PARP8, PCOLCE2, PDGFC, PDS5B, PHF3, PIK3C2A, PLA2G7, POGZ, PRKD2, PRKDC, PRPF38B, PRSS23, PYHIN1, QRICH1, RAB32, RBM15, RBM23, RFC1, RNASE6, RUNX2, RYK, SAP130, SEMA4D, SIDT1, SMPDL3A, SPIN1, ST3GAL2, SYTL2, TGFBR3, TLE3, TLR5, TMEM165, TSPO, UTRN, YPEL1, ZFP36L2, ZHX2. Non-limiting examples of nucleotide sequences for these BaSIRS biomarkers are listed in SEQ ID NOs: 1-94. Non-limiting examples of amino acid sequences for these BaSIRS biomarkers are listed in SEQ ID NOs: 95-188. 
     VaSIRS biomarkers are suitably selected from expression products of any one or more of the following VaSIRS genes: ABAT, ABHD2, ABI1, ABLIM1, ACAA1, ACAP2, ACVR1B, AIF1, ALDH3A2, ANKRD49, AOAH, APBB1IP, APLP2, ARAP1, ARHGAP15, ARHGAP25, ARHGAP26, ARHGEF2, ARRB1, ARRB2, ASAP1, ATAD2B, ATF7IP2, ATM, ATP6V1B2, BACH1, BANP, BAZ2B, BCL2, BEX4, BMP2K, BRD1, BRD4, BTG1, C19orf66, C2orf68, CAMK1D, CAMK2G, CAP1, CASC3, CASP8, CBX7, CCND3, CCNG2, CCNT2, CCR7, CD37, CD93, ADGRE5, CDIPT, CEP170, CEP68, CHD3, CHMP1B, CHMP7, CHST11, CIAPIN1, CLEC4A, CLK4, CNPY3, CREB1, CREBBP, CRLF3, CRTC3, CSAD, CSF2RB, CSNK1D, CST3, CTBP2, CTDSP2, CUL1, CYLD, CYTH4, DCP2, DDX60, DGCR2, DGKA, DHX58, DIDO1, DOCK9, DOK3, DPEP2, DPF2, EIF2AK2, EIF3H, EMR2, ERBB2IP, ETS2, FAIM3, FAM134A, FAM65B, FBXO11, FBXO9, FCGRT, FES, FGR, FLOT2, FNBP1, FOXJ2, FOXO1, FOXO3, FRY, FYB, GABARAP, GCC2, GMIP, GNA12, GNAQ, GOLGA7, GPBP1L1, GPR97, GPS2, GPSM3, GRB2, GSK3B, GYPC, HAL, HCK, HERCS, HERC6, HGSNAT, HHEX, HIP1, HPCAL1, HPS1, ICAM3, IFI44, IFI6, IFIH1, IGSF6, IKBKB, IL10RB, IL13RA1, IL16, IL1RAP, IL27RA, IL4R, IL6R, IL6ST, INPP5D, IQSEC1, ISG15, ITGAX, ITGB2, ITPKB, ITSN2, JAK1, KBTBD2, KIAA0232, KIAA0247, KIAA0513, KLF3, KLF6, KLF7, KLHL2, LAP3, LAPTM5, LAT2, LCP2, LDLRAP1, LEF1, LILRA2, LILRB3, LIMK2, LPAR2, LPIN2, LRMP, LRP10, LST1, LTB, LYL1, LYN, LYST, MAML1, MANSC1, MAP1LC3B, MAP3K11, MAP3K3, MAP3K5, MAP4K4, MAPK1, MAPK14, MAPRE2, MARCH7, MARCH8, MARK3, MAST3, MAX, MBP, MCTP2, MED13, MEF2A, METTL3, MKLN1, MKRN1, MMP25, MORC3, MOSPD2, MPPE1, MSL1, MTMR3, MX1, MXI1, MYC, N4BP1, NAB1, NACA, NCBP2, NCOA1, NCOA4, NDE1, NDEL1, NDFIP1, NECAP2, NEK7, NFKB1, NFYA, NLRP1, NOD2, NOSIP, NPL, NR3C1, NRBF2, NSUN3, NUMB, OAS2, OASL, OGFRL1, OSBPL11, OSBPL2, PACSIN2, PAFAH1B1, PARP12, PBX3, PCBP2, PCF11, PCNX, PDCD6IP, PDE3B, PECAM1, PFDNS, PGS1, PHC2, PHF11, PHF2, PHF20, PHF20L1, PHF3, PIAS1, PIK3IP1, PINK1, PISD, PITPNA, PLEKHO1, PLEKHO2, PLXNC1, POLB, POLD4, POLR1D, PPARD, PPM1F, PPP1R11, PPP1R2, PPP2R5A, PPP3R1, PPP4R1, PRKAA1, PRKAG2, PRKCD, PRMT2, PRUNE, PSAP, PSEN1, PSTPIP1, PTAFR, PTEN, PTGER4, PTPN6, PTPRE, PUM2, R3HDM2, RAB11FIP1, RAB14, RAB31, RAB4B, RAB7A, RAF1, RALB, RARA, RASSF2, RBM23, RBMS1, RC3H2, RERE, RGS14, RGS19, RHOG, RIN3, RNASET2, RNF130, RNF141, RNF146, RNF19B, RPL10A, RPL22, RPS6KA1, RPS6KA3, RSAD2, RTN3, RTP4, RXRA, RYBP, SAFB2, SATB1, SEC62, SEMA4D, SERINC3, SERINCS, SERTAD2, SESN1, SETD2, SH2B3, SH2D3C, SIRPA, SIRPB1, SLCO3A1, SMAD4, SNN, SNRK, SNX27, SOAT1, SORL1, SOS2, SP3, SSBP2, SSFA2, ST13, ST3GAL1, STAM2, STAT1, STAT5A, STAT5B, STK38L, STX10, STX3, STX6, SYPL1, TAP1, TFE3, TFEB, TGFBI, TGFBR2, TGOLN2, TIAM1, TLE3, TLE4, TLR2, TM2D3, TMBIM1, TMEM127, TMEM204, TNFRSF1A, TNFSF13, TNIP1, TNK2, TNRC6B, TOPORS, TRAK1, TREM1, TRIB2, TRIMS, TRIOBP, TSC22D3, TYK2, TYROBP, UBE2D2, UBE2L6, UBN1, UBQLN2, UBXN2B, USP10, USP15, USP18, USP4, UTP14A, VAMP3, VAV3, VEZF1, VPS8, WASF2, WBP2, WDR37, WDR47, XAF1, XPC, XP06, YPEL5, YTHDF3, ZBP1, ZBTB18, ZC3HAV1, ZDHHC17, ZDHHC18, ZFAND5, ZFC3H1, ZFYVE16, ZMIZ1, ZNF143, ZNF148, ZNF274, ZNF292, ZXDC, ZYX. Non-limiting examples of nucleotide sequences for these VaSIRS biomarkers are listed in SEQ ID NOs: 189-601. Non-limiting examples of amino acid sequences for these VaSIRS biomarkers are listed in SEQ ID NOs: 602-1013. 
     PaSIRS biomarkers are suitably selected from expression products of any one or more of the following PaSIRS genes: ACSL4, ADK, ADSL, AHCTF1, APEX1, ARHGAP17, ARID1A, ARIH2, ASXL2, ATOX1, ATP2A2, ATP6V1B2, BCL11A, BCL3, BCL6, C3AR1, CAMK2G, CCND3, CCR7, CD52, CD55, CD63, CEBPB, CEP192, CHN2, CLIP4, CNOT7, CSNK1G2, CSTB, DNAJC10, EN01, ERLIN1, ETV6, EXOSC10, EXOSC2, EXOSC9, FBL, FBX011, FCER1G, FGR, FLII, FLOT1, FNTA, G6PD, GLG1, GNG5, GPI, GRINA, HCK, HERC6, HLA-DPA1, IL10RA, IMP3, IRF1, IRF8, JUNB, KIF1B, LAP3, LDHA, LY9, METAP1, MGEA5, MLLT10, MYD88, NFIL3, NFKBIA, NOSIP, NUMB, NUP160, PCBP1, PCID2, PCMT1, PGD, PLAUR, PLSCR1, POMP, PREPL, PRKCD, RAB27A, RAB7A, RALB, RBMS1, RITZ, RPL15, RPL22, RPL9, RPS14, RPS4X, RTN4, SEH1L, SERBP1, SERPINB1, SERTAD2, SETX, SH3GLB1, SLAMF7, SOCS3, SORT1, SPI1, SQRDL, STAT3, SUCLG2, TANK, TAP1, TCF4, TCIRG1, TIMP2, TMEM106B, TMEM50B, TNIP1, TOP2B, TPP1, TRAF3IP3, TRIB1, TRIT1, TROVE2, TRPC4AP, TSPO, TTC17, TUBA1B, UBE2L6, UFM1, UPP1, USP34, VAMP3, WARS, WAS, ZBED5, ZMYND11, ZNF266. Non-limiting examples of nucleotide sequences for these PaSIRS biomarkers are listed in SEQ ID NOs: 1014-1143. Non-limiting examples of amino acid sequences for these PaSIRS biomarkers are listed in SEQ ID NOs: 1144-1273. 
     InSIRS biomarkers are suitably selected from expression products of any one or more of the following InSIRS genes: ADAM19, ADRBK2, ADSL, AGA, AGPAT5, ANK3, ARHGAP5, ARHGEF6, ARL6IP5, ASCC3, ATP8A1, ATXN3, BCKDHB, BRCC3, BTN2A1, BZW2, C14orf1, CD28, CD40LG, CD84, CDA, CDK6, CDKN1B, CKAP2, CLEC4E, CLOCK, CLUAP1, CPA3, CREB1, CYP4F3, CYSLTR1, DIAPH2, EFHD2, EFTUD1, EIF5B, ENOSF1, ENTPD1, ERCC4, ESF1, EXOC7, EXTL3, FASTKD2, FCF1, FUT8, G3BP1, GAB2, GGPS1, GOLPH3L, HAL, HEATR1, HEBP2, HIBCH, HLTF, HRH4, IDE, IGF2R, IKBKAP, IP07, IQCB1, IQSEC1, KCMF1, KIAA0391, KLHL20, KLHL24, KRIT1, LANCL1, LARP1, LARP4, LRRC8D, MACF1, MANEA, MDH1, METTL5, MLLT10, MRPS10, MT01, MTRR, MXD1, MYH9, MY09A, NCBP1, NEK1, NFX1, NGDN, NIP7, NOL10, NOL8, NOTCH2, NR2C1, PELI1, PEX1, PHC3, PLCL2, POLR2A, PRKAB2, PRPF39, PRUNE, PSMDS, PTGS1, PWP1, RAB11FIP2, RABGAP1L, RAD50, RBM26, RCBTB2, RDX, REPS1, RFC1, RGS2, RIOK2, RMND1, RNF170, RNMT, RRAGC, S100PBP, SIDT2, SLC35A3, SLC35D1, SLCO3A1, SMC3, SMC6, STK17B, SUPT7L, SYNE2, SYT11, TBCE, TCF12, TCF7L2, TFIP11, TGS1, THOC2, TIA1, TLK1, TMEM87A, TNFSF8, TRAPPC2, TRIP11, TTC17, TTC27, VEZT, VNN3, VPS13A, VPS13B, VPS13C, WDR70, XP04, YEATS4, YTHDC2, ZMYND11, ZNF507, ZNF562. Non-limiting examples of nucleotide sequences for these InSIRS biomarkers are listed in SEQ ID NOs: 1274-1424. Non-limiting examples of amino acid sequences for these InSIRS biomarkers are listed in SEQ ID NOs: 1425-1575. 
     The present inventors have determined that certain BaSIRS biomarkers have strong diagnostic performance when combined with one or more other BaSIRS biomarkers. In particular, pairs of BaSIRS biomarkers have been identified, each of which forms a BaSIRS derived biomarker combination that is advantageously not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, and which is thus useful as a BaSIRS indicator of high specificity. Accordingly, in specific embodiments, an indicator is determined that correlates to a derived biomarker value corresponding to a ratio of BaSIRS biomarker values, which can be used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS. Exemplary BaSIRS derived biomarker combinations are listed in TABLE A. 
     It has also been determined that certain VaSIRS biomarkers have strong diagnostic performance when combined with one or more other VaSIRS biomarkers. In particular embodiments, pairs of VaSIRS biomarkers are employed, each of which forms a VaSIRS derived biomarker combination that is advantageously not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, and which is thus useful as a VaSIRS indicator of high specificity. In non-limiting examples of this type, an indicator is determined that correlates to a derived biomarker value corresponding to a ratio of VaSIRS biomarker values, which can be used in assessing a likelihood of a subject having a presence, absence or degree of VaSIRS. Representative VaSIRS derived biomarker combinations are listed in TABLE B. 
     Additionally, certain PaSIRS biomarkers have been identified with strong diagnostic performance when combined with one or more other PaSIRS biomarkers. In certain embodiments, pairs of PaSIRS biomarkers are utilized, each of which forms a VaSIRS derived biomarker combination that is advantageously not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, and which is useful, therefore, as a PaSIRS indicator of high specificity. Accordingly, in representative examples, an indicator is determined that correlates to a derived biomarker value corresponding to a ratio of PaSIRS biomarker values, which can be used in assessing a likelihood of a subject having a presence, absence or degree of PaSIRS. Non-limiting PaSIRS derived biomarker combinations are listed in TABLE C. 
     The present inventors have also determined that certain InSIRS biomarkers have strong diagnostic performance when combined with one or more other InSIRS biomarkers. In particular, pairs of InSIRS biomarkers have been identified, each of which forms an InSIRS derived biomarker combination that is advantageously not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS, and which is thus useful as a InSIRS indicator of high specificity. Accordingly, in specific embodiments, an indicator is determined that correlates to a derived biomarker value corresponding to a ratio of InSIRS biomarker values, which can be used in assessing a likelihood of a subject having a presence, absence or degree of InSIRS. Exemplary InSIRS derived biomarker combinations are listed in TABLE D. 
     In these embodiments, the indicator-determining methods suitably include: (1) determining a pair of SIRS biomarker values, wherein each biomarker value is a value measured for at least one corresponding SIRS biomarker (e.g., BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker) of the subject and is at least partially indicative of a level of the SIRS biomarker in a sample taken from the subject; and (2) combining the biomarker values using a function. The function is suitably selected from multiplication, subtraction, addition or division. In particular embodiments, the function is a division and one member of the pair of host response specific biomarker values is divided by the other member of the pair to provide a ratio of levels of the pair of SIRS biomarkers. Thus, in these embodiments, if the host response SIRS biomarker values denote the levels of a pair of SIRS biomarkers (e.g., BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers), then the host response SIRS ‘derived biomarker’ values will be based on a ratio of the host response SIRS biomarker values. However, in other embodiments in which the host response SIRS biomarker values represent amplification amounts, or cycle times (e.g., PCR cycle times), which are a logarithmic representation of the level of the SIRS biomarkers within a sample, then the SIRS biomarker values may be combined in some other manner, such as by subtracting the cycle times to determine a host response derived biomarker value indicative of a ratio of the levels of the SIRS biomarkers. 
     In specific embodiments, the indicator-determining methods involve: (1) determining a first derived biomarker value using a first pair of host response specific biomarker values that are measured for a corresponding first and second SIRS biomarkers in a sample, wherein the first and second SIRS biomarkers are selected from biomarkers of a single SIRS etiological type (e.g., one of BaSIRS, VaSIRS, PaSIRS or inSIRS biomarkers), the first derived biomarker value being indicative of a ratio of levels of the first and second SIRS biomarkers in the sample, (2) determining a second derived biomarker value using a second pair of host response specific biomarker values that are measured for a corresponding third and fourth SIRS biomarkers in the sample, wherein the third and fourth SIRS biomarkers are selected from SIRS biomarkers of the same etiological type as the first and second SIRS biomarkers, the second derived biomarker value being indicative of a ratio of levels of the third and fourth SIRS biomarkers in the sample; and optionally (3) determining a third derived biomarker value using a third pair of host response specific biomarker values that are measured for a corresponding fifth and sixth SIRS biomarkers in the sample, wherein the fifth and sixth SIRS biomarkers are selected from SIRS biomarkers of a same etiological type as the first and second SIRS biomarkers, the third derived biomarker value being indicative of a ratio of levels of the fifth and sixth SIRS biomarkers in the sample. 
     In advantageous embodiments that provide higher levels of specificity for determining the indicator, the indicator-determining methods may further comprise: determining at least one pathogen specific biomarker value, wherein each pathogen specific biomarker value is a value measured for at least one corresponding pathogen specific biomarker (e.g., a BIP, VIP or PIP biomarker) of the subject and is at least partially indicative of a level of the pathogen specific biomarker in the sample. The pathogen to which the pathogen specific biomarker relates is typically one that associates with a SIRS of the same etiological type to which the host response specific biomarkers relate. Representative pathogen specific biomarker values are suitably selected from presence/absence, level, or PCR cycle time, and if positive, to include a descriptor of the pathogen category (e.g., Gram positive or Gram negative, virus type or protozoan species). Thus, the use of BaSIRS biomarkers in the indicator-determining methods of the present invention can be augmented through use of one or more BIP biomarkers to provide host response specific derived BaSIRS biomarker values and at least one BIP biomarker value to thereby determine a compound biomarker value that is at least partially indicative of the presence, absence or degree of BaSIRS. Likewise, the use of VaSIRS biomarkers in the indicator-determining methods of the present invention can be augmented through use of one or more VIP biomarkers to provide host response specific VaSIRS derived biomarker values and at least one VIP biomarker value to thereby determine a compound biomarker value that is at least partially indicative of the presence, absence or degree of VaSIRS. Similarly, the use of PaSIRS biomarkers in the indicator-determining methods of the present invention can be augmented through use of one or more PIP biomarkers to provide host response specific PaSIRS derived biomarker values and at least one PIP biomarker value to thereby determine a compound biomarker value that is at least partially indicative of the presence, absence or degree of PaSIRS. 
     Typically the pathogen specific biomarkers belong to pathogens associated with the development or progression of SIRS. A limited number of microorganisms (bacteria, viruses, protozoans) cause disease in humans, with only few causing the majority of infectious diseases, even fewer causing SIRS, and still even fewer number causing bacteremia, viremia or protozoan parasitemia. TABLE 1 lists common bacterial, viral and protozoal pathogens associated with human BaSIRS, VaSIRS and PaSIRS that can also be found in peripheral blood (in whole or part), respectively. Such pathogens have multiple methods of interacting with the host and its cells and if a host mounts a systemic inflammatory response to an infection it means that the immune system has been exposed to sufficient levels of novel pathogen molecules. Representative types of pathogen molecules that can elicit a systemic inflammatory response include proteins, nucleic acids (RNA and/or DNA), lipoproteins, lipoteichoic acid and lipopolysaccharides, many of which can be detected (and typed) circulating in blood at some stage during the disease pathogenesis. 
     Molecular nucleic acid-based tests have been developed to detect the major sepsis-causing bacterial pathogens in whole blood from patients with suspected sepsis (e.g., SeptiFast® from Roche, Iridica® from Abbott, Sepsis Panel from Biofire (Biomerieux), Prove-it® Sepsis from Mobidiag). Reference also can be made to U.S. Pat. Appl. Pub. No. 2016/0032364, which discloses methods of detecting and distinguishing a myriad of bacterial species through detection of 16S ribosomal ribonucleic acid (rRNA) using antisense probes. An alternative method is disclosed in U.S. Pat. Appl. Pub. No. 2014/0249037, which characterizes bacteria by amplifying bacterial 16S rRNA and characterizing the bacteria based on the 16S rRNA gene sequence. 
     In specific embodiments, bacterial pathogen Gram status (i.e., Gram-positive or Gram-negative) is detected using methods and kits disclosed in U.S. Pat. Appl. Pub. No. 2016/0145696, which is incorporated herein by reference, through interrogation of polymorphisms at nucleotide positions of bacterial 16S rRNA that correspond to positions 396 and 398 of the  Escherichia coli  16S rRNA gene. Positions corresponding to positions 396 and 398 of SEQ ID NO:1576 in any prokaryotic 16S rRNA gene (or 16S rRNA molecule or DNA copy thereof) are readily identifiable by alignment with the  E. coli  16S rRNA gene set forth in SEQ ID NO:1576. The general rules for differentiating Gram-positive and Gram-negative bacteria that can cause BaSIRS using these two pathogen biomarker SNP molecules are depicted in TABLE E. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE E 
               
               
                   
                   
               
               
                   
                 Gram Status 
                 SNP 396 
                 SNP 398 
               
               
                   
                   
               
             
            
               
                   
                 Negative 
                 C 
                 T/A/C 
               
               
                   
                 Positive 
                 A/T/G 
                 C 
               
               
                   
                   
               
            
           
         
       
     
     Thus, the pathogen biomarker SNPs in TABLE E provide the means for determining the Gram status of a bacterium in a sample by analyzing nucleic acid from the sample for SNPs in the 16S rRNA gene (or 16S rRNA or DNA copy thereof) at positions corresponding to positions 396 and 398 of the 16S rRNA gene set forth in SEQ ID NO:1576, wherein a C at position 396 and a T, A or C at position 398 indicates that the bacterium in the sample is a Gram-negative bacterium; and an A, T or G at position 396 and a C at position 398 indicates that the bacterium is a Gram-positive bacterium. Bacteria that can be classified as Gram-positive or Gram-negative using SNPs at positions corresponding to 396 and 398 of the  E. coli  16S rRNA gene set forth in SEQ ID NO:1576 include, for example,  Acinetobacter  spp.,  Actinobacillus  spp.,  Actinomadura  spp.,  Actinomyces  spp.,  Actinoplanes  spp.,  Aeromonas  spp.,  Agrobacterium  spp.,  Alistipes  spp.,  Anaerococcus  spp.,  Arthrobacter  spp.,  Bacillus  spp.,  Brucella  spp.,  Bulleidia  spp.,  Burkholderia  spp.,  Cardiobacterium  spp.,  Citrobacter  spp.,  Clostridium  spp.,  Corynebacterium  spp.,  Dermatophilus  spp.,  Dorea  spp.,  Edwardsiella  spp.,  Enterobacter  spp.,  Enterococcus  spp.,  Erysipelothrix  spp.,  Escherichia  spp.,  Eubacterium  spp.,  Faecalibacterium  spp.,  Filifactor  spp.,  Finegoldia  spp.,  Flavobacterium  spp.,  Gallicola  spp.,  Haemophilus  spp.,  Helcococcus  spp.,  Holdemania  spp.,  Hyphomicrobium  spp.,  Klebsiella  spp.,  Lactobacillus  spp.,  Legionella  spp.,  Listeria  spp.,  Methylobacterium  spp.,  Micrococcus  spp.,  Micromonospora  spp.,  Mobiluncus  spp.,  Moraxella  spp.,  Morganella  spp.,  Mycobacterium  spp.,  Neisseria  spp.,  Nocardia  spp.,  Paenibacillus  spp.,  Parabacteroides  spp.,  Pasteurella  spp.,  Entomophile&#39;s  spp.,  Peptostreptococcus  spp.,  Planococcus  spp.,  Planomicrobium  spp.,  Plesiomonas  spp.,  Porphyromonas  spp.,  Prevotella  spp.,  Propionibacterium  spp.,  Proteus  spp.,  Providentia  spp.,  Pseudomonas  spp.,  Ralstonia  spp.,  Rhodococcus  spp.,  Roseburia  spp.,  Ruminococcus  spp.,  Salmonella  spp.,  Sedimentibacter  spp.,  Serratia  spp.,  Shigella  spp.,  Solobacterium  spp.,  Sphingomonas  spp.,  Sporanaerobacter  spp.,  Staphylococcus  spp.,  Stenotrophomonas  spp.,  Streptococcus  spp.,  Streptomyces  spp.,  Tissierella  spp.,  Vibrio  spp., and  Yersinia  spp. Accordingly, in instances in which the pathogen specific biomarker is a bacterial biomarker, the biomarker is preferably a 16S rRNA gene, more preferably polymorphisms at nucleotide positions of bacterial 16S rRNA that correspond to positions 396 and 398 of the  Escherichia coli  16S rRNA gene, which can be used to provide the Gram status of a bacterial pathogen. 
     For virus detection, numerous sensitive and specific assays are available in the art. For example, amplification of viral DNA and RNA (e.g., PCR) as well as viral antigen detection assays are known that are rapid and do not require lengthy incubation periods needed for viral isolation in cell cultures. To cover the possibility of a mixed infection, as well as to cover multiple possible viral causes or strains, there are commercially available assays capable of detecting more than one virus and/or strain at a time (e.g., BioMerieux, BioFire, FilmArray®, Respiratory Panel; Luminex, xTAG® Respiratory Viral Panel). Further, there are techniques that allow for amplification of viral DNA of unknown sequence which could be useful in situations where the clinical signs are generalized, for viruses with high mutation rates, for new and emerging viruses, or for detecting biological weapons of man-made nature (Clem et al.,  Virol J  4: 65, 2007; Liang et al.,  Science  257(5072:967-971), 1992; Nie X et al.,  J Virol Methods  91(1):37-49, 2001; Ralph et al.,  Proc Natl Acad Sci USA  90(22):10710-10714, 1993). Further, a microarray has been designed to detect every known virus for which there is DNA sequence information in GenBank (called “Virochip”) (Greninger et al.,  PLoS ONE,  5(10), e13381, 2010; Chiu et al.,  Proc Natl Acad Sci USA  105: 14124-14129, 2008). 
     In some instances, detection of host antibodies to an infecting virus remains the diagnostic gold standard, because either the virus cannot be grown, or the presence of virus in a biological fluid is transient (e.g., arboviral infections) and therefore cannot be detected at times when the patient is symptomatic. In some instances the ratio of IgM to IgG antibodies can be used to determine the recency of virus infection. IgM is usually produced early in the immune response and is non-specific, whereas IgG is produced later in the immune response and is specific. Examples of the use of this approach include the diagnosis of hepatitis E (Tripathy et al.,  PLoS ONE,  7(2), e31822, 2012), dengue (SA-Ngasang et al.,  Epidemiology and Infection,  134(04), 820, 2005), and Epstein-Barr Virus (Hess, R. D.  Journal of Clinical Microbiology,  42(8), 3381-3387, 2004). 
     In specific embodiments, viruses that are capable of causing pathology in humans, as for example those listed in TABLE 1, which are capable of causing SIRS, and cause a viremia are detected and/or quantified using any suitable nucleic acid detection and/or amplification assay, with oligonucleotide primers and/or probes listed in TABLE F. 
     
       
         
           
               
               
               
               
             
               
                 TABLE F 
               
               
                   
               
               
                 Reagent 
                 5′-3′ Sequence 
                 SEQ ID NO. 
                 Virus Detected 
               
               
                   
               
             
            
               
                 Forward (F) 
                 CATC/TCTGTTGTATATGAGGCCCAT 
                 1577 
                 Influenza A 
               
               
                   
               
               
                 Reverse (R) 
                 GGACTGCAGCGTAGACGCTT 
                 1578 
                 Influenza A 
               
               
                   
               
               
                 Probe (P) 
                 CTCAGTTATTCTGCTGGTGCACTTGCCA 
                 1579 
                 Influenza A 
               
               
                   
               
               
                 F 
                 AAATACGGTGGATTAAATAAAAGCAA 
                 1580 
                 Influenza B 
               
               
                   
               
               
                 R 
                 CCAGCAATAGCTCCGAAGAAA 
                 1581 
                 Influenza B 
               
               
                   
               
               
                 P 
                 CACCCATATTGGGCAATTTCCTATGGC 
                 1582 
                 Influenza B 
               
               
                   
               
               
                 F 
                 ATCCCTACAATCCCCAAAGTCAAGGAGT 
                 1583 
                 HIV-1 
               
               
                   
               
               
                 R 
                 CCTGCACTGTACCCCCCAATCC 
                 1584 
                 HIV-1 
               
               
                   
               
               
                 P 
                 ACAGCAGTACAAATGGCA 
                 1585 
                 HIV-1 
               
               
                   
               
               
                 F 
                 ACTGATGGCAGTTCATTGCATGAATTTTAAAAG 
                 1586 
                 HIV-2 
               
               
                   
               
               
                 R 
                 GGCCATTGTTTAACTTTTGGGCCATCCA 
                 1587 
                 HIV-2 
               
               
                   
               
               
                 P 
                 ATAAGCCCCATAGCC 
                 1588 
                 HIV-2 
               
               
                   
               
               
                 F 
                 GGACCCCTGCTCGTGTTACA 
                 1589 
                 HBV 
               
               
                   
               
               
                 R 
                 GAGAGAAGTCCACCMCGAGTCTAG 
                 1590 
                 HBV 
               
               
                   
               
               
                 P 
                 TGTTGACAARAATCCTCACCATACCRCAGA 
                 1591 
                 HBV 
               
               
                   
               
               
                 F 
                 GTGGTCTGCGGAACCGGTGA 
                 1592 
                 HCV 
               
               
                   
               
               
                 R 
                 CGCAAGCACCCTATCAGGCAGT 
                 1593 
                 HCV 
               
               
                   
               
               
                 P 
                 CCGAGTAGTGTTGGGTCGCGAAAGG 
                 1594 
                 HCV 
               
               
                   
               
               
                 F-HSV-1 
                 GCAGTTTACGTACAACCACATACAGC 
                 1595 
                 HSV-1 
               
               
                   
               
               
                 F-HSV-2 
                 TGCAGTTTACGTATAACCACATACAGC 
                 1596 
                 HSV-2 
               
               
                   
               
               
                 R 
                 AGCTTGCGGGCCTCGTT 
                 1597 
                 HSV-1/2 
               
               
                   
               
               
                 P-HSV-1 
                 CGGCCCAACATATCGTTGACATGGC 
                 1598 
                 HSV-1 
               
               
                   
               
               
                 P-HSV-2 
                 CGCCCCAGCATGTCGTTCACGT 
                 1599 
                 HSV-2 
               
               
                   
               
               
                 F 
                 AACAGATGTAAGCAGCTCCGTTATC 
                 1600 
                 RSV 
               
               
                   
               
               
                 R 
                 CGATTTTTATTGGATGCTGTACATTT 
                 1601 
                 RSV 
               
               
                   
               
               
                 P 
                 TGCCATAGCATGACACAATGGCTCCT 
                 1602 
                 RSV 
               
               
                   
               
               
                 F 
                 TCCTCCGGCCCCTGAAT 
                 1603 
                 Rhinovirus 
               
               
                   
               
               
                 R 
                 GAAACACGGACACCCAAAGTAGT 
                 1604 
                 Rhinovirus 
               
               
                   
               
               
                 P 
                 YGGCTAACCTWAACCC 
                 1605 
                 Rhinovirus 
               
               
                   
               
               
                 F 
                 CCGCTCCTACCTGCAATATCA 
                 1606 
                 EBV 
               
               
                   
               
               
                 R 
                 GGAAACCAGGGAGGCAAATG 
                 1607 
                 EBV 
               
               
                   
               
               
                 P 
                 TGCAGCTTTGACGATGG 
                 1608 
                 EBV 
               
               
                   
               
               
                 F 
                 GCTGACGCGTTTGGTCATC 
                 1609 
                 CMV 
               
               
                   
               
               
                 R 
                 ACGATTCACGGAGCACCAG 
                 1610 
                 CMV 
               
               
                   
               
               
                 P 
                 TCGGCGGATCACCACGTTCG 
                 1611 
                 CMV 
               
               
                   
               
               
                 F 
                 TCGAAATAAGCATTAATAGGCACACT 
                 1612 
                 HHV6 
               
               
                   
               
               
                 R 
                 CGGAGTTAAGGCATTGGTTGA 
                 1613 
                 HHV6 
               
               
                   
               
               
                 P 
                 CCAAGCAGTTCCGTTTCTCTGAGCCA 
                 1614 
                 HHV6 
               
               
                   
               
               
                 F 
                 CASRGTGATCAAARTGRRARYGAGCT 
                 1615 
                 Measles 
               
               
                   
               
               
                 R 
                 CCTGCCATGGYYTGCA 
                 1616 
                 Measles 
               
               
                   
               
               
                 P 
                 TCYGATRCAGTRTCAAT 
                 1617 
                 Measles 
               
               
                   
               
               
                 F 
                 TCAGCGATCTCTCCACCAAAG 
                 1618 
                 WNV 
               
               
                   
               
               
                 R 
                 GGGTCAGCACGTTTGTCATTG 
                 1619 
                 WNV 
               
               
                   
               
               
                 P 
                 TGCCCGACCATGGGAGAAGCTC 
                 1620 
                 WNV 
               
               
                   
               
               
                 F 
                 ACWCARHTVAAYYTNAARTAYGC 
                 1621 
                 Coronavirus 
               
               
                   
               
               
                 R 
                 TCRCAYTTDGGRTARTCCA 
                 1622 
                 Coronavirus 
               
               
                   
               
               
                 F 
                 GCACAGCCACGTGACGAA 
                 1623 
                 Bocavirus 
               
               
                   
               
               
                 R 
                 TGGACTCCCTTTTCTTTTGTAGGA 
                 1624 
                 Bocavirus 
               
               
                   
               
               
                 P 
                 TGAGCTCAGGGAATATGAAAGACAAGCATC 
                 1625 
                 Bocavirus 
               
               
                   
               
               
                 F 
                 CCCTGAATGCGGCTAATCC 
                 1626 
                 Enterovirus 
               
               
                   
               
               
                 R 
                 ATTGTCACCATAAGCAGCCA 
                 1627 
                 Enterovirus 
               
               
                   
               
               
                 P 
                 AACCGACTACTTTGGGTGTCCGTGTTTC 
                 1628 
                 Enterovirus 
               
               
                   
               
               
                 F 
                 TTCCAGCATAATAACTCWGGCTTTG 
                 1629 
                 Adenovirus 
               
               
                   
               
               
                 R 
                 AATTTTTTCTGWGTCAGGCTTGG 
                 1630 
                 Adenovirus 
               
               
                   
               
               
                 P 
                 CCATACCCCCTTATTGG 
                 1631 
                 Adenovirus 
               
               
                   
               
               
                 F 
                 CAGTGGTTGATGCTCAAGATGGA 
                 1632 
                 Rotavirus 
               
               
                   
               
               
                 R 
                 TCATTGTAATCATATTGAATCCCCA 
                 1633 
                 Rotavirus 
               
               
                   
               
               
                 P 
                 ACAACTGCAGCTTCAAAAGAAGWGT 
                 1634 
                 Rotavirus 
               
               
                   
               
               
                 F 
                 TCAATATGCTGAAACGCGCGAGAAACCG 
                 1635 
                 Dengue 
               
               
                   
               
               
                 R 
                 TTGCACCAACAGTCAATGTCTTCAGGTTC 
                 1636 
                 Deng ue 
               
               
                   
               
               
                 P 
                 GAAGAATGGAGCGATCAAAGTG 
                 1637 
                 Dengue 
               
               
                   
               
               
                 F 
                 GTAACASWWGCCTCTGGGSCCAAAAG 
                 1638 
                 Parechovirus 
               
               
                   
               
               
                 R 
                 GGCCCCWGRTCAGATCCAYAGT 
                 1639 
                 Parechovirus 
               
               
                   
               
               
                 P 
                 CCTRYGGGTACCTYCWGGGCATCCTTC 
                 1640 
                 Parechovirus 
               
               
                   
               
               
                 F 
                 AGTCTTTAGGGTCTTCTACCTT 
                 1641 
                 BK virus 
               
               
                   
               
               
                 R 
                 GGTGCCAACCTATGGAACAG 
                 1642 
                 BK virus 
               
               
                   
               
               
                 P 
                 TCATCACTGGCAAACAT 
                 1643 
                 BK virus 
               
               
                   
               
               
                 F 
                 ACAGGAATTGGCTCAGATATGYG 
                 1644 
                 Parainfluenza 
               
               
                   
               
               
                 R 
                 GACTTCCCTATATCTGCACATCCTTGAGTG 
                 1645 
                 Parainfluenza 
               
               
                   
               
               
                 P 
                 ACCATGCAGACGGC 
                 1646 
                 Parainfluenza 
               
               
                   
               
               
                 F 
                 CACTTCCGAATGGCTGA 
                 1647 
                 TTV 
               
               
                   
               
               
                 R 
                 GCCTTGCCCATAGCCCGC 
                 1648 
                 TTV 
               
               
                   
               
               
                 P 
                 TCCCGAGCCCGAATTGCCCCT 
                 1649 
                 TTV 
               
               
                   
               
               
                 F 
                 GAACCATCACTCCACAGAGGAG 
                 1650 
                 Coxsackie 
               
               
                   
               
               
                 R 
                 GTACCTGTGGTGGGCATTG 
                 1651 
                 Coxsackie 
               
               
                   
               
               
                 P 
                 CAGCCATTGGGAATTTCTTTAGCCGTG 
                 1652 
                 Coxsackie 
               
               
                   
               
               
                 F 
                 TGGCCCATTTTCAAGGAAGT 
                 1653 
                 Parvo B19 
               
               
                   
               
               
                 R 
                 CTGAAGTCATGCTTGGGTATTTTTC 
                 1654 
                 Parvo B19 
               
               
                   
               
               
                 P 
                 CCGGAAGTTCCCGCTTACAAC 
                 1655 
                 Parvo B19 
               
               
                   
               
            
           
         
       
     
     Current diagnosis of protozoal infections is achieved by pathogen detection using a variety of methods including light microscopy, or antigen or nucleic acid detection using different techniques such as tissue biopsy and histology, fecal or blood smears and staining, ELISA, lateral flow immunochromatography, and nucleic acid amplification. Common protozoan human pathogens, which can be detected using these techniques, include  Plasmodium  (malaria),  Leishmania  (leishmaniasis),  Trypanosoma  (sleeping sickness and Chagas disease),  Cryptosporidium, Giardia, Toxoplasma, Babesia, Balantidium  and  Entamoeba . Common and well-known protozoan human pathogens that can be found in peripheral blood (causing a parasitemia—see TABLE 1 for a list) include  Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae, Plasmodium vivax, Leishmania donovani, Trypanosoma brucei, Trypanosoma cruzi, Toxoplasma gondii  and  Babesia microti.    
     In specific embodiments, protozoans that are capable of causing pathology in humans, as for example those listed in TABLE 1, which are capable of causing SIRS and cause a parasitemia are detected and/or quantified using any suitable nucleic acid detection and/or amplification assay, with oligonucleotide primers and/or probes in TABLE G. 
     
       
         
           
               
               
               
               
             
               
                 TABLE G 
               
               
                   
               
               
                 Reagent 
                 5′-3′ Sequence 
                 SEQ ID NO. 
                 Organisms Detected 
               
               
                   
               
             
            
               
                 Forward (F) 
                 TTTCATTAATCAAGAACGAAAGTTAGGGG 
                 1656 
                   Toxoplasma gondii  and 
               
               
                   
                   
                   
                 
                   Babesia microti 
                 
               
               
                   
               
               
                 F2 
                 TTCCATTAATCAAGAACGAAAGTTAAGGG 
                 1657 
                   Plasmodium ovale , 
               
               
                   
                   
                   
                   falciparum ,  malariae ,  vivax   
               
               
                   
               
               
                 F3 
                 AAACGATGACACCCATGAATTGGGGA 
                 1658 
                   Trypanosoma cruzi ,  brucei   
               
               
                   
                   
                   
                 and  Leishmania donovani   
               
               
                   
               
               
                 Probe (Pr) 
                 CGTAGTCCTAACCATAAAC 
                 1659 
                 
                   Babesia microti 
                 
               
               
                   
               
               
                 Pr2 
                 AAACTATGCCGACTAGG 
                 1660 
                   Plasmodium ovale , 
               
               
                   
                   
                   
                   falciparum ,  malariae ,  vivax   
               
               
                   
               
               
                 Pr3 
                 GACTTCTCCTGCACCTTAT 
                 1661 
                 
                   Toxoplasma gondii 
                 
               
               
                   
               
               
                 Pr4 
                 ACGGGAATATCCTCAGCACGTT 
                 1662 
                   Trypanosoma cruzi ,  brucei   
               
               
                   
                   
                   
                 and  Leishmania donovani   
               
               
                   
               
               
                 Reverse (R) 
                 TCAAAGTCTTTGGGTTCTGGGGGG 
                 1663 
                   Toxoplasma gondii  and 
               
               
                   
                   
                   
                 
                   Babesia microti 
                 
               
               
                   
               
               
                 R2 
                 TCAAAGTCTTTGGGTTCTGGGGCG 
                 1664 
                   Plasmodium ovale , 
               
               
                   
                   
                   
                   falciparum, malariae ,  vivax   
               
               
                   
               
               
                 R3 
                 CGTTCGCAAGAGTGAAACTTAAAG 
                 1665 
                   Trypanosoma cruzi ,  brucei   
               
               
                   
                   
                   
                 and  Leishmania donovani   
               
               
                   
               
            
           
         
       
     
     The indicator-determining methods of the present invention typically include obtaining a sample from a subject that typically has at least one clinical sign of SIRS. The sample typically comprises a biological fluid and in preferred embodiments comprises blood, suitably peripheral blood. The sample will typically include one or more BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers (e.g., polynucleotide or polypeptide expression products of BaSIRS, VaSIRS, PaSIRS or InSIRS genes) and none, one or more BIP, VIP or PIP biomarkers, quantifying at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the BaSIRS, VaSIRS, PaSIRS or InSIRS host response specific biomarkers and optionally quantifying at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the BIP, VIP or PIP pathogen specific biomarkers) within the sample to determine biomarker values. This can be achieved using any suitable technique, and will depend on the nature of the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers. Suitably, a BaSIRS, VaSIRS, PaSIRS or InSIRS host response specific biomarker value corresponds to the level of a respective BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers or to a function that is applied to that level. Suitably, an individual measured BIP, VIP or PIP pathogen specific biomarker value corresponds to the level of a respective BIP, VIP or PIP biomarker or to a function that is applied to that level or amount. 
     The host response specific derived biomarker values can be used alone or in combination with the at least one pathogen specific biomarker value to at least partially determine the indicator. For example, the indicator may be determined directly simply by combining the host response specific derived biomarker values using a combining function. Alternatively, the host response specific derived biomarker values and the at least one pathogen specific biomarker value are combined using a combining function to provide a compound biomarker value that is used to directly determine the indicator. In other embodiments, the host response specific derived biomarker values and optionally the at least one pathogen specific biomarker value are subjected to further processing, such as comparing the derived biomarker value to a reference, or using a cut-off value for pathogen specific biomarker, or the like, as will be described in more detail below, for determining the indicator. In certain of these embodiments, the indicator-determining methods additionally involve: combining the at least one pathogen specific biomarker value and the first, second and optionally third host response specific derived biomarker values using a combining function to provide a compound biomarker value and determining the indicator based at least in part on the compound biomarker value. Thus, in these embodiments, two or more pairs of host response specific derived biomarker values can be used in combination with one or more pathogen specific biomarker values, to provide a compound biomarker value that can assist in increasing the ability of the indicator to reliably determine the likelihood of a subject having, or not having, BaSIRS, VaSIRS, PaSIRS or InSIRS. 
     As disclosed herein, a combination of host response specific derived biomarker values and optionally at least one pathogen specific biomarker value can be combined using a combining function such as an additive model; a linear model; a support vector machine; a neural network model; a random forest model; a regression model; a genetic algorithm; an annealing algorithm; a weighted sum; a nearest neighbor model; and a probabilistic model. Various combinations of host response derived biomarkers and pathogen specific biomarkers are envisaged. 
     In some embodiments, the indicator is compared to an indicator reference, with a likelihood being determined in accordance with results of the comparison. The indicator reference may be derived from indicators determined for a number of individuals in a reference population. The reference population typically includes individuals having different characteristics, such as a plurality of individuals of different sexes; and/or ethnicities, with different groups being defined based on different characteristics, with the subject&#39;s indicator being compared to indicator references derived from individuals with similar characteristics. The reference population can also include a plurality of healthy individuals, a plurality of individuals suffering from BaSIRS, VaSIRS, PaSIRS or InSIRS, a plurality of individuals showing clinical signs of BaSIRS, VaSIRS, PaSIRS or InSIRS, and/or first and second groups of individuals, each group of individuals suffering from a respective diagnosed SIRS. 
     The indicator can also be used for determining a likelihood of the subject having a first or second condition, wherein the first condition is BaSIRS, VaSIRS, PaSIRS or InSIRS and the second condition is a healthy condition; in other words to distinguish between these conditions. In this case, this would typically be achieved by comparing the indicator to first and second indicator references, the first and second indicator references being indicative of first and second conditions and determining the likelihood in accordance with the results of the comparison. In particular, this can include determining first and second indicator probabilities using the results of the comparisons and combining the first and second indicator probabilities, for example using a Bayes method, to determine a condition probability corresponding to the likelihood of the subject having one of the conditions. In this situation the first and second conditions could include BaSIRS, VaSIRS, PaSIRS or InSIRS, or BaSIRS, VaSIRS, PaSIRS or InSIRS and a healthy condition. In this case, the first and second indicator references are distributions of indicators determined for first and second groups of a reference population, the first and second group consisting of individuals diagnosed with the first or second condition respectively. 
     In specific embodiments, the indicator-determining methods of the present invention are performed using at least one electronic processing device, such as a suitably programmed computer system or the like. In this case, the electronic processing device typically obtains at least one pair of measured host response specific biomarker values, and at least one pathogen specific biomarker value, either by receiving these from a measuring or other quantifying device, or by retrieving these from a database or the like. The processing device then determines a first derived biomarker value indicative of a ratio of levels of first and second host response specific biomarkers in a sample under test. In some embodiments, the processing device determines a second derived biomarker value indicative of a ratio of levels of third and fourth host response specific biomarkers, and optionally a third derived biomarker value indicative of a ratio of levels of fifth and sixth host response specific biomarkers in the sample. In its simplest form, the processing device may at least partially determine the indicator using only the first host response specific derived biomarker value. In other embodiments, the processing device combines the first host response specific derived biomarker value and the at least one pathogen specific biomarker value to provide a compound biomarker value that is used to at least partially determine the indicator. In still other embodiments, the processing device combines the first host response specific derived biomarker value, the second host response specific derived biomarker value, and optionally the third host response specific derived biomarker value to provide a combined derived biomarker value that is used to at least partially determine the indicator. In further embodiments, the processing device combines the first host response specific derived biomarker value, the second host response specific derived biomarker value, and optionally the third host response specific derived biomarker value and the at least one pathogen specific biomarker value to provide a compound derived biomarker value that is used to at least partially determine the indicator. 
     The processing device can then generate a representation of the indicator, for example by generating an alphanumeric indication of the indicator, a graphical indication of a comparison of the indicator to one or more indicator references or an alphanumeric indication of a likelihood of the subject having at least one medical condition. 
     The indicator-determining methods of the present invention are based on determining the level of individual host response specific biomarkers and optionally pathogen specific biomarkers to thereby determine their biomarker values. It should be understood, however, that a biomarker level does not need to be an absolute amount of biomarker. Instead, biomarker levels may correspond for example to a relative amount or concentration of a biomarker as well as any value or parameter which correlates thereto or can be derived therefrom. For example, in some embodiments of the indicator-determining methods, which employ a pair of host response specific biomarker polynucleotides and at least one pathogen specific biomarker polynucleotide, the methods may involve quantifying the host response specific biomarker polynucleotides and the at least one pathogen specific biomarker polynucleotide for example by nucleic acid amplification (e.g., by PCR) of the host response specific biomarker polynucleotides and the at least one pathogen specific polynucleotide in the sample, determining an amplification amount representing a degree of amplification required to obtain a defined level of each of the pair of host response specific biomarker polynucleotides and of the at least one pathogen specific polynucleotide and determining the indicator by first determining a difference between the amplification amounts of the pair of host response specific biomarker polynucleotides to provide a difference amplification amount and then combining the difference amplification amount and the amplification amount of the pathogen specific polynucleotide to thereby determine an indicator value that is at least partially indicative of the presence, absence or degree of the corresponding SIRS condition under test. In this regard, the amplification amount is generally a cycle time, a number of cycles, a cycle threshold and an amplification time. 
     Accordingly, in some embodiments, the methods may broadly comprise: determining a host response specific derived biomarker value by determining a difference between the amplification amounts of a first pair of host response specific biomarker polynucleotides; determining at least one pathogen specific biomarker value; and determining the indicator by combining the host response specific derived biomarker value and then the at least one pathogen specific biomarker value. In further illustrations of these embodiments, the methods may include: determining a first host response specific derived biomarker value by determining a difference between the amplification amounts of a first pair of host response specific biomarker polynucleotides; determining a second host response specific derived biomarker value by determining a difference between the amplification amounts of a second pair of host response specific biomarker polynucleotides; optionally determining a third host response specific derived biomarker value by determining a difference between the amplification amounts of a third pair of host response specific biomarker polynucleotides; determining at least one pathogen specific biomarker value; and determining the indicator by adding the first, second and/or third derived biomarker values to provide a combined derived biomarker value and combining the combined derived biomarker value and the pathogen specific biomarker value(s) to thereby determine an indicator value that is at least partially indicative of the presence, absence or degree of the corresponding SIRS condition under test. 
     In some embodiments, the presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject is established by determining one or more of BaSIRS, VaSIRS, PaSIRS or InSIRS host response specific biomarker values, wherein individual BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker values are indicative of a value measured or derived for a BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker in a subject or in a sample taken from the subject. These biomarkers are referred to herein as “sample BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers”. In accordance with the present invention, a sample BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker corresponds to a reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker (also referred to herein as a “corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker”). By “corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker” is meant a BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker that is structurally and/or functionally similar to a reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker as set forth for example in SEQ ID NOs: 1-1575. Representative corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers include expression products of allelic variants (same locus), homologues (different locus), and orthologues (different organism) of reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker genes. Nucleic acid variants of reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker genes and encoded BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polynucleotide expression products can contain nucleotide substitutions, deletions, inversions and/or insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions (as compared in the encoded product). For nucleotide sequences, conservative variants include those sequences that, because of the degeneracy of the genetic code, encode the amino acid sequence of a reference BaSIRS, VaSIRS, PaSIRS or InSIRS polypeptide. 
     Generally, variants of a particular BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker gene or polynucleotide will have at least about 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to that particular nucleotide sequence as determined by sequence alignment programs known in the art using default parameters. In some embodiments, the BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker gene or polynucleotide displays at least about 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to a nucleotide sequence selected from any one of SEQ ID NO: 1-94, 189-601, 1014-1143 and 1274-1424, as summarized in TABLES 3, 5, 7 and 9. 
     Corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarkers also include amino acid sequences that display substantial sequence similarity or identity to the amino acid sequence of a reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polypeptide. In general, an amino acid sequence that corresponds to a reference amino acid sequence will display at least about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 97, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or even up to 100% sequence similarity or identity to a reference amino acid sequence selected from any one of SEQ ID NO: 95-188, 602-103, 1144-1273 and 1425-1575, as summarized in TABLES 4, 6, 8 and 10. 
     In some embodiments, calculations of sequence similarity or sequence identity between sequences are performed as follows: 
     To determine the percentage identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In some embodiments, the length of a reference sequence aligned for comparison purposes is at least 30%, usually at least 40%, more usually at least 50%, 60%, and even more usually at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, then the molecules are identical at that position. For amino acid sequence comparison, when a position in the first sequence is occupied by the same or similar amino acid residue (i.e., conservative substitution) at the corresponding position in the second sequence, then the molecules are similar at that position. 
     The percentage identity between the two sequences is a function of the number of identical amino acid residues shared by the sequences at individual positions, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. By contrast, the percentage similarity between the two sequences is a function of the number of identical and similar amino acid residues shared by the sequences at individual positions, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. 
     The comparison of sequences and determination of percentage identity or percentage similarity between sequences can be accomplished using a mathematical algorithm. In certain embodiments, the percentage identity or similarity between amino acid sequences is determined using the Needleman and Wunsch, (1970 , J. Mol. Biol.  48: 444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In specific embodiments, the percent identity between nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. An non-limiting set of parameters (and the one that should be used unless otherwise specified) includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. 
     In some embodiments, the percentage identity or similarity between amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller (1989 , Cabios,  4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. 
     The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al., (1990 , J Mol Biol.,  215: 403-10). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to 53010 nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997 , Nucleic Acids Res,  25: 3389-3402). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. 
     Corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polynucleotides also include nucleic acid sequences that hybridize to reference BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polynucleotides, or to their complements, under stringency conditions described below. As used herein, the term “hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions” describes conditions for hybridization and washing. “Hybridization” is used herein to denote the pairing of complementary nucleotide sequences to produce a DNA-DNA hybrid or a DNA-RNA hybrid. Complementary base sequences are those sequences that are related by the base-pairing rules. In DNA, A pairs with T and C pairs with G. In RNA, U pairs with A and C pairs with G. In this regard, the terms “match” and “mismatch” as used herein refer to the hybridization potential of paired nucleotides in complementary nucleic acid strands. Matched nucleotides hybridize efficiently, such as the classical A-T and G-C base pair mentioned above. Mismatches are other combinations of nucleotides that do not hybridize efficiently. 
     Guidance for performing hybridization reactions can be found in Ausubel et al., (1998, supra), Sections 6.3.1-6.3.6. Aqueous and non-aqueous methods are described in that reference and either can be used. Reference herein to low stringency conditions include and encompass from at least about 1% v/v to at least about 15% v/v formamide and from at least about 1 M to at least about 2 M salt for hybridization at 42° C., and at least about 1 M to at least about 2 M salt for washing at 42° C. Low stringency conditions also may include 1% Bovine Serum Albumin (BSA), 1 mM EDTA, 0.5 M NaHPO 4  (pH 7.2), 7% SDS for hybridization at 65° C., and (i) 2×SSC, 0.1% SDS; or (ii) 0.5% BSA, 1 mM EDTA, 40 mM NaHPO 4  (pH 7.2), 5% SDS for washing at room temperature. One embodiment of low stringency conditions includes hybridization in 6×sodium chloride/sodium citrate (SSC) at about 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at 50° C. (the temperature of the washes can be increased to 55° C. for low stringency conditions). Medium stringency conditions include and encompass from at least about 16% v/v to at least about 30% v/v formamide and from at least about 0.5 M to at least about 0.9 M salt for hybridization at 42° C., and at least about 0.1 M to at least about 0.2 M salt for washing at 55° C. Medium stringency conditions also may include 1% Bovine Serum Albumin (BSA), 1 mM EDTA, 0.5 M NaHPO 4  (pH 7.2), 7% SDS for hybridization at 65° C., and (i) 2×SSC, 0.1% SDS; or (ii) 0.5% BSA, 1 mM EDTA, 40 mM NaHPO 4  (pH 7.2), 5% SDS for washing at 60-65° C. One embodiment of medium stringency conditions includes hybridizing in 6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 60° C. High stringency conditions include and encompass from at least about 31% v/v to at least about 50% v/v formamide and from about 0.01 M to about 0.15 M salt for hybridization at 42° C., and about 0.01 M to about 0.02 M salt for washing at 55° C. High stringency conditions also may include 1% BSA, 1 mM EDTA, 0.5 M NaHPO 4  (pH 7.2), 7% SDS for hybridization at 65° C., and (i) 0.2×SSC, 0.1% SDS; or (ii) 0.5% BSA, 1 mM EDTA, 40 mM NaHPO 4  (pH 7.2), 1% SDS for washing at a temperature in excess of 65° C. One embodiment of high stringency conditions includes hybridizing in 6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C. 
     In certain embodiments, a corresponding BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker polynucleotide is one that hybridizes to a disclosed nucleotide sequence under very high stringency conditions. One embodiment of very high stringency conditions includes hybridizing 0.5 M sodium phosphate, 7% SDS at 65° C., followed by one or more washes at 0.2×SSC, 1% SDS at 65° C. 
     Other stringency conditions are well known in the art and a skilled addressee will recognize that various factors can be manipulated to optimize the specificity of the hybridization. Optimization of the stringency of the final washes can serve to ensure a high degree of hybridization. For detailed examples, see Ausubel et al., supra at pages 2.10.1 to 2.10.16 and Sambrook et al. (1989, supra) at sections 1.101 to 1.104. 
     Generally, a sample is processed prior to BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker detection or quantification. For example, nucleic acid and/or proteins may be extracted, isolated, and/or purified from a sample prior to analysis. Various DNA, mRNA, and/or protein extraction techniques are well known to those skilled in the art. Processing may include centrifugation, ultracentrifugation, ethanol precipitation, filtration, fractionation, resuspension, dilution, concentration, etc. In some embodiments, methods and systems provide analysis (e.g., quantification of RNA or protein biomarkers) from raw sample (e.g., biological fluid such as blood, serum, etc.) without or with limited processing. 
     Methods may comprise steps of homogenizing a sample in a suitable buffer, removal of contaminants and/or assay inhibitors, adding a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker capture reagent (e.g., a magnetic bead to which is linked an oligonucleotide complementary to a target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP nucleic acid biomarker), incubated under conditions that promote the association (e.g., by hybridization) of the target biomarker with the capture reagent to produce a target biomarker:capture reagent complex, incubating the target biomarker:capture complex under target biomarker-release conditions. In some embodiments, multiple BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers are isolated in each round of isolation by adding multiple BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers capture reagents (e.g., specific to the desired biomarkers) to the solution. For example, multiple BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker capture reagents, each comprising an oligonucleotide specific for a different target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker can be added to the sample for isolation of multiple BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker. It is contemplated that the methods encompass multiple experimental designs that vary both in the number of capture steps and in the number of target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker captured in each capture step. In some embodiments, capture reagents are molecules, moieties, substances, or compositions that preferentially (e.g., specifically and selectively) interact with a particular biomarker sought to be isolated, purified, detected, and/or quantified. Any capture reagent having desired binding affinity and/or specificity to the particular BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker can be used in the present technology. For example, the capture reagent can be a macromolecule such as a peptide, a protein (e.g., an antibody or receptor), an oligonucleotide, a nucleic acid, (e.g., nucleic acids capable of hybridizing with the VaSIRS biomarkers), vitamins, oligosaccharides, carbohydrates, lipids, or small molecules, or a complex thereof. As illustrative and non-limiting examples, an avidin target capture reagent may be used to isolate and purify targets comprising a biotin moiety, an antibody may be used to isolate and purify targets comprising the appropriate antigen or epitope, and an oligonucleotide may be used to isolate and purify a complementary oligonucleotide. 
     Any nucleic acids, including single-stranded and double-stranded nucleic acids, that are capable of binding, or specifically binding, to a target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker can be used as the capture reagent. Examples of such nucleic acids include DNA, RNA, aptamers, peptide nucleic acids, and other modifications to the sugar, phosphate, or nucleoside base. Thus, there are many strategies for capturing a target and accordingly many types of capture reagents are known to those in the art. 
     In addition, BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker capture reagents may comprise a functionality to localize, concentrate, aggregate, etc. the capture reagent and thus provide a way to isolate and purify the target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker when captured (e.g., bound, hybridized, etc.) to the capture reagent (e.g., when a target:capture reagent complex is formed). For example, in some embodiments the portion of the capture reagent that interacts with the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker (e.g., an oligonucleotide) is linked to a solid support (e.g., a bead, surface, resin, column, and the like) that allows manipulation by the user on a macroscopic scale. Often, the solid support allows the use of a mechanical means to isolate and purify the target:capture reagent complex from a heterogeneous solution. For example, when linked to a bead, separation is achieved by removing the bead from the heterogeneous solution, e.g., by physical movement. In embodiments in which the bead is magnetic or paramagnetic, a magnetic field is used to achieve physical separation of the capture reagent (and thus the target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker) from the heterogeneous solution. 
     The BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers may be quantified or detected using any suitable means. In specific embodiments, the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers are quantified using reagents that determine the level, abundance or amount of individual BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers. Non-limiting reagents of this type include reagents for use in nucleic acid- and protein-based assays. 
     In illustrative nucleic acid-based assays, nucleic acid is isolated from cells contained in the biological sample according to standard methodologies (Sambrook, et al., 1989, supra; and Ausubel et al., 1994, supra). The nucleic acid is typically fractionated (e.g., poly A +  RNA) or whole cell RNA. Where RNA is used as the subject of detection, it may be desired to convert the RNA to a complementary DNA (cDNA). In some embodiments, the nucleic acid is amplified by a template-dependent nucleic acid amplification reaction. A number of template dependent processes are available to amplify the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker sequences present in a given template sample. An exemplary nucleic acid amplification technique is the polymerase chain reaction (referred to as PCR), which is described in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,800,159, Ausubel et al. (supra), and in Innis et al., (“PCR Protocols”, Academic Press, Inc., San Diego Calif., 1990). Briefly, in PCR, two primer sequences are prepared that are complementary to regions on opposite complementary strands of the biomarker sequence. An excess of deoxynucleotide triphosphates are added to a reaction mixture along with a DNA polymerase, e.g., Taq polymerase. If a cognate BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker sequence is present in a sample, the primers will bind to the biomarker and the polymerase will cause the primers to be extended along the biomarker sequence by adding on nucleotides. By raising and lowering the temperature of the reaction mixture, the extended primers will dissociate from the biomarker to form reaction products, excess primers will bind to the biomarker and to the reaction products and the process is repeated. A reverse transcriptase PCR amplification procedure may be performed in order to quantify the amount of mRNA amplified. Methods of reverse transcribing RNA into cDNA are well known and described in Sambrook et al., 1989, supra. Alternative methods for reverse transcription utilize thermostable, RNA-dependent DNA polymerases. These methods are described in WO 90/07641. Polymerase chain reaction methodologies are well known in the art. In specific embodiments in which whole cell RNA is used, cDNA synthesis using whole cell RNA as a sample produces whole cell cDNA. 
     Detection and/or quantification of the amplified target polynucleotides may be facilitated by attachment of a heterologous detectable label to an oligonucleotide primer or probe that is used in the amplification reaction, illustrative examples of which include radioisotopes, fluorophores, chemiluminophores, bioluminescent molecules, lanthanide ions (e.g., Eu 34 ), enzymes, colloidal particles, dye particles and fluorescent microparticles or nanoparticles, as well as antigens, antibodies, haptens, avidin/streptavidin, biotin, enzyme cofactors/substrates, enzymes, and the like. A label can optionally be attached to or incorporated into an oligonucleotide probe or primer to allow detection and/or quantitation of a target polynucleotide representing the target sequence of interest. The target polynucleotide may be the expressed target sequence RNA itself, a cDNA copy thereof, or an amplification product derived therefrom, and may be the positive or negative strand, so long as it can be specifically detected in the assay being used. In certain multiplex formats, labels used for detecting different targets may be distinguishable. The label can be attached directly (e.g., via covalent linkage) or indirectly, e.g., via a bridging molecule or series of molecules (e.g., a molecule or complex that can bind to an assay component, or via members of a binding pair that can be incorporated into assay components, e.g., biotin-avidin or streptavidin). Many labels are commercially available in activated forms which can readily be used for such conjugation (for example through amine acylation), or labels may be attached through known or determinable conjugation schemes, many of which are known in the art. 
     Labels useful in the invention described herein include any substance which can be detected when bound to or incorporated into the biomolecule of interest. Any effective detection method can be used, including optical, spectroscopic, electrical, piezoelectrical, magnetic, Raman scattering, surface plasmon resonance, colorimetric, calorimetric, etc. A label is typically selected from a chromophore, a lumiphore, a fluorophore, one member of a quenching system, a chromogen, a hapten, an antigen, a magnetic particle, a material exhibiting nonlinear optics, a semiconductor nanocrystal, a metal nanoparticle, an enzyme, an antibody or binding portion or equivalent thereof, an aptamer, and one member of a binding pair, and combinations thereof. Quenching schemes may be used, wherein a quencher and a fluorophore as members of a quenching pair may be used on a probe, such that a change in optical parameters occurs upon binding to the target introduce or quench the signal from the fluorophore. One example of such a system is a molecular beacon. Suitable quencher/fluorophore systems are known in the art. The label may be bound through a variety of intermediate linkages. For example, a polynucleotide may comprise a biotin-binding species, and an optically detectable label may be conjugated to biotin and then bound to the labeled polynucleotide. Similarly, a polynucleotide sensor may comprise an immunological species such as an antibody or fragment, and a secondary antibody containing an optically detectable label may be added. 
     Chromophores useful in the methods described herein include any substance which can absorb energy and emit light. For multiplexed assays, a plurality of different signaling chromophores can be used with detectably different emission spectra. The chromophore can be a lumiphore or a fluorophore. Typical fluorophores include fluorescent dyes, semiconductor nanocrystals, lanthanide chelates, polynucleotide-specific dyes and green fluorescent protein. 
     In certain advantageous embodiments, the template-dependent amplification reaction involves quantification of transcripts. For example, RNA or DNA may be quantified using a quantitative real-time PCR technique (Higuchi, 1992, et al.,  Biotechnology  10: 413-417). By determining the concentration of the amplified products of the target DNA in PCR reactions that have completed the same number of cycles and are in their linear ranges, it is possible to determine the relative levels of the specific target sequence in the original DNA mixture. If the DNA mixtures are cDNAs synthesized from RNAs isolated from different tissues or cells, the relative abundance of the specific mRNA from which the target sequence was derived can be determined for the respective tissues or cells. This direct proportionality between the concentration of the PCR products and the relative mRNA abundance is only true in the linear range of the PCR reaction. The final concentration of the target DNA in the plateau portion of the curve is determined by the availability of reagents in the reaction mix and is independent of the original concentration of target DNA. In specific embodiments, quantitative PCR (qPCR) is combined with fluorescence chemistry to enable real-time monitoring of the amplification reaction using detection of a fluorescent light signal. In illustrative examples, the qPCR methods use a sequence nonspecific fluorescent reporter dye such as SYBR green (see, Wittwer et al.,  Biotechniques  22(1):176-181, 1997). In other examples, the qPCR methods use a sequence specific fluorescent reporter such as a TAQMAN probe (see, Heid, et al., Genome Res. 6(10):986-994, 1996). During execution of the PCR cycling program, the samples are excited using a light source. A fluorescent signal, indicating the amount of PCR amplification product produced, is monitored in each reaction well using a photodetector or CCD/CMOS camera. By monitoring the fluorescence in the sample during the reaction precise quantitative measurements can be made. The probe based PCR method is considered to more accurate than the SYBR green method. PCR or qPCR is typically performed in plastic 96 or 384 well microtiter plates, each reaction having a volume in the order of 5-50 μL. PCR can however be carried out in very small (nanoliter) volumes. Other quantification strategies may be employed such as Molecular Beacon Probes (see, Tyagi et al.,  Nature Biotechnology  14: 303-308, 1996; or Situma et al., Analytical Biochemistry 363: 35-45, 2007). 
     Real-time PCR can be performed to detect a single gene or RNA molecule, however, multiple genes or RNA molecules may be detected in one reaction, i.e., by multiplexing. Detection of nucleic acids by multiplexing is described by Kosman, et al. ( Science,  305: 846, 2004); Sakai et al. ( BioScience Trends  2(4):164-168, 2008); or Gu et al. ( Journal of Clinical Microbiology,  41(10): 4636-4641, 2003). For example, one or more biomarker mRNAs may be detected simultaneously, optionally with one or more housekeeping mRNAs in a single reaction. In certain embodiments, multiple biomarkers (e.g., target polynucleotides) are analyzed using real-time quantitative multiplex RT-PCR platforms and other multiplexing technologies such as GenomeLab GeXP Genetic Analysis System (Beckman Coulter, Foster City, Calif.), SmartCycler® 9600 or GeneXpert® Systems (Cepheid, Sunnyvale, Calif.), ABI 7900 HT Fast Real Time PCR system (Applied Biosystems, Foster City, Calif.), LightCycler® 480 System (Roche Molecular Systems, Pleasanton, Calif.), xMAP 100 System (Luminex, Austin, Tex.) Solexa Genome Analysis System (Illumina, Hayward, Calif.), OpenArray Real Time qPCR (BioTrove, Woburn, Mass.) and BeadXpress System (Illumina, Hayward, Calif.). In illustrative examples, multiplexed, tandem PCR (MT-PCR) is employed, which uses a two-step process for gene expression profiling from small quantities of RNA or DNA, as described for example in U.S. Pat. Appl. Pub. No. 20070190540. In the first step, RNA is converted into cDNA and amplified using multiplexed gene specific primers. In the second step each individual gene is quantitated by real-time PCR. 
     In certain embodiments, target nucleic acids are quantified using blotting techniques, which are well known to those of skill in the art. Southern blotting involves the use of DNA as a target, whereas Northern blotting involves the use of RNA as a target. Each provides different types of information, although cDNA blotting is analogous, in many aspects, to blotting or RNA species. Briefly, a probe is used to target a DNA or RNA species that has been immobilized on a suitable matrix, often a filter of nitrocellulose. The different species should be spatially separated to facilitate analysis. This often is accomplished by gel electrophoresis of nucleic acid species followed by “blotting” on to the filter. Subsequently, the blotted target is incubated with a probe (usually labeled) under conditions that promote denaturation and rehybridization. Because the probe is designed to base pair with the target, the probe will bind a portion of the target sequence under renaturing conditions. Unbound probe is then removed, and detection is accomplished as described above. Following detection/quantification, one may compare the results seen in a given subject with a control reaction or a statistically significant reference group or population of control subjects as defined herein. In this way, it is possible to correlate the amount of BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker nucleic acid detected with the progression or severity of the disease. 
     Also contemplated are biochip-based technologies such as those described by Hacia et al. (1996 , Nature Genetics  14: 441-447) and Shoemaker et al. (1996 , Nature Genetics  14: 450-456). Briefly, these techniques involve quantitative methods for analyzing large numbers of genes rapidly and accurately. By tagging genes with oligonucleotides or using fixed nucleic acid probe arrays, one can employ biochip technology to segregate target molecules as high-density arrays and screen these molecules on the basis of hybridization. See also Pease et al. (1994 , Proc. Natl. Acad. Sci. U.S.A.  91: 5022-5026); Fodor et al. (1991 , Science  251: 767-773). Briefly, nucleic acid probes to BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polynucleotides are made and attached to biochips to be used in screening and diagnostic methods, as outlined herein. The nucleic acid probes attached to the biochip are designed to be substantially complementary to specific expressed BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker nucleic acids, i.e., the target sequence (either the target sequence of the sample or to other probe sequences, for example in sandwich assays), such that hybridization of the target sequence and the probes of the present invention occur. This complementarity need not be perfect; there may be any number of base pair mismatches, which will interfere with hybridization between the target sequence and the nucleic acid probes of the present invention. However, if the number of mismatches is so great that no hybridization can occur under even the least stringent of hybridization conditions, the sequence is not a complementary target sequence. In certain embodiments, more than one probe per sequence is used, with either overlapping probes or probes to different sections of the target being used. That is, two, three, four or more probes, with three being desirable, are used to build in a redundancy for a particular target. The probes can be overlapping (i.e. have some sequence in common), or separate. 
     In an illustrative biochip analysis, oligonucleotide probes on the biochip are exposed to or contacted with a nucleic acid sample suspected of containing one or more BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polynucleotides under conditions favoring specific hybridization. Sample extracts of DNA or RNA, either single or double-stranded, may be prepared from fluid suspensions of biological materials, or by grinding biological materials, or following a cell lysis step which includes, but is not limited to, lysis effected by treatment with SDS (or other detergents), osmotic shock, guanidinium isothiocyanate and lysozyme. Suitable DNA, which may be used in the method of the invention, includes cDNA. Such DNA may be prepared by any one of a number of commonly used protocols as for example described in Ausubel, et al., 1994, supra, and Sambrook, et al., 1989, supra. 
     Suitable RNA, which may be used in the method of the invention, includes messenger RNA, complementary RNA transcribed from DNA (cRNA) or genomic or subgenomic RNA. Such RNA may be prepared using standard protocols as for example described in the relevant sections of Ausubel, et al. 1994, supra and Sambrook, et al. 1989, supra). 
     cDNA may be fragmented, for example, by sonication or by treatment with restriction endonucleases. Suitably, cDNA is fragmented such that resultant DNA fragments are of a length greater than the length of the immobilized oligonucleotide probe(s) but small enough to allow rapid access thereto under suitable hybridization conditions. Alternatively, fragments of cDNA may be selected and amplified using a suitable nucleotide amplification technique, as described for example above, involving appropriate random or specific primers. 
     Usually the target BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polynucleotides are detectably labeled so that their hybridization to individual probes can be determined. The target polynucleotides are typically detectably labeled with a heterologous label or reporter molecule illustrative examples of which include those mentioned above in respect for the primers or probes used in. 
     The hybrid-forming step can be performed under suitable conditions for hybridizing oligonucleotide probes to test nucleic acid including DNA or RNA. In this regard, reference may be made, for example, to NUCLEIC ACID HYBRIDIZATION, A PRACTICAL APPROACH (Homes and Higgins, eds.) (IRL press, Washington D.C., 1985). In general, whether hybridization takes place is influenced by the length of the oligonucleotide probe and the polynucleotide sequence under test, the pH, the temperature, the concentration of mono- and divalent cations, the proportion of G and C nucleotides in the hybrid-forming region, the viscosity of the medium and the possible presence of denaturants. Such variables also influence the time required for hybridization. The preferred conditions will therefore depend upon the particular application. Such empirical conditions, however, can be routinely determined without undue experimentation. 
     After the hybrid-forming step, the probes are washed to remove any unbound nucleic acid with a hybridization buffer. This washing step leaves only bound target polynucleotides. The probes are then examined to identify which probes have hybridized to a target polynucleotide. 
     The hybridization reactions are then detected to determine which of the probes has hybridized to a corresponding target sequence. Depending on the nature of the reporter molecule associated with a target polynucleotide, a signal may be instrumentally detected by irradiating a fluorescent label with light and detecting fluorescence in a fluorimeter; by providing for an enzyme system to produce a dye which could be detected using a spectrophotometer; or detection of a dye particle or a colored colloidal metallic or non-metallic particle using a reflectometer; in the case of using a radioactive label or chemiluminescent molecule employing a radiation counter or autoradiography. Accordingly, a detection means may be adapted to detect or scan light associated with the label which light may include fluorescent, luminescent, focused beam or laser light. In such a case, a charge couple device (CCD) or a photocell can be used to scan for emission of light from a probe:target polynucleotide hybrid from each location in the micro-array and record the data directly in a digital computer. In some cases, electronic detection of the signal may not be necessary. For example, with enzymatically generated color spots associated with nucleic acid array format, visual examination of the array will allow interpretation of the pattern on the array. In the case of a nucleic acid array, the detection means is suitably interfaced with pattern recognition software to convert the pattern of signals from the array into a plain language genetic profile. In certain embodiments, oligonucleotide probes specific for different VaSIRS biomarker polynucleotides are in the form of a nucleic acid array and detection of a signal generated from a reporter molecule on the array is performed using a ‘chip reader’. A detection system that can be used by a ‘chip reader’ is described for example by Pirrung et al. (U.S. Pat. No. 5,143,854). The chip reader will typically also incorporate some signal processing to determine whether the signal at a particular array position or feature is a true positive or maybe a spurious signal. Exemplary chip readers are described for example by Fodor et al. (U.S. Pat. No. 5,925,525). Alternatively, when the array is made using a mixture of individually addressable kinds of labeled microbeads, the reaction may be detected using flow cytometry. 
     In certain embodiments, the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker is a target RNA (e.g., mRNA) or a DNA copy of the target RNA whose level or abundance is measured using at least one nucleic acid probe that hybridizes under at least low, medium, or high stringency conditions to the target RNA or to the DNA copy, wherein the nucleic acid probe comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) contiguous nucleotides of BaSIRS, VaSIRS, PaSIRS, BIP, VIP or PIP biomarker polynucleotide. In some embodiments, the measured level or abundance of the target RNA or its DNA copy is normalized to the level or abundance of a reference RNA or a DNA copy of the reference RNA. Suitably, the nucleic acid probe is immobilized on a solid or semi-solid support. In illustrative examples of this type, the nucleic acid probe forms part of a spatial array of nucleic acid probes. In some embodiments, the level of nucleic acid probe that is bound to the target RNA or to the DNA copy is measured by hybridization (e.g., using a nucleic acid array). In other embodiments, the level of nucleic acid probe that is bound to the target RNA or to the DNA copy is measured by nucleic acid amplification (e.g., using a polymerase chain reaction (PCR)). In still other embodiments, the level of nucleic acid probe that is bound to the target RNA or to the DNA copy is measured by nuclease protection assay. 
     Sequencing technologies such as Sanger sequencing, pyrosequencing, sequencing by ligation, massively parallel sequencing, also called “Next-generation sequencing” (NGS), and other high-throughput sequencing approaches with or without sequence amplification of the target can also be used to detect or quantify the presence of BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP nucleic acid biomarker in a sample. Sequence-based methods can provide further information regarding alternative splicing and sequence variation in previously identified genes. Sequencing technologies include a number of steps that are grouped broadly as template preparation, sequencing, detection and data analysis. Current methods for template preparation involve randomly breaking genomic DNA into smaller sizes from which each fragment is immobilized to a support. The immobilization of spatially separated fragment allows thousands to billions of sequencing reaction to be performed simultaneously. A sequencing step may use any of a variety of methods that are commonly known in the art. One specific example of a sequencing step uses the addition of nucleotides to the complementary strand to provide the DNA sequence. The detection steps range from measuring bioluminescent signal of a synthesized fragment to four-color imaging of single molecule. In some embodiments in which NGS is used to detect or quantify the presence of BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP nucleic acid biomarker in a sample, the methods are suitably selected from semiconductor sequencing (Ion Torrent; Personal Genome Machine); Helicos True Single Molecule Sequencing (tSMS) (Harris et al. 2008 , Science  320:106-109); 454 sequencing (Roche) (Margulies et al. 2005 , Nature,  437, 376-380); SOLiD technology (Applied Biosystems); SOLEXA sequencing (Illumina); single molecule, real-time (SMRT™) technology of Pacific Biosciences; nanopore sequencing (Soni and Meller, 2007 . Clin Chem  53: 1996-2001); DNA nanoball sequencing; sequencing using technology from Dover Systems (Polonator), and technologies that do not require amplification or otherwise transform native DNA prior to sequencing (e.g., Pacific Biosciences and Helicos), such as nanopore-based strategies (e.g., Oxford Nanopore, Genia Technologies, and Nabsys). 
     In other embodiments, BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker protein levels are assayed using protein-based assays known in the art. For example, when BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker protein is an enzyme, the protein can be quantified based upon its catalytic activity or based upon the number of molecules of the protein contained in a sample. Antibody-based techniques may be employed including, for example, immunoassays, such as the enzyme-linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). 
     In other embodiments, BIP, VIP or PIP biomarker proteins, carbohydrates, lipids, metabolites or combinations of such pathogenic molecules are assayed using assays known in the art. Such assays could include, by example; enzyme immunoassay, mass spectrometry, liquid chromatography, lateral immunochromatography, or other methods capable of quantifying such molecules. 
     In specific embodiments, protein-capture arrays that permit simultaneous detection and/or quantification of a large number of proteins are employed. For example, low-density protein arrays on filter membranes, such as the universal protein array system (Ge, 2000  Nucleic Acids Res.  28(2):e3) allow imaging of arrayed antigens using standard ELISA techniques and a scanning charge-coupled device (CCD) detector. Immuno-sensor arrays have also been developed that enable the simultaneous detection of clinical analytes. It is now possible using protein arrays, to profile protein expression in bodily fluids, such as in sera of healthy or diseased subjects, as well as in subjects pre- and post-drug treatment. 
     Exemplary protein capture arrays include arrays comprising spatially addressed antigen-binding molecules, commonly referred to as antibody arrays, which can facilitate extensive parallel analysis of numerous proteins defining a proteome or subproteome. Antibody arrays have been shown to have the required properties of specificity and acceptable background, and some are available commercially (e.g., BD Biosciences, Clontech, Bio-Rad and Sigma). Various methods for the preparation of antibody arrays have been reported (see, e.g., Lopez et al., 2003  J. Chromatogram. B  787:19-27; Cahill, 2000  Trends in Biotechnology  7:47-51; U.S. Pat. App. Pub. 2002/0055186; U.S. Pat. App. Pub. 2003/0003599; PCT publication WO 03/062444; PCT publication WO 03/077851; PCT publication WO 02/59601; PCT publication WO 02/39120; PCT publication WO 01/79849; PCT publication WO 99/39210). The antigen-binding molecules of such arrays may recognize at least a subset of proteins expressed by a cell or population of cells, illustrative examples of which include growth factor receptors, hormone receptors, neurotransmitter receptors, catecholamine receptors, amino acid derivative receptors, cytokine receptors, extracellular matrix receptors, antibodies, lectins, cytokines, serpins, proteases, kinases, phosphatases, ras-like GTPases, hydrolases, steroid hormone receptors, transcription factors, heat-shock transcription factors, DNA-binding proteins, zinc-finger proteins, leucine-zipper proteins, homeodomain proteins, intracellular signal transduction modulators and effectors, apoptosis-related factors, DNA synthesis factors, DNA repair factors, DNA recombination factors and cell-surface antigens. 
     Individual spatially distinct protein-capture agents are typically attached to a support surface, which is generally planar or contoured. Common physical supports include glass slides, silicon, microwells, nitrocellulose or PVDF membranes, and magnetic and other microbeads. 
     Particles in suspension can also be used as the basis of arrays, providing they are coded for identification; systems include color coding for microbeads (e.g., available from Luminex, Bio-Rad and Nanomics Biosystems) and semiconductor nanocrystals (e.g., QDots™, available from Quantum Dots), and barcoding for beads (UltraPlex™, available from Smartbeads) and multimetal microrods (Nanobarcodes™ particles, available from Surromed). Beads can also be assembled into planar arrays on semiconductor chips (e.g., available from LEAPS technology and BioArray Solutions). Where particles are used, individual protein-capture agents are typically attached to an individual particle to provide the spatial definition or separation of the array. The particles may then be assayed separately, but in parallel, in a compartmentalized way, for example in the wells of a microtiter plate or in separate test tubes. 
     In operation, a protein sample, which is optionally fragmented to form peptide fragments (see, e.g., U.S. Pat. App. Pub. 2002/0055186), is delivered to a protein-capture array under conditions suitable for protein or peptide binding, and the array is washed to remove unbound or non-specifically bound components of the sample from the array. Next, the presence or amount of protein or peptide bound to each feature of the array is detected using a suitable detection system. The amount of protein bound to a feature of the array may be determined relative to the amount of a second protein bound to a second feature of the array. In certain embodiments, the amount of the second protein in the sample is already known or known to be invariant. 
     In specific embodiments, the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker is a target polypeptide whose level is measured using at least one antigen-binding molecule that is immuno-interactive with the target polypeptide. In these embodiments, the measured level of the target polypeptide is normalized to the level of a reference polypeptide. Suitably, the antigen-binding molecule is immobilized on a solid or semi-solid support. In illustrative examples of this type, the antigen-binding molecule forms part of a spatial array of antigen-binding molecule. In some embodiments, the level of antigen-binding molecule that is bound to the target polypeptide is measured by immunoassay (e.g., using an ELISA). 
     All the essential reagents required for detecting and quantifying the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers of the invention may be assembled together in a kit. In some embodiments, the kit comprises a reagent that permits quantification of at least one BaSIRS, VaSIRS, PaSIRS, InSIRS biomarker in combination with at least one BIP, VIP or PIP biomarker. In some embodiments the kit comprises: (i) a reagent that allows quantification (e.g., determining the level) of a first BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker; and (ii) a reagent that allows quantification (e.g., determining the level) of a second BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker, wherein the first and second biomarkers form a pair of derived biomarkers, as defined herein; and (iii) a reagent that allows quantification (e.g., determining the level or abundance) of a BIP, VIP or PIP biomarker. In some embodiments, the kit further comprises (iv) a reagent that allows quantification (e.g., determining the level or abundance) of a third BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker; and (v) a reagent that allows quantification (e.g., determining the level or abundance) of a fourth BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker, wherein the third and fourth biomarkers form a pair of derived biomarkers, as defined herein; and, (vi) a reagent that allows quantification (e.g., determining the level or abundance) of a second BIP, VIP or PIP biomarker. In some embodiments, the kit further comprises (vii) a reagent that allows quantification (e.g., determining the level or abundance) of a fifth BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker; and (viii) a reagent that allows quantification (e.g., determining the level or abundance) of a sixth BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker, wherein the fifth and sixth biomarkers form a pair of derived biomarkers, as defined herein; and, (ix) a reagent that allows quantification (e.g., determining the level or abundance) of a third BIP, VIP or PIP biomarker. 
     In the context of the present invention, “kit” is understood to mean a product containing the different reagents necessary for carrying out the methods of the invention packed so as to allow their transport and storage. Materials suitable for packing the components of the kit include crystal, plastic (polyethylene, polypropylene, polycarbonate and the like), bottles, vials, paper, envelopes and the like. Additionally, the kits of the invention can contain instructions for the simultaneous, sequential or separate use of the different components contained in the kit. The instructions can be in the form of printed material or in the form of an electronic support capable of storing instructions such that they can be read by a subject, such as electronic storage media (magnetic disks, tapes and the like), optical media (CD-ROM, DVD) and the like. Alternatively or in addition, the media can contain Internet addresses that provide the instructions. 
     Reagents that allow quantification of a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker include compounds or materials, or sets of compounds or materials, which allow quantification of the BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarkers. In specific embodiments, the compounds, materials or sets of compounds or materials permit (i) determining the expression level of a gene (e.g., BaSIRS, VaSIRS, PaSIRS or InSIRS biomarker gene), and (ii) determining the presence, absence, type, sequence of nucleic acid (e.g., BIP, VIP or PIP biomarker gene), including without limitation the extraction of RNA or DNA material, the determination of the level of a corresponding RNA, DNA etc., the determination of a particular nucleic acid sequence, primers for the synthesis of a corresponding cDNA and DNA, a thermostable DNA polymerase, primers for amplification of DNA, and/or probes capable of specifically hybridizing with the RNAs, corresponding cDNAs encoded by the genes, DNAs, TaqMan probes, etc. 
     The kits may also optionally include appropriate reagents for detection of labels, positive and negative controls, washing solutions, blotting membranes, microtiter plates, dilution buffers and the like. For example, a nucleic acid-based detection kit may include (i) a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polynucleotide (which may be used as a positive control), (ii) a primer or probe that specifically hybridizes to a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polynucleotide. Also included may be enzymes suitable for amplifying nucleic acids including various polymerases (reverse transcriptase, Taq, Sequenase™ DNA ligase etc. depending on the nucleic acid amplification technique employed), deoxynucleotides and buffers to provide the necessary reaction mixture for amplification. Such kits also generally will comprise, in suitable means, distinct containers for each individual reagent and enzyme as well as for each primer or probe. Alternatively, a protein-based detection kit may include (i) a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polypeptide (which may be used as a positive control), (ii) an antibody that binds specifically to a BaSIRS, VaSIRS, PaSIRS, InSIRS, BIP, VIP or PIP biomarker polypeptide. The kit can also feature various devices (e.g., one or more) and reagents (e.g., one or more) for performing one of the assays described herein; and/or printed instructions for using the kit to quantify the expression of a BaSIRS, VaSIRS, PaSIRS, InSIRS biomarker gene in combination with the determination of the presence, absence, type, sequence of nucleic acid of a BIP, VIP or PIP biomarker gene. 
     The reagents described herein, which may be optionally associated with detectable labels, can be presented in the format of a microfluidics card, a chip or chamber, a Point-of-Care cartridge, a microarray or a kit adapted for use with the assays described in the examples or below, e.g., RT-PCR or Q PCR techniques described herein. 
     The reagents also have utility in compositions for detecting and quantifying the biomarkers of the invention. For example, a reverse transcriptase may be used to reverse transcribe RNA transcripts, including mRNA, in a nucleic acid sample, to produce reverse transcribed transcripts, including reverse transcribed mRNA (also referred to as “cDNA”). In specific embodiments, the reverse transcribed mRNA is whole cell reverse transcribed mRNA (also referred to herein as “whole cell cDNA”). The nucleic acid sample is suitably derived from components of the immune system, representative examples of which include components of the innate and adaptive immune systems as broadly discussed for example above. In specific embodiments, the reverse transcribed RNA is derived blood cells (e.g., peripheral blood cells). Suitably, the reverse transcribed RNA is derived leukocytes. 
     The reagents are suitably used to quantify the reverse transcribed transcripts. For example, oligonucleotide primers that hybridize to the reverse transcribed transcript can be used to amplify at least a portion of the reverse transcribed transcript via a suitable nucleic acid amplification technique, e.g., RT-PCR or qPCR techniques described herein. Alternatively, oligonucleotide probes may be used to hybridize to the reverse transcribed transcript for the quantification, using a nucleic acid hybridization analysis technique (e.g., microarray analysis), as described for example above. Thus, in some embodiments, a respective oligonucleotide primer or probe is hybridized to a complementary nucleic acid sequence of a reverse transcribed transcript in the compositions of the invention. The compositions typically comprise labeled reagents for detecting and/or quantifying the reverse transcribed transcripts. Representative reagents of this type include labeled oligonucleotide primers or probes that hybridize to RNA transcripts or reverse transcribed RNA, labeled RNA, labeled reverse transcribed RNA as well as labeled oligonucleotide linkers or tags (e.g., a labeled RNA or DNA linker or tag) for labeling (e.g., end labeling such as 3′ end labeling) RNA or reverse transcribed RNA. The primers, probes, RNA or reverse transcribed RNA (i.e., cDNA) (whether labeled or non-labeled) may be immobilized or free in solution. Representative reagents of this type include labeled oligonucleotide primers or probes that hybridize to reverse transcribed and transcripts as well as labeled reverse transcribed transcripts. The label can be any reporter molecule as known in the art, illustrative examples of which are described above and elsewhere herein. 
     The present invention also encompasses non-reverse transcribed RNA embodiments in which cDNA is not made and the RNA transcripts are directly the subject of the analysis. Thus, in other embodiments, reagents are suitably used to quantify RNA transcripts directly. For example, oligonucleotide probes can be used to hybridize to transcripts for quantification of immune system biomarkers of the invention, using a nucleic acid hybridization analysis technique (e.g., microarray analysis), as described for example above. Thus, in some embodiments, a respective oligonucleotide probe is hybridized to a complementary nucleic acid sequence of an immune system biomarker transcript in the compositions of the invention. In illustrative examples of this type, the compositions may comprise labeled reagents that hybridize to transcripts for detecting and/or quantifying the transcripts. Representative reagents of this type include labeled oligonucleotide probes that hybridize to transcripts as well as labeled transcripts. The primers or probes may be immobilized or free in solution. 
     3. Management, Treatment and Predictive Medicine Embodiments 
     The present invention also extends to the management of BaSIRS, VaSIRS, PaSIRS or InSIRS, or prevention of further progression of BaSIRS, VaSIRS, PaSIRS or InSIRS, or assessment of the efficacy of therapies in subjects following positive diagnosis for the presence of BaSIRS, VaSIRS, PaSIRS or InSIRS, in a subject. Once a subject is positively identified as having BaSIRS, VaSIRS, PaSIRS or InSIRS, the subject may be administered a therapeutic agent for treating the BaSIRS, VaSIRS, PaSIRS or InSIRS such as an anti-bacterial, anti-viral or anti-protozoal agent, illustrative examples of which include: 
     Anti-bacterial agents: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spectinomycin, Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplanin, Vancomycin, Telavancin, Dalbavancin, Oritavancin, Clindamycin, Lincomycin, Daptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Aztreonam, Furazolidone, Nitrofurantoin, Linezolid, Posizolid, Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Penicillin G, Temocillin, Ticarcillin, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, Ticarcillin/clavulanate, Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Sulfonamidochrysoidine, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, Streptomycin, Arsphenamine, Chloramphenicol, Fosfomycin, Fusidic acid, Metronidazole, Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Thiamphenicol, Tigecycline, Tinidazole, and Trimethoprim; 
     Anti-viral agents: asunaprevir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, bacavir, boceprevir, cidofovir, combivir, complera, daclatasvir, darunavir, delavirdine, didanosine, docosanol, dolutegravir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, neuraminidase blocking agents, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podofilox, podophyllin, podophyllotoxin, raltegravir, monoclonal antibody respigams, ribavirin, inhaled rhibovirons, rimantadine, ritonavir, pyrimidine, saquinavir, stavudine, stribild, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate (TAF), tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viperin, viramidine, zalcitabine, zanamivir, zidovudine, or salts and combinations thereof; and 
     Anti-protozoal agents: Eflornithine, Furazolidone, Melarsoprol, Metronidazole, Ornidazole, Paromomycin sulfate, Pentamidine, Pyrimethamine, Tinidazole. 
     In a related aspect, the present invention contemplates the use of the indicator-determining methods, apparatus, compositions and kits disclosed herein in methods of treating, preventing or inhibiting the development or progression of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject. These methods (also referred to herein as “treatment methods”) generally comprise: exposing the subject to a treatment regimen for treating BaSIRS, VaSIRS, PaSIRS or InSIRS, or avoiding exposing the subject to a treatment regimen for treating a SIRS other than BaSIRS, VaSIRS, PaSIRS or InSIRS based on an indicator obtained from an indicator-determining method as disclosed herein. 
     Typically, the treatment regimen involves the administration of therapeutic agents effective amounts to achieve their intended purpose. The therapeutic agents are typically administered in the form a pharmaceutical composition that suitably includes a pharmaceutically acceptable carrier. The dose of active compounds administered to a subject should be sufficient to achieve a beneficial response in the subject over time such as a reduction in, or relief from, the symptoms of BaSIRS, VaSIRS, PaSIRS or InSIRS. The quantity of the of therapeutic agents to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. In this regard, precise amounts of the active agents(s) for administration will depend on the judgment of the practitioner. In determining the effective amount of the active agent(s) to be administered in the treatment or prevention of BaSIRS, VaSIRS, PaSIRS or InSIRS, the medical practitioner or veterinarian may evaluate severity of any symptom or clinical sign associated with the presence of BaSIRS, VaSIRS, PaSIRS or InSIRS or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS including, inflammation, blood pressure anomaly, tachycardia, tachypnea fever, chills, vomiting, diarrhea, skin rash, headaches, confusion, muscle aches, seizures. In any event, those of skill in the art may readily determine suitable dosages of the therapeutic agents and suitable treatment regimens without undue experimentation. 
     The therapeutic agents may be administered in concert with adjunctive (palliative) therapies to increase oxygen supply to major organs, increase blood flow to major organs and/or to reduce the inflammatory response. Illustrative examples of such adjunctive therapies include non-steroidal-anti-inflammatory drugs (NSAIDs), intravenous saline and oxygen. 
     The present invention can be practiced in the field of predictive medicine for the purpose of diagnosis or monitoring the presence or development of BaSIRS, VaSIRS, PaSIRS or InSIRS in a subject, and/or monitoring response to therapy efficacy. The biomarker profiles and corresponding indicators of the present invention further enable determination of endpoints in pharmacotranslational studies. For example, clinical trials can take many months or even years to establish the pharmacological parameters for a medicament to be used in treating or preventing BaSIRS, VaSIRS, PaSIRS or InSIRS. However, these parameters may be associated with a biomarker profile and corresponding indicator of a health state (e.g., a healthy condition). Hence, the clinical trial can be expedited by selecting a treatment regimen (e.g., medicament and pharmaceutical parameters), which results in a biomarker profile associated with a desired health state (e.g., healthy condition). In these embodiments, the methods may comprise: (1) obtaining a biomarker profile of a sample taken from the subject after treatment of the subject with the treatment regimen, wherein the sample biomarker profile comprises (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) comparing the sample biomarker profile to a reference biomarker profile that is correlated with a presence, absence or degree of the SIRS condition to thereby determine whether the treatment regimen is effective for changing the health status of the subject to the desired health state. Accordingly, this aspect of the present invention advantageously provides methods of monitoring the efficacy of a particular treatment regimen in a subject (for example, in the context of a clinical trial) already diagnosed with BaSIRS, VaSIRS, PaSIRS or InSIRS. These methods take advantage of derived biomarker values that correlate with treatment efficacy to determine, for example, whether derived biomarker values of a subject undergoing treatment partially or completely normalize during the course of or following therapy or otherwise shows changes associated with responsiveness to the therapy. 
     Accordingly, the invention also contemplates methods of correlating a biomarker profile with an effective treatment regimen for a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In these embodiments, the methods may comprise: (1) determining a biomarker profile of a sample taken from a subject with the SIRS condition and for whom an effective treatment has been identified, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) correlating the biomarker profile so determined with an effective treatment regimen for the SIRS condition. In specific embodiments, an indicator or biomarker profile is correlated to a global probability or a particular outcome, using receiver operating characteristic (ROC) curves. 
     The invention further provides methods of determining whether a treatment regimen is effective for treating a subject with a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In some embodiments, these methods comprise: (1) determining a post-treatment biomarker profile of a sample taken from the subject after treatment with a treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) determining a post-treatment indicator using the post-treatment biomarker profile, wherein the post-treatment indicator is at least partially indicative of the presence, absence or degree of the SIRS condition, wherein the post-treatment indicator indicates whether the treatment regimen is effective for treating the SIRS condition in the subject on the basis that post-treatment indicator indicates the presence of a healthy condition or the presence of the SIRS condition of a lower degree relative to the degree of the SIRS condition in the subject before treatment with the treatment regimen. 
     The invention can also be practiced to evaluate whether a subject is responding (i.e., a positive response) or not responding (i.e., a negative response) to a treatment regimen. This aspect of the invention provides methods of correlating a biomarker profile with a positive or negative response to a treatment regimen for treating a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In some embodiments, these methods comprise: (1) determining a biomarker profile of a sample taken from a subject with the SIRS condition following commencement of the treatment regimen, wherein the reference biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; and (2) correlating the sample biomarker profile with a positive or negative response to the treatment regimen 
     The invention also encompasses methods of determining a positive or negative response to a treatment regimen by a subject with a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In some embodiments, these methods comprise: (1) correlating a reference biomarker profile with a positive or negative response to the treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; (2) detecting a biomarker profile of a sample taken from the subject, wherein the sample biomarker profile comprises (i) a plurality of host response specific derived biomarker values for each of the plurality of derived biomarkers in the reference biomarker profile, and optionally (ii) a pathogen specific biomarker value for the pathogen biomarker in the reference biomarker profile, wherein the sample biomarker profile indicates whether the subject is responding positively or negatively to the treatment regimen. 
     In related embodiments, the present invention further contemplates methods of determining a positive or negative response to a treatment regimen by a subject with a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In some embodiments, these methods comprise: (1) correlating a reference biomarker profile with a positive or negative response to the treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition; (2) detecting a biomarker profile of a sample taken from the subject, wherein the sample biomarker profile comprises (i) a plurality of host response specific derived biomarker values for each of the plurality of derived biomarkers in the reference biomarker profile, and optionally (ii) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value for the pathogen biomarker in the reference biomarker profile, wherein the sample biomarker profile indicates whether the subject is responding positively or negatively to the treatment regimen. 
     The invention also contemplates methods of determining a positive or negative response to a treatment regimen by a subject with a SIRS condition selected from BaSIRS, VaSIRS, PaSIRS and InSIRS. In certain embodiments, these methods comprise: (1) obtaining a biomarker profile of a sample taken from the subject following commencement of the treatment regimen, wherein the biomarker profile comprises: (a) for each of a plurality of derived biomarkers as broadly defined above and elsewhere herein a plurality of host response specific derived biomarker values, and optionally (b) if the SIRS condition is an IpSIRS, a pathogen specific biomarker value as broadly defined above and elsewhere herein for a pathogen biomarker associated with the SIRS condition, wherein the sample biomarker profile is correlated with a positive or negative response to the treatment regimen; and (2) and determining whether the subject is responding positively or negatively to the treatment regimen. 
     The above methods can be practiced to identify responders or non-responders relatively early in the treatment process, i.e., before clinical manifestations of efficacy. In this way, the treatment regimen can optionally be discontinued, a different treatment protocol can be implemented and/or supplemental therapy can be administered. Thus, in some embodiments, a sample BaSIRS, VaSIRS, PaSIRS, InSIRS in combination with BIP, VIP or PIP biomarker profile is obtained within about 2 hours, 4 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, six months or longer of commencing therapy. 
     4. Device Embodiments 
     The present invention also contemplates embodiments in which the indicator-determining method of the invention is implemented using one or more processing devices. In representative embodiments of this type, the method that is implemented by the processing device(s) determines an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS, wherein the method comprises: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values and a plurality of VaSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value and at least one VaSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, and each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers; (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, wherein the BaSIRS derived biomarker combination is suitably selected from TABLE A and wherein the VaSIRS derived biomarker combination is suitably selected from TABLE B; (4) retrieving previously determined indicator references from a database, the indicator references being determined based on indicators determined from a reference population consisting of individuals diagnosed with BaSIRS or VaSIRS; (5) comparing the indicator to the indicator references to thereby determine a probability indicative of the subject having or not having BaSIRS or VaSIRS; and (6) generating a representation of the probability, the representation being displayed to a user to allow the user to assess the likelihood of a biological subject having BaSIRS or VaSIRS. 
     In some embodiments, the indicator-determining method that is implemented by the processing device(s) determines an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS or PaSIRS, wherein the method comprises: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values and a plurality of PaSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, and the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value and at least one PaSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, and each derived PaSIRS biomarker value being determined using at least a subset of the plurality of PaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers; (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, wherein the BaSIRS derived biomarker combination is suitably selected from TABLE A, wherein the VaSIRS derived biomarker combination is suitably selected from TABLE B, and wherein the PaSIRS derived biomarker combination is suitably selected from TABLE C; (4) retrieving previously determined indicator references from a database, the indicator references being determined based on indicators determined from a reference population consisting of individuals diagnosed with BaSIRS, VaSIRS or PaSIRS; (5) comparing the indicator to the indicator references to thereby determine a probability indicative of the subject having or not having BaSIRS, VaSIRS or PaSIRS; and (6) generating a representation of the probability, the representation being displayed to a user to allow the user to assess the likelihood of a biological subject having BaSIRS, VaSIRS or PaSIRS. 
     In other embodiments, the method that is implemented by the processing device(s) determines an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS or InSIRS, wherein the method comprises: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values and a plurality of InSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, and the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value and at least one InSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, and each derived InSIRS biomarker value being determined using at least a subset of the plurality of InSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, and wherein the at least a subset of InSIRS biomarkers forms a InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS, wherein the BaSIRS derived biomarker combination is suitably selected from TABLE A, wherein the VaSIRS derived biomarker combination is suitably selected from TABLE B, and wherein the InSIRS derived biomarker combination is suitably selected from TABLE D; (4) retrieving previously determined indicator references from a database, the indicator references being determined based on indicators determined from a reference population consisting of individuals diagnosed with BaSIRS, VaSIRS or InSIRS; (5) comparing the indicator to the indicator references to thereby determine a probability indicative of the subject having or not having BaSIRS, VaSIRS or InSIRS; and (6) generating a representation of the probability, the representation being displayed to a user to allow the user to assess the likelihood of a biological subject having BaSIRS, VaSIRS or InSIRS. 
     In still other embodiments, the method that is implemented by the processing device(s) determines an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS, VaSIRS, PaSIRS or InSIRS, wherein the method comprises: (1) determining a plurality of host response specific biomarker values including a plurality of BaSIRS biomarker values, a plurality of VaSIRS biomarker values, a plurality of PaSIRS biomarker values and a plurality of InSIRS biomarker values, the plurality of BaSIRS biomarker values being indicative of values measured for a corresponding plurality of BaSIRS biomarkers in a sample taken from the subject, the plurality of VaSIRS biomarker values being indicative of values measured for a corresponding plurality of VaSIRS biomarkers in the sample, the plurality of PaSIRS biomarker values being indicative of values measured for a corresponding plurality of PaSIRS biomarkers in the sample, and the plurality of InSIRS biomarker values being indicative of values measured for a corresponding plurality of InSIRS biomarkers in the sample; (2) determining a plurality of host response specific derived biomarker values including at least one BaSIRS derived biomarker value, at least one VaSIRS derived biomarker value, at least one PaSIRS derived biomarker value and at least one InSIRS derived biomarker value, each derived BaSIRS biomarker value being determined using at least a subset of the plurality of BaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of BaSIRS biomarkers, each derived VaSIRS biomarker value being determined using at least a subset of the plurality of VaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of VaSIRS biomarkers, each derived PaSIRS biomarker value being determined using at least a subset of the plurality of PaSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of PaSIRS biomarkers, and each derived InSIRS biomarker value being determined using at least a subset of the plurality of InSIRS biomarker values, and being indicative of a ratio of levels of a corresponding at least a subset of the plurality of InSIRS biomarkers; (3) determining the indicator using the plurality of host response specific derived biomarker values, wherein the at least a subset of BaSIRS biomarkers forms a BaSIRS derived biomarker combination which is not a derived biomarker combination for VaSIRS, PaSIRS or InSIRS, wherein the at least a subset of VaSIRS biomarkers forms a VaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, PaSIRS or InSIRS, wherein the at least a subset of PaSIRS biomarkers forms a PaSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or InSIRS, and wherein the at least a subset of InSIRS biomarkers forms a InSIRS derived biomarker combination which is not a derived biomarker combination for BaSIRS, VaSIRS or PaSIRS, wherein the BaSIRS derived biomarker combination is suitably selected from TABLE A, wherein the VaSIRS derived biomarker combination is suitably selected from TABLE B, wherein the PaSIRS derived biomarker combination is suitably selected from TABLE C, and wherein the InSIRS derived biomarker combination is suitably selected from TABLE D; (4) retrieving previously determined indicator references from a database, the indicator references being determined based on indicators determined from a reference population consisting of individuals diagnosed with BaSIRS, VaSIRS, PaSIRS or InSIRS; (5) comparing the indicator to the indicator references to thereby determine a probability indicative of the subject having or not having BaSIRS, VaSIRS, PaSIRS or InSIRS; and (6) generating a representation of the probability, the representation being displayed to a user to allow the user to assess the likelihood of a biological subject having BaSIRS, VaSIRS, PaSIRS or InSIRS. 
     In any of the above embodiments, the method that is implemented by the processing device(s) determines an indicator used in assessing a likelihood of a subject having a presence, absence or degree of BaSIRS or VaSIRS, or optionally one of PaSIRS or InSIRS, wherein the methods further comprise: (a) determining a plurality of pathogen specific biomarker values including at least one bacterial biomarker value and at least one viral biomarker value, and optionally at least one protozoal biomarker value, the least one bacterial biomarker value being indicative of a value measured for a corresponding bacterial biomarker in the sample, the least one viral biomarker value being indicative of a value measured for a corresponding viral biomarker in the sample, and the least one protozoal biomarker value being indicative of a value measured for a corresponding protozoal biomarker in the sample; (b) determining the indicator using the host response specific derived biomarker values in combination with the pathogen specific biomarker values; (c) retrieving previously determined indicator references from a database, the indicator references being determined based on indicators determined from a reference population consisting of individuals diagnosed with BaSIRS, VaSIRS or optionally one of PaSIRS or InSIRS; (d) comparing the indicator to the indicator references to thereby determine a probability indicative of the subject having or not having BaSIRS, VaSIRS, PaSIRS or InSIRS; and (6) generating a representation of the probability, the representation being displayed to a user to allow the user to assess the likelihood of the subject having BaSIRS or VaSIRS, or optionally one of PaSIRS or InSIRS. 
     Similarly apparatus can be provided for determining the likelihood of a subject having BaSIRS or VaSIRS, or optionally one of PaSIRS or InSIRS, the apparatus including: (A) a sampling device that obtains a sample taken from a subject, the sample including a plurality of host response specific biomarkers, and optionally at least one pathogen specific biomarker selected from BIP and VIP biomarkers, and optionally PIP biomarkers, wherein the host response specific biomarkers include a plurality of BaSIRS biomarkers, a plurality of VaSIRS biomarkers, and optionally one or both of a plurality of PaSIRS biomarkers and a plurality of InSIRS biomarkers; (B) a measuring device that quantifies for each of the host response specific biomarkers within the sample a corresponding host response specific biomarker value, and optionally that quantifies for each of the pathogen specific biomarkers within the sample a corresponding pathogen specific biomarker value; (C) at least one processing device that: (i) receives the host response specific biomarker values, and optionally receives the pathogen specific biomarker values from the measuring device; (ii) determines for at least a subset of the plurality of biomarker values of a specific SIRS type, a host response specific derived biomarker value indicative of a ratio of levels of a corresponding at least a subset of the plurality of host response specific biomarkers; (iii) determines an indicator that is at least partially indicative of the presence, absence or degree of BaSIRS or VaSIRS, or optionally one of PaSIRS or InSIRS using the host response specific derived biomarker values in combination with the pathogen specific biomarker values; (iv) compares the indicator to at least one indicator reference; (v) determines a likelihood of the subject having or not having a BaSIRS, VaSIRS, or optionally one of PaSIRS or InSIRS using the results of the comparison; and (v) generates a representation of the indicator and the likelihood for display to a user. 
     In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples. 
     EXAMPLES 
     Example 1 
     General Approach—BaSIRS, VaSIRS, PaSIRS and InSIRS Host Response Specific Biomarker Derivation (Derived Biomarkers) 
     An illustrative process for the identification of BaSIRS, VaSIRS, PaSIRS and InSIRS host response biomarkers for use in diagnostic algorithms will now be described. 
     Gene expression data (derived from clinical trials performed by the inventors and/or from Gene Expression Omnibus) were analyzed using a variety of statistical approaches to identify derived biomarkers (ratios) and largely follows the method described in WO 2015/117204. Individual and derived markers were graded based on performance (Area Under Curve). Datasets derived from GEO (which are all MIAME-compliant) were used with the following restrictions; peripheral blood samples were used, appropriate controls were used, an appropriate number of samples were used to provide significance following False-Discovery Rate (FDR) adjustment, all data passed standard quality control metrics, principle component analysis did not reveal any artifacts or potential biases. The datasets were allocated into two groups (or combined samples from all datasets split evenly into two groups)—“discovery” and “validation”. The datasets in the “discovery” groups were deliberately chosen to enable the identification of specific BaSIRS, VaSIRS, PaSIRS and InSIRS biomarker profiles that could be used generically for a variety of known bacterial pathogens that cause BaSIRS, all Baltimore virus classification groups and across different mammalian species, a variety of protozoans with high morbidity that cause systemic inflammation and a variety of different non-infectious SIRS conditions. The studies therefore included; (a) for BaSIRS; Gram positive and Gram negative bacteria, a variety of different affected body systems, across a range of severity (b) for VaSIRS; DNA and RNA viruses, multiple mammalian species (human, macaque, chimpanzee, pig, mice, rat), high likelihood of generating a systemic inflammatory response (c) for PaSIRS; a variety of malarial ( Plasmodium ) species, a variety of protozoal species including  Plasmodium, Leishmania  and  Toxoplasma  (d) for InSIRS; a variety of non-infectious causes of systemic inflammation (e.g., trauma, asthma, allergy, cancer). For all studies the following parameters were also considered to be important: experimentally-infected subjects where a control sample was taken prior to inoculation, samples taken over time, in particular early-stage samples with a low likelihood of secondary complications from other infections (e.g., viral etiology with a secondary bacterial infection or a protozoan infection with a secondary bacterial infection). 
     Prior to analysis each dataset was filtered to include only the top genes (usually between 3000 and 6000 (of 35,000) depending upon data quality, level of expression and commonality across the datasets) as measured by the mean gene expression level across all samples in the dataset. This ensured that only those genes with relatively strong expression were analyzed and that a limited number of candidates were taken forward to the next compute-time intensive step. Receiver Operating Characteristic (ROC) curves and the area under theses curves (also referred to herein as Area Under Curve (AUC)) were then calculated across all derived biomarkers using the difference in the log 2 of the expression values for each derived biomarker. This resulted in approximately 36,000,000 (6000×5999) derived biomarkers per dataset. An AUC&gt;0.5 was defined as a derived biomarker value being higher in cases than controls, i.e. where the numerator is potentially up-regulated in cases and/or the denominator is potentially down-regulated in cases. Generally, a ‘numerator’ biomarker of an individual biomarker pair disclosed herein is up-regulated or expressed at a higher level relative to a control (e.g., a healthy control) and a ‘denominator’ biomarker of the biomarker pair is unchanged or expressed at about the same level, or is down-regulated or expressed at a lower level, relative to a control (e.g., a healthy control). “Discovery” datasets were then combined by taking the mean AUC for each derived biomarker. Resulting derived biomarkers were then filtered by keeping only those with a mean AUC greater than a pre-determined threshold across all relevant datasets relevant to each of BaSIRS, VaSIRS, PaSIRS and InSIRS. The pool of remaining derived biomarkers after this step was a small percentage of the original number but still contained a large number of derived biomarkers with many that were common to each of the conditions of BaSIRS, VaSIRS, PaSIRS and InSIRS. 
     To ensure that the derived biomarkers were specific to either bacterial, viral, protozoan or non-infectious systemic inflammation a number of additional datasets (listed in TABLES 13, 18, 22 and 23) were used to identify derived biomarkers of generalized, non-infectious and infectious inflammation. Appropriate datasets from this list were used to provide specificity—by example, for identification of specific VaSIRS derived biomarkers datasets for systemic inflammation other than VaSIRS were used, and for identification of specific BaSIRS derived biomarkers datasets for systemic inflammation other than BaSIRS were used. These datasets were subjected to the same restrictions as the “discovery” and “validation” datasets including; peripheral blood samples were used, appropriate controls were used, an appropriate number of samples were used to provide significance following False-Discovery Rate (FDR) adjustment, all data passed standard quality control metrics, principle component analysis did not reveal any artifacts or potential biases. Derived biomarkers that had strong performance, based on an AUC threshold in more than a set number of these individual datasets, were removed (“subtracted”) from the list of identified BaSIRS, VaSIRS, PaSIRS or InSIRS derived biomarkers to ensure specificity Each unique pool of biomarkers, one for each of BaSIRS, VaSIRS, PaSIRS and InSIRS, was then taken forward to the next steps (validation and greedy search). Without this “subtraction” step derived biomarkers common to the SIRS conditions would be taken forward, which would result in different outcomes with respect to AUC performance of derived biomarkers and the final selection of the best combination of derived biomarkers (see Example 2). 
     A further filtering step was then applied. Only derived biomarkers with an AUC greater than a set threshold in a set number of the discovery and validation datasets for each condition (BaSIRS, VaSIRS, PaSIRS, InSIRS) were retained. Generally, a cut-off of around AUC of 0.75 or higher was chosen for the following reasons: 1). simple diagnostic heuristics for the diagnosis of influenza have an AUC between 0.7 and 0.79 (Ebell, M. H., &amp; Afonso, A. (2011). A Systematic Review of Clinical Decision Rules for the Diagnosis of Influenza. The Annals of Family Medicine, 9(1), 69-77); 2). clinicians can predict patients that are ultimately blood culture positive from those with suspected infection with an AUC of 0.77 (Fischer, J. E., Harbarth, S., Agthe, A. G., Benn, A., Ringer, S. A., Goldmann, D. A., &amp; Fanconi, S. (2004). Quantifying uncertainty: physicians&#39; estimates of infection in critically ill neonates and children. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America, 38(10), 1383-1390); 3). The use of polymerase chain reaction-based tests, compared to conventional tests, for respiratory pathogens in patients with suspected lower respiratory tract infections (LRTI) increased the diagnostic yield from 21% to 43% of cases (that is, molecular-based pathogen tests in this study only detected a pathogen in 43% of suspected LRTI) (Oosterheert, J. J., van Loon, A. M., Schuurman, R., Hoepelman, A. I. M., Hak, E., Thijsen, S., et al. (2005). Impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection. Clinical Infectious Diseases, 41(10), 1438-1444); 4). the sensitivity of point-of-care tests for influenza is about 70% (Foo, H., &amp; Dwyer, D. E. (2009). Rapid tests for the diagnosis of influenza. Australian Prescriber 32:64-67); 5). The performance of clinical algorithms and lack of trust in diagnostic tests for diagnosing malaria in febrile children in high incidence areas does not result or warrant the withholding anti-malarial drugs (Chandramohan, D., Jaffar, S., &amp; Greenwood, B. (2002). Use of clinical algorithms for diagnosing malaria. Tropical Medicine &amp; International Health: TM &amp; IH, 7(1), 45-52; Bisoffi, Z., Sirima, B. S., Angheben, A., Lodesani, C., Gobbi, F., Tinto, H., &amp; Van den Ende, J. (2009). Rapid malaria diagnostic tests vs. clinical management of malaria in rural Burkina Faso: safety and effect on clinical decisions. A randomized trial. Tropical Medicine &amp; International Health: TM &amp; IH, 14(5), 491-498; Amexo, M., Tolhurst, R., Barnish, G., &amp; Bates, I. (2004). Malaria misdiagnosis: effects on the poor and vulnerable. The Lancet, 364(9448), 1896-1898). Thus, current existing diagnostic procedures and tests for bacterial, viral or protozoan infections do not have either good diagnostic performance or clinician trust, and in many instances no pathogen or antibody response is detected in samples taken at the time a patient presents with clinical signs. BaSIRS, VaSIRS, PaSIRS or InSIRS signatures with an AUC of at least 0.75 will therefore likely have greater clinical utility than most existing bacterial, viral or protozoal diagnostic assays, and at the critical time when the patient presents with clinical signs. Following this filtering step, usually a limited number of derived biomarkers remained, which were considered to be specific to the condition under investigation. 
     Example 2 
     BaSIRS, VaSIRS, PaSIRS and InSIRS Host Response Biomarker Derivation (General Approach—Combination of Derived Biomarkers) 
     Next, a search for the best combination and number of derived biomarkers for each of BaSIRS, VaSIRS, PaSIRS and InSIRS in each of the derived biomarker pools was performed with the aim of finding a minimal set of derived biomarkers with optimal commercial utility. Optimal commercial utility in this instance means consideration of the following non-limiting factors; diagnostic performance, clinical utility, diagnostic noise (introduced by using too many derived biomarkers), transferability to available molecular chemistries (e.g., PCR, microarray, DNA sequencing), transferability to available point-of-care platforms (e.g., Biocartis Idylla, Cepheid GeneXpert, Becton Dickinson BD Max, Curetis Unyvero, Oxford Nanopore Technologies MinION), cost of assay manufacture (the more reagents and biomarkers the larger the cost), ability to multiplex biomarkers, availability of suitable reporter dyes, complexity of results interpretation. 
     To be able to determine the best combination of derived markers all study datasets for each of BaSIRS, VaSIRS, PaSIRS or InSIRS needed to be combined. As such, each dataset was normalized individually using mean centering to zero and variance set to one. The mean of a biomarker in a dataset was calculated in three steps: (a) calculation of the mean of the cases, (b) calculation of the mean of the controls, and (c) calculation of the mean of the preceding two values. Once the mean for each biomarker had been calculated, the expression value for that biomarker in each sample was adjusted by subtracting the mean value. The values were further adjusted by dividing by the variance. This was performed for all biomarker expression values for every sample in every dataset. All of the datasets for each condition category were then combined into four separate (bacterial, viral, protozoal and InSIRS) expression matrices. 
     Following normalization, a search (greedy) for the best performing pair of derived biomarkers was performed (by AUC in the normalized dataset) using the corresponding specific derived biomarker pool for each of the bacterial, viral, protozoal and InSIRS expression matrices. This was accomplished by first identifying the best performing derived biomarker. Each of the other remaining derived biomarkers was then added and, as long as neither biomarker in the newly added derived biomarker was already part of the first derived biomarker, the AUC was calculated. This process continued and an AUC plot was generated based on sequential adding of derived biomarkers. 
     Example 3 
     Host Response Specific Biomarkers are Grouped Based on their Correlation to BaSIRS (OPLAH, ZHX2, TSPO, HCLS1), VaSIRS (ISG15, IL16, OASL and ADGRE5), PaSIRS (TTC17, G6PD, HERC6, LAP3, NUP160 and TPP1) and InSIRS (ARL6IP5, ENTPD1, HEATR1 and TNFSF8) Biomarkers, and Based on Greedy Search Results 
     The individual host response specific biomarkers in the signature for BaSIRS are: TSPO, HCLS1, OPLAH and ZHX2. The individual host response specific biomarkers in the signature for VaSIRS are: ISG15, IL16, OASL and ADGRE5. The individual host response specific biomarkers in the signature for PaSIRS are: TTC17, G6PD, HERC6, LAP3, NUP160 and TPP1. The individual host response specific biomarkers in the signature for InSIRS are: ARL6IP5, ENTPD1, HEATR1 and TNFSF8. There were 94, 413, 130 and 151 unique biomarkers in the lists of 102, 473, 523 and 164 host response specific derived biomarkers with an AUC over a set threshold for BaSIRS, VaSIRS, PaSIRS and InSIRS, respectively. For each unique biomarker, a correlation coefficient was calculated. 
     Two pairs of derived biomarkers (OPLAH/ZHX2; TSPO/HCLS1) were discovered that provided the highest AUC across all of the bacterial datasets studied after non-bacterial derived biomarkers had been subtracted. Biomarkers as ratios that provided an AUC above a set threshold were then allocated to one of four Groups, as individual biomarkers, based on their correlation to either OPLAH (Group A BaSIRS biomarkers), ZHX2 (Group B BaSIRS biomarkers), TSPO (Group C BaSIRS biomarkers) or HCSL1 (Group D BaSIRS biomarkers), as presented in TABLE 24. 
     Two pairs of derived biomarkers (IL16/ISG15; ADGRE5/OASL) were discovered that provided the highest AUC across all of the viral datasets studied after non-viral derived biomarkers had been subtracted. Biomarkers as ratios that provided an AUC above a set threshold were then allocated to one of four Groups, as individual biomarkers, based on their correlation to either ISG15 (Group A VaSIRS biomarkers), IL16 (Group B VaSIRS biomarkers), OASL (Group C VaSIRS biomarkers) or ADGRE5 (Group D VaSIRS biomarkers), as presented in TABLE 26. 
     Three pairs of derived biomarkers (TTC17/G6PD; HERC6/LAP3; NUP160/TPP1) were discovered that provided the highest AUC across all of the protozoan datasets studied after non-protozoan derived biomarkers had been subtracted. Biomarkers as ratios that provided an AUC above a set threshold were then allocated to one of six Groups, as individual biomarkers, based on their correlation to either TTC17 (Group A PaSIRS biomarkers), G6PD (Group B PaSIRS biomarkers), HERC6 (Group C PaSIRS biomarkers), LAP3 (Group D PaSIRS biomarkers), NUP160 (Group E PaSIRS biomarkers) or TPP1 (Group F PaSIRS biomarkers), as presented in TABLE 27. 
     Two pairs of derived biomarkers (ARL6IP5/ENTPD1; HEATR1/TNFSF8) were discovered that provided the highest AUC across all of the InSIRS datasets studied after infectious SIRS (bacterial, viral, protozoal) derived biomarkers had been subtracted. Biomarkers as ratios that provided an AUC above a set threshold were then allocated to one of four Groups, as individual biomarkers, based on their correlation to either ARL6IP5 (Group A InSIRS biomarkers), ENTPD1 (Group B InSIRS biomarkers), HEATR1 (Group C InSIRS biomarkers) or TNFSF8 (Group D InSIRS biomarkers), as presented in TABLE 28. 
     Following greedy searches, the best host response derived biomarkers, including any combination of such biomarkers, for BaSIRS, VaSIRS, PaSIRS and InSIRS are:
         BaSIRS—TSPO:HCLS1, OPLAH:ZHX2, TSPO:RNASE6, GAS7:CAMK1D, STGAL2:PRKD2, PCOLE2:NMUR1, CR1:HAL   VaSIRS—ISG15:1L16, OASL:ADGRE5, TAP1:TGFBR2, IFIH1:CRLF3, IFI44:IL4R, EIFAK2:SYPL1, OAS2:LEF1, STAT1/PCBP2   PaSIRS—TTC17:G6PD, HERC6:LAP3, NUP160:TPP1, RPL15:GP1, ARID1A:CSTB,   AHCTF1:WARS, FBXO11:TANK, ADSL:ENO1, RPL9:TNIP1, ASXL2:IRF1.   InSIRS—ENTPD1:ARL6IP5, TNFSF8:HEATR1, ADAM19:POLR2A, SYNE2:VPS13C,   TNFSF8: NIP7, CDA: EFHD2, ADAM19:MLLT10, CDA: PTGS1, ADAM19:EXOC7, TNFSF8:TRIP11.       

     Example 4 
     BaSIRS Host Response Biomarker Derivation 
     A step-wise procedure was undertaken to identify biomarkers useful in determining a host systemic immune response to bacterial infection, which largely employs the same steps that were used to identify host systemic immune response biomarkers of viral infection, as described in Australian provisional patent application 2015903986. 
     In brief, bacterial derived biomarkers were discovered that are capable of determining a specific mammalian systemic host response to bacteria. This was achieved using a step-wise approach of derived biomarker discovery, subtraction and validation. Data pre-processing included; log 2 transformation (if gene expression data was from arrays), choice of the most intense probe to represent a gene, and choice of those ˜40% of genes with the largest variance within our own in-house datasets, which equalled approximately 3700 genes (which were then applied to publicly available datasets). 
     Discovery of a large pool of derived biomarkers was performed using carefully selected samples from in-house datasets (“Fever”, “MARS” and “GAPPSS”, n=6) and Gene Expression Omnibus (GSE) datasets (n=7)). Samples were pre-selected and categorized into InSIRS or BaSIRS using other known host response signatures and then split into two groups used for either “discovery” (n=984) or “validation” (n=1045) (see TABLES 11 and 12 for details on the datasets and samples in each group). 
     Derived biomarkers were computed for every combination in both the Discovery and Validation datasets, resulting in a total of 13,671,506 binary combinations. A total of 255 derived biomarkers had an AUC&gt;0.8 across all discovery datasets and 102 that had an AUC&gt;0.85 across the validation datasets (see TABLE 15). These same 102 derived biomarkers were then tested on other datasets containing samples derived from subjects with systemic inflammation not related to BaSIRS (see TABLE 13 for a list of these datasets). Other non-BaSIRS systemic conditions in these datasets included; viral infection, asthma, coronary artery disease, stress, sarcoidosis and cancer. The mean AUC range for the 102 derived biomarkers across these datasets was between 0.28 and 0.53 indicating specificity of the derived biomarkers for BaSIRS. 
     Datasets were then merged so that a greedy search could be performed with the aim of finding the best combination of derived biomarkers for separating InSIRS and BaSIRS subjects. Merging of datasets was achieved in the following manner. Each dataset was normalized by mean centering to zero and forcing gene variance to one as follows: The mean of a gene in a dataset was calculated in three steps: (a) calculation of the mean of the cases, (b) calculation of the mean of the controls, and (c) calculation of the mean of those two values. Once the mean was calculated, the expression values for that gene in each sample were adjusted by subtracting the mean value. An expression matrix was then standardized to unit variance by dividing by the genes variance. All datasets were then combined into a single “expression” matrix after normalizing each dataset individually. The matrix had dimensions of 102 biomarkers and 984 samples. 
     The best combinations of derived ratios were then determined using a greedy search. A number of factors, including the use of a limited number of derived biomarkers, ease of porting onto a Point-of-Care platform, and performance based on AUC, were used to select the final combination of derived biomarkers.  FIG. 1  and TABLE 29 show the AUC performance of the successive addition of individual derived biomarkers in the balanced-scale discovery datasets. The final BaSIRS signature chosen was OPLAH/ZHX2:TSPO/HCLS1 which had an AUC in the balance-scaled data of 0.863. Performance of this signature in each of the individual un-scaled (i.e. raw data) Validation, Discovery and non-BaSIRS datasets is shown in TABLE 14. The mean AUC for this signature in the Discovery, Validation and Non-BaSIRS datasets was 0.923, 0.880 and 0.614 respectively. The performance of this signature is also demonstrated in graphical form in  FIGS. 2-5 . 
     Some numerators and denominators occurred more often in the 102 derived biomarkers, perhaps indicating that specific pathways are involved in the immune response to bacteria, or that some biomarkers are expressed in such a manner that makes them more suitable as a numerator or denominator. TABLE 30 lists those individual BaSIRS biomarkers that appear more than once as either a numerator or denominator that are a component of the 102 derived biomarkers with a mean AUC&gt;0.85. 
     Example 5 
     VaSIRS Host Response Biomarker Derivation 
     A step-wise procedure was undertaken to identify biomarkers useful in determining a host systemic immune response to viral infection which largely the same as described in Australian provisional patent application 2015903986. 
     In brief, “pan-viral” derived biomarkers were discovered that are capable of determining a specific mammalian systemic host response to viruses belonging to any of the seven Baltimore virus classification groups. This was achieved using a step-wise approach of derived biomarker discovery, subtraction and validation. Discovery of a large pool of derived biomarkers was performed using a set of four “core” datasets containing samples from subjects with no known infectious co-morbidities and a confirmed viral infection. Derived biomarkers in this large pool were then removed, or subtracted, if they had diagnostic performance, above a set threshold, in other datasets containing samples derived from subjects with other systemic inflammatory conditions, such as bacterial sepsis, allergy, autoimmune disease and sarcoidosis. Derived biomarkers for age, gender, body mass index and race were also subtracted from the pool. Following these steps there remained a total of 473 derived biomarkers with an AUC&gt;0.8 in at least 11 of 14 individual viral datasets (see TABLE 20 for a list of these derived biomarkers and their performance). Using a greedy search on combined datasets, derived biomarkers and combinations of derived biomarkers were then identified that provided good diagnostic performance (AUC=0.936) in the viral datasets (n=14) (See  FIG. 6  and TABLE 31). Validation of the diagnostic performance of a “pan-viral” signature, composed of the two derived biomarkers of ISG15/IL16 and OASL/ADGRE5, in a number of other validation datasets was then determined and some results are shown in  FIGS. 7-13 . Thus, the combination of four biomarkers consisting of ISG15/IL16 and OASL/ADGRE5, and other biomarkers correlated to each of these individual biomarkers, is considered to be a “pan-viral” diagnostic signature that provides strong diagnostic performance across various mammals, including humans, and across different virus types based on Baltimore classification groups I-VII. 
     Some numerators and denominators occurred more often in the 473 derived biomarkers, perhaps indicating that specific pathways are involved in the immune response to viruses, or that some biomarkers are expressed in such a manner that makes them more suitable as a numerator or denominator. TABLE 31 lists those individual VaSIRS biomarkers that appear more than once as either a numerator or denominator that are a component of the 473 derived biomarkers with a mean AUC&gt;0.8. 
     Example 6 
     PaSIRS Host Response Biomarker Derivation 
     A step-wise procedure was undertaken to identify biomarkers useful in determining a host systemic immune response to protozoal infection. 
     Four suitable datasets were identified in Gene Expression Omnibus covering studies on malaria and  leishmania  protozoal organisms—see TABLE 21 for details of the number and type of samples in each patient cohort for biomarker discovery. The data was preprocessed by cleaning duplicate genes and performing balanced univariate scaling on all the datasets. All the datasets were then merged by gene name which resulted in 4421 potential target genes. 
     AUCs were then calculated for all possible combinations of two biomarkers (19,540,820 derived biomarkers). A cut-off of 0.9 was applied and, as such, 9329 derived biomarkers were taken through to the next step of derived biomarker identification. 
     Sixteen gene expression omnibus datasets were then identified that contained patients or subjects with other conditions, or systemic inflammation due to causes other than protozoal infection (see TABLE 23). These datasets were then merged, as described for the protozoal datasets above, and an AUC calculated for each of the 9329 derived biomarkers. Only derived biomarkers that had an AUC &lt;0.7 in this non-specific merged dataset were taken forward to the next step. As a result 523 derived biomarkers that were considered to be specific to protozoal systemic inflammation were taken forward to the next step. 
     A greedy search was then applied to the protozoal (including the four “discovery” datasets and five “validation” datasets—see TABLE 22) and non-protozoal datasets using all 523 derived biomarkers. The search parameters were set to maximize the difference in AUC between the protozoal and non-protozoal datasets.  FIG. 14  shows the results of this greedy search in the form of a plot of AUC versus identified derived biomarkers when added sequentially. TABLE 32 shows the AUC obtained using a single derived biomarker and when using a combination of two and three derived biomarkers. A combination of three derived biomarkers resulted in an AUC of 0.99 and such a combination is considered to be the best through a balance of diagnostic performance, fewest biomarkers and least likelihood of introduction of noise. TABLE 32 identifies the three derived biomarkers and the AUC obtained in the merged datasets used in this study. Performance of these derived biomarkers across all of the datasets used is shown in the box and whisker plots of  FIGS. 15 and 16 . From these figures it can be clearly seen that the derived biomarkers provide good separation of patients with systemic inflammation due to a protozoal infection compared to control subjects and that these same derived biomarkers have little or no diagnostic utility in patients with systemic inflammation due to causes other than protozoal infection. Performance (AUC) of each of the derived biomarkers alone across each of the protozoal datasets is shown in TABLE 34. 
     Validation of these derived biomarkers was then performed on five independent datasets obtained from gene expression omnibus (GEO). These datasets represented studies in four types of protozoans, in blood and tissues other than blood, and in vitro and in vivo (see TABLE 21). Because some of these datasets used tissues other than whole blood, and the signature is designed to detect systemic inflammation using circulating leukocytes, diagnostic performance was not expected to be as strong.  FIGS. 15-21  shows the performance of the final PaSIRS signature in these datasets, and other datasets, as box and whisker plots. 
     Some numerators and denominators occurred more often in the 523 derived biomarkers, perhaps indicating that specific pathways are involved in the immune response to protozoans, or that some biomarkers are expressed in such a manner that makes them more suitable as a numerator or denominator. TABLE 33 lists those biomarkers that appear more than once in the 523 derived biomarkers. 
     Example 7 
     InSIRS Host Response Biomarker Derivation 
     A step-wise procedure was undertaken to identify biomarkers useful in determining a host systemic immune response to non-infectious causes, which largely employs the same steps that were used to identify host systemic immune response biomarkers of viral infection, as described in Australian provisional patent application 2015903986. 
     In brief, InSIRS derived biomarkers were discovered that are capable of determining a specific mammalian systemic host response to non-infectious causes. This was achieved using a step-wise approach of derived biomarker discovery, subtraction and validation. Discovery of a large pool of derived biomarkers was performed using a set of datasets containing samples from subjects with no known infectious co-morbidities. Derived biomarkers in this large pool were then removed, or subtracted, if they had diagnostic performance, above a set threshold, in other datasets containing samples derived from subjects with infectious systemic inflammatory conditions, such as bacterial sepsis, viral systemic inflammation and protozoal systemic inflammation. Derived biomarkers for age, gender and race were also subtracted from the pool. Following these steps there remained a total of 164 derived biomarkers with an AUC&gt;0.82 (see TABLE 37 for a list of these derived biomarkers and their performance). Using a greedy search on combined datasets, derived biomarkers and combinations of derived biomarkers were then identified that provided good diagnostic performance (AUC=0.935) in the non-infectious SIRS datasets (See  FIG. 22  and TABLE 35). Validation of the diagnostic performance of a InSIRS signature, composed of the two derived biomarkers of ARL6IP5/ENTPD1 and HEATR1/TNFSF8, in a number of other validation datasets was then determined. Thus, the combination of four biomarkers consisting of ARL6IP5/ENTPD1 and HEATR1/TNFSF8, and other biomarkers correlated to each of these individual biomarkers, is considered to be a InSIRS diagnostic signature that provides strong diagnostic performance. 
     Some numerators and denominators occurred more often in the 164 derived biomarkers, perhaps indicating that specific pathways are involved in the immune response to non-infectious insult, or that some biomarkers are expressed in such a manner that makes them more suitable as a numerator or denominator. TABLE 37 lists those individual InSIRS biomarkers that appear more than once as either a numerator or denominator that are a component of the 164 derived biomarkers with a mean AUC&gt;0.82. 
     Example 8 
     BaSIRS, VaSIRS, PaSIRS and InSIRS Host Response Biomarker Performance (Derived Biomarkers and Combined Derived Biomarkers) 
     Following normalization of each of the BaSIRS, VaSIRS, PaSIRS and InSIRS datasets and a greedy search the best performing individual host response specific derived BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers were: TSPO:HCLS1; ISG15:IL16; TTC17:G6PD; and ARL6IP5:ENTPD1, with AUCs of 0.84, 0.92, 0.96 and 0.89, respectively. The best second unique host response derived biomarkers to add to the first BaSIRS, VaSIRS, PaSIRS and InSIRS derived biomarkers were: OPLAH:ZHX2; OASL:ADGRE5; HERC6:LAP3; and HEATR1:TNFSF8, respectively. The AUCs obtained across the normalized datasets using the two host response specific derived biomarkers for BaSIRS, VaSIRS, PaSIRS and InSIRS was 0.86, 0.936, 0.99 and 0.93, a 0.2, 0.016, 0.3 and 0.36 improvement over the use of single host response specific derived biomarkers (see  FIGS. 1, 6, 14 and 22 ). The addition of third host response specific derived biomarkers (TSPO:RNASE6, TAP1:TGFBR2, NUP160:TPP1 and ADAM19:POLR2A) only improved the AUC by 0.2, 0.009, 0.0 and 0.006 and it is possible that a third derived biomarker created overfitting and noise. However, it was considered that embodiments of optimal signatures consist essentially of the following derived biomarkers: OPLAH:ZHX2/TSPO:HCLS1 (BaSIRS); ISG15:IL16/OASL:ADGRE5 (VaSIRS); TTC17:G6PD/HERC6:LAP3/NUP160:TPP1 (PaSIRS); and ARL6IP5:ENTPD1/HEATR1:TNFSF8 (InSIRS).  FIGS. 1, 6, 14 and 22  show the effect on the overall AUC of sequentially adding derived biomarkers to TSPO:HCLS1, ISG15:IL16, TTC17:G6PD and ARL6IP5:ENTPD1. 
     TABLES 28, 30, 32 and 35 show the performance (AUC) of some of the top host response specific derived biomarkers individually and when added sequentially to the top performing derived biomarkers for the combined datasets. 
     Example 8 
     BaSIRS, VaSIRS, PaSIRS and InSIRS Host Response Specific Biomarker Frequent Denominators and Numerators 
     The BaSIRS, VaSIRS, PaSIRS and InSIRS individual biomarkers can be grouped based on the number of times they appear as numerators or denominators in the top performing derived biomarkers. 
     TABLES 29, 31, 33 and 36 show the frequency of individual biomarkers that appear often in the numerator and denominator positions of the derived biomarkers for BaSIRS, VaSIRS, PaSIRS and InSIRS, respectively. For BaSIRS, PDGFC and TSPO are the most frequent numerators appearing 28 and 11 times, respectively, and INPP5D and KLRD1 are the most frequent denominators appearing 6 times each. For VaSIRS, OASL and USP18 are the most frequent numerators appearing 344 and 50 times, respectively, and ABLIM and IL16 are the most frequent denominators appearing 12 and 9 times, respectively. For PaSIRS, ARID1A and CEP192 are the most frequent numerators appearing 62 and 35 times, respectively, and SQRDL and CEBPB are the most frequent denominators appearing 45 and 40 times, respectively. For InSIRS, TNFSF8 and ADAM19 are the most frequent numerators appearing 90 and 17 times, respectively, and MACF1 and ARL6IP5 are the most frequent denominators appearing 8 and 6 times respectively. 
     Example 9 
     Example Applications of a Combination of BaSIRS, VaSIRS, PaSIRS and InSIRS Host Response Biomarker Profiles 
     Use of the BaSIRS, VaSIRS, PaSIRS and InSIRS biomarker profiles in combination in patient populations and the benefits with respect to differentiating various conditions, will now be described. 
     An assay capable of differentiating patients presenting with clinical signs of systemic inflammation can be used in multiple settings in both advanced and developing countries including: Intensive Care Units (medical and surgical ICU), medical wards, Emergency Departments (ED) and medical clinics. An assay capable of differentiating such patients can be used to identify those patients that (1) need to be isolated from others as part of managing spread of disease; (2) need specific treatments or management procedures; (3) do not need treatment. Such an assay can also be used as part of efforts to ensure judicious use of medical facilities and therapies including antibiotic, anti-viral and anti-protozoal medicines, detection of re-activation of latent or dormant viruses, determination of the severity of a BaSIRS, VaSIRS, PaSIRS or InSIRS, and determination of the etiology of an infection causing the presenting systemic inflammation. Such an assay can also be used to determine whether isolated microorganisms (bacterium, virus, protozoa) are more likely to be true pathogens or a contaminant/commensal/pathobiont/resident/residual microorganism. 
     Detecting an Immune Response to Key Pathogens when Patients Present 
     There are a limited number of human pathogens that cause a bacteremia, viremia or parasitemia and of those that do, their presence in blood is often only for a short period as part of the pathogenesis, making direct detection of the pathogen difficult when using blood as a sample. Further, it takes 10-14 days following an initial infection for specific immunoglobulin G antibodies to appear in blood which can persist for some time making the determination of when a patient became infected difficult. Systemic infection with a pathogen causes a detectable systemic immune response (BaSIRS, VaSIRS, PaSIRS) prior to, and during, the development of peak clinical signs. As such, host response biomarkers are useful for early diagnosis, diagnosis and monitoring in the key periods of pathogen incubation, and when patients present with clinical signs. TABLE 1 lists common human pathogens that are known to cause SIRS and a bacteremia, viremia or parasitemia. 
     Detecting a Specific Immune Response to Key Pathogens for which there are Tailored Therapies 
     It is important to be able to distinguish bacterial, viral and protozoan systemic infections so that appropriate therapies can be administered. Most systemic bacterial infections require immediate treatment with antibiotics and the risk to the patient of missing such a diagnosis is high. For most viruses there are no available anti-viral compounds; however, it is important that viruses, as for example shown in TABLE 2 be detected and identified because 1) they can be treated with anti-viral medication 2) most other viral infections cause transient clinical signs and are not life-threatening. Systemic protozoal infections also require immediate treatment with anti-protozoal therapies; however, in many instances such therapies are administered without a proper diagnostic work-up or even in the face of negative diagnostic test results. In many viral and protozoal infections it is also important to know if there is a co-infection with bacteria so that antibiotics can be prescribed since, in many instances, a systemic bacterial infection can be more life-threatening. The host response biomarkers described herein can determine the extent of systemic inflammation due to a bacterial, viral or protozoal infection and, as such, judgment can be made as to whether antibiotic prescription is appropriate. Further, once it has been determined that systemic inflammation is due to a bacterium, virus or protozoan, other more specific diagnostic tests can be used downstream to identify the pathogen. 
     Detecting an Immune Response to Key Pathogens that Cause Respiratory Disease 
     It is known that the respiratory tract has its own microbiome and virome and that interactions between different bacteria (whether known pathogens, commensals or pathobionts), different viruses and host immune defenses (including innate, cellular, adaptive, physical barriers) determine whether respiratory disease is induced or not (Bosch, A. A. T. M., Biesbroek, G., Trzcinski, K., Sanders, E. A. M., &amp; Bogaert, D. (2013). Viral and Bacterial Interactions in the Upper Respiratory Tract. PLoS Pathogens, 9(1), e1003057-12). Further, it is known that respiratory clinical signs are common in patients with malaria (Taylor, W. R. J., Hanson, J., Turner, G. D. H., White, N. J., &amp; Dondorp, A. M. (2012). Respiratory manifestations of malaria. Chest, 142(2), 492-505). It is also known that both bacteria and viruses are commonly isolated in respiratory tract samples (e.g., Bronchial Alveolar Lavage) from both healthy and diseased subjects, and that different bacteria and viruses can potentiate the pathogenic effects of each other (McCullers, J. A. (2006). Insights into the Interaction between Influenza Virus and Pneumococcus. Clinical Microbiology Reviews, 19(3), 571-582). Therefore, isolating a known pathogen or commensal from a respiratory sample does not necessarily mean it is a causative organism and/or whether it is contributing to respiratory pathology and a host systemic inflammatory response. As such, in patients presenting to medical facilities with respiratory clinical signs in combination with systemic inflammation, it is important to determine an etiology and the extent of systemic inflammation and whether it is due to an infectious organism. The host response biomarkers described herein can determine the extent of systemic inflammation in patients with respiratory clinical signs and whether it is due to a bacterial, viral or protozoal infection. As such, judgment can be made regarding appropriate management procedures, specific anti-viral or anti-protozoal treatments and/or antibiotic treatments. 
     Differentiating Patients with Bacterial and Viral Conditions in ICU 
     It has been shown that greater than 50% and 80% of patients in medical and surgical ICUs respectively have SIRS (Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26 Suppl 1: S64-S74). From a clinician&#39;s perspective these patients present with non-specific clinical signs and the source and type of infection, if there is one, must be determined quickly so that appropriate therapies can be administered. Patients with InSIRS have a higher likelihood of being infected with bacteria (compared to patients without SIRS), and have a much higher 28-day mortality (Comstedt P, Storgaard M, Lassen A T (2009) The Systemic Inflammatory Response Syndrome (SIRS) in acutely hospitalised medical patients: a cohort study. Scand J Trauma Resusc Emerg Med 17: 67. doi:10.1186/1757-7241-17-67). Further, patients with prolonged sepsis (BaSIRS) have a higher frequency of viral infections, possibly due to reactivation of latent viruses as a result of immunosuppression (Walton, A. H., Muenzer, J. T., Rasche, D., Boomer, J. S., &amp; Sato, B. (2014). Reactivation of multiple viruses in patients with sepsis. PLoS ONE). The higher the prevalence of SIRS in ICU, the higher the risk of infection and death will be in SIRS-affected patients. The re-activation of viruses in ICU patients with BaSIRS, and the benefits of early intervention in patients with BaSIRS (Rivers E P (2010) Point: Adherence to Early Goal-Directed Therapy: Does It Really Matter? Yes. After a Decade, the Scientific Proof Speaks for Itself. Chest 138: 476-480) creates a need for triaging patients with clinical signs of SIRS to determine whether they have a viral or bacterial infection, or both. Monitoring intensive care patients on a regular basis with biomarkers of the present invention will allow medical practitioners to determine the presence, or absence, of a bacterial or viral infection. If positive, further diagnostic tests could then be performed on appropriate clinical samples to determine the type of infection so that appropriate therapy can be administered. For example, if a patient tested positive for a viral infection, and further testing demonstrated the presence of a herpes virus, then appropriate anti-herpes viral therapies could be administered. 
     In pediatric ICUs the incidence of viral infections is reportedly low (1%), consisting mostly of enterovirus, parechovirus and respiratory syncytial virus infections (Verboon-Maciolek, M. A., Krediet, T. G., Gerards, L. J., Fleer, A., &amp; van Loon, T. M. (2005). Clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a 12-year period. The Pediatric Infectious Disease Journal, 24(10), 901-904). However, because viral infections often predispose infants to bacterial infections, and the mortality rate of virus-infected patients is high, and such patients present with similar clinical signs, it is important to either rule in or rule out the possibility of a bacterial or viral infection so that other appropriate therapies can be administered, and appropriate downstream diagnostic tests and management procedures can be performed. 
     Determining which patients have which type of infection in the ICU will allow for early intervention, appropriate choice of therapies, when to start and stop therapies, whether a patient needs to be isolated, when to start and stop appropriate patient management procedures, and in determining how a patient is responding to therapy. Information provided by the BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers of the present invention will therefore allow medical intensivists to tailor and modify therapies and management procedures to ensure infected patients survive and spend less time in intensive care. Less time in intensive care leads to considerable savings in medical expenses including through less occupancy time and through appropriate use and timing of medications. 
     Differentiating Patients with Systemic Inflammation Due to an Infection in Hospital Wards 
     In a study in a U.S. hospital of over 4000 inpatients over an 11-week period at least one episode of fever occurred in 1,194 patients (29%) (McGowan J E J, Rose R C, Jacobs N F, Schaberg D R, Haley R W (1987) Fever in hospitalized patients. With special reference to the medical service. Am J Med 82: 580-586). The rate of fever was highest on medical and surgical services and the authors found that both infectious and non-infectious processes played important roles in the cause. However, determining the cause of fever was complicated by the fact that over 390 different factors were identified. In this study, a review of 341 episodes of fever in 302 patients on the medical service identified a single potential cause in 56%, multiple factors were present in 26%, and no potential causes were found in 18%. Of all factors identified, 44% were community-acquired infections, 9% were nosocomial infections, 20% possibly involved infection, and 26% were non-infectious processes. Thus, fever is common in hospital surgical and medical wards, there are many causes including infectious and non-infectious, diagnosis is difficult and in many instances a cause is not found. The biomarkers outlined herein can differentiate bacterial, viral and protozoal infections from other causes of SIRS which will assist medical practitioners in determining the cause of fever, ensuring that resources are not wasted on unnecessary diagnostic procedures and that patients are managed and treated appropriately. 
     The estimated number of hospital acquired infections (HAI) in the USA in 2002 was 1.7 million of which approximately 100,000 caused patient death (Klevens et al., Estimating Health Care-Associated Infections and Deaths in U.S. Hospitals. Public Health Reports, March-April 2007 Vol 122, p 160-166, 2002). Common sites and microorganism for HAIs include the respiratory and urinary tracts, and canulas with  Staphylococcus  and  E. coli  (Spelman, D. W. (2002). 2: Hospital-acquired infections. The Medical Journal of Australia, 176(6), 286-291). Viruses are also an important cause of HAI where it has been reported that between 5 and 32% of all nosocomial infections are due to viruses, depending upon the hospital location and patient type (Aitken, C., &amp; Jeffries, D. J. (2001). Nosocomial spread of viral disease. Clinical Microbiology Reviews, 14(3), 528-546); Valenti, W. M., Menegus, M. A., Hall, C. B., Pincus, P. H., &amp; Douglas, R. G. J. (1980). Nosocomial viral infections: I. Epidemiology and significance. Infection Control: IC, 1(1), 33-37). Identification of those patients in wards with a BaSIRS or VaSIRS, especially early in the course of infection when there are non-specific clinical signs, would assist clinicians and hospital staff in determining appropriate measures (e.g quarantine, hygiene methods) to be put in place to reduce the risk of spread of infection to other non-infected patients. 
     Differentiating Patients with an Infection in Emergency Departments 
     In 2010, approximately 130 million people presented to emergency departments in the USA and the third most common primary reason for the visit was fever (5.6 million people had a fever (&gt;38° C.) and for 5 million people it was the primary reason for the visit) (Niska R, Bhuiya F, Xu J (2010) National hospital ambulatory medical care survey: 2007 emergency department summary. Natl Health Stat Report 26: 1-31). Of those patients with a fever, 664,000 had a fever of unknown origin—that is, the cause of the fever was not obvious at presentation. As part of diagnosing the reason for the emergency department visit 48,614,000 complete blood counts (CBC) were performed and 5.3 million blood cultures were taken. In 3.65 million patients presenting the primary diagnosis was “infectious” and in approximately 25% of cases (32.4 million) antibiotics were administered. 13.5% of all people presenting to emergency were admitted to hospital. Clinicians in emergency need to determine the answer to a number of questions quickly, including: what is the reason for the visit, is the reason for the visit an infection, does the patient need to be admitted? The diagnosis, treatment and management of patients with a fever, InSIRS, VaSIRS or BaSIRS are different. By way of example, a patient with a fever without other SIRS clinical signs and no obvious source of viral, or bacterial infection may be sent home, or provided with other non-hospital services, without further hospital treatment. However, a patient with a fever may have early BaSIRS, and not admitting such a patient and aggressively treating with antibiotics may put their life at risk. Such a patient may also have VaSIRS and quickly deteriorate, or progress to BaSIRS without appropriate hospital care and/or the use of anti-viral agents. The difference in the number of patients presenting to emergency that are ultimately diagnosed with an “infection” (3.65 million) and the number treated with antibiotics (32.4 million) suggests the following; 1) diagnostic tools that determine the presence of an infection are not available, or are not being used, or are not accurate enough, or do not provide strong enough negative predictive value, or are not providing accurate information that can be acted on within a reasonable timeframe 2) when it comes to suspected infection, and because of the acute nature of infections, clinicians err on the side of caution by administering antibiotics. Further, in a study performed in the Netherlands on patients presenting to emergency with fever, 36.6% of patients admitted to hospital had a suspected bacterial infection (that is, it was not confirmed) (Limper M, Eeftinck Schattenkerk D, de Kruif M D, van Wissen M, Brandjes D P M, et al. (2011) One-year epidemiology of fever at the Emergency Department. Neth J Med 69: 124-128). This suggests that a large proportion of patients presenting to emergency are admitted to hospital without a diagnosis. The BaSIRS and VaSIRS biomarkers described herein can identify those patients with a BaSIRS or VaSIRS from those without a BaSIRS or VaSIRS, assisting medical practitioners in the USA in triaging patients with fever or SIRS. Such effective triage tools make best use of scarce hospital resources, including staff, equipment and therapies. Accurate triage decision-making also ensures that patients requiring hospital treatment are given it, and those that don&#39;t are provided with other appropriate services. 
     In a study performed in Argentina in patients presenting to emergency with influenza-like symptoms, only 37% of samples taken and analyzed for the presence of viruses (using immunofluorescence, RT-PCR and virus culture) were positive (Santamaria, C., Uruena, A., Videla, C., Suarez, A., Ganduglia, C., Carballal, G., et al. (2008). Epidemiological study of influenza virus infections in young adult outpatients from Buenos Aires, Argentina. Influenza and Other Respiratory Viruses, 2(4), 131-134). In a study based in Boston, USA, acute respiratory infections were a common reason children presented to emergency departments in Winter (Bourgeois, F. T., Valim, C., Wei, J. C., McAdam, A. J., &amp; Mandl, K. D. (2006). Influenza and other respiratory virus-related emergency department visits among young children. Pediatrics, 118(1), e1-8). Using a respiratory classifier (based on clinical signs) these authors found that in children less than, or equal to, 7 years of age an acute respiratory infection was suspected in 39.8% of all emergency department visits (less at a whole city or state level). In this latter study only 55.5% of these patients had a virus isolated. Thus, a large percentage of patients with influenza-like symptoms presenting to emergency are likely not being diagnosed as having a viral infection using laboratory-based tests. The VaSIRS biomarkers outlined herein can identify those patients with a VaSIRS from those without a VaSIRS, assisting medical practitioners in making an accurate diagnosis of a viral infection in patients with influenza-like symptoms. Such patients can then be further tested to determine the presence of specific viruses amenable to anti-viral therapies. Accurate diagnosis of a VaSIRS also assists in ensuring that only those patients that need either anti-viral treatment or antibiotics receive them which may lead to fewer side effects and fewer days on antibiotics (Adcock, P. M., Stout, G. G., Hauck, M. A., &amp; Marshall, G. S. (1997). Effect of rapid viral diagnosis on the management of children hospitalized with lower respiratory tract infection. The Pediatric Infectious Disease Journal, 16(9), 842-846). 
     In a study of febrile pediatric patients presenting to an emergency department in Tanzania, 56.7% had a positive urine test, 19.2% were HIV positive and 8.7% were positive for malaria. Clinical diagnoses included; malaria (24.3%), pneumonia (15.2%), sepsis (9.5%), urinary tract infection (7.6%) and sickle cell anemia (2.9%). A wide range of infections were diagnosed (Ringo, F H., et al., (2013). Clinical presentation, diagnostic evaluation, treatment and diagnoses of febrile children presenting to the emergency department at Muhimbili national hospital in Dar es Salaam, Tanzania. African Journal of Emergency Medicine, 3(4), S21-S22). In this population with systemic inflammation it would therefore be important to distinguish between bacterial, viral and protozoal infection to ensure appropriate treatment and management procedures were rapidly implemented. The biomarkers described in the present specification would assist clinicians in determining whether the cause of the presenting clinical signs of systemic inflammation were due to a bacterial, viral or protozoal infection. 
     Differentiating Patients with a Systemic Inflammatory Response to Infection in Medical Clinics 
     Patients presenting to medical clinics as outpatients often have clinical signs of SIRS including abnormal temperature, heart rate or respiratory rate and there are many causes of these clinical signs. Such patients need to be assessed thoroughly to determine the cause of the clinical signs because in some instances it could be a medical emergency. By way of example, a patient with colic might present with clinical signs of increased heart rate. Differential diagnoses could be (but not limited to) appendicitis, urolithiasis, cholecystitis, pancreatitis, enterocolitis. In each of these conditions it would be important to determine if there was a non-infectious systemic inflammatory response (InSIRS) or whether an infection was contributing to the systemic response. The treatment and management of patients with non-infectious systemic inflammation and/or SIRS due to infectious causes are different. The BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers detailed herein can differentiate infectious causes of SIRS from other causes of SIRS so that a medical practitioner can either rule in or rule out a systemic inflammation of bacterial, viral or protozoal etiology. As a result medical practitioners can more easily determine the next medical actions and procedure(s) to perform to satisfactorily resolve the patient issue. 
     Detection of Reactivation of Latent Viruses 
     Reactivation of latent viruses is common in patients that are immunocompromised, including those with prolonged sepsis and those on immunosuppressive therapy (Walton A H, Muenzer J T, Rasche D, Boomer J S, Sato B, et al. (2014) Reactivation of multiple viruses in patients with sepsis. PLoS ONE 9: e98819; Andersen, H. K., and E. S. Spencer. 1969. Cytomegalovirus infection among renal allograft recipients. Acta Med. Scand. 186:7-19; Bustamante C I, Wade J C (1991) Herpes simplex virus infection in the immunocompromised cancer patient. J Clin Oncol 9: 1903-1915). For patients with sepsis (Walton et al., 2014), cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and anellovirus TTV were all detectable in blood at higher rates compared to control patients, and those patients with detectable CMV had higher 90-day mortality. However, because these viruses have only been detected in sepsis patients it is not known whether reactivated latent viruses contribute to pathology, morbidity and mortality. The BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers detailed herein can differentiate infectious causes of SIRS, and the VaSIRS biomarkers can also detect systemic inflammation due to reactivation of latent herpes viruses. Patients with reactivated herpes virus infection could then be put on appropriate anti-viral therapies. 
     Determining the Extent of Systemic Inflammation in Patients 
     Patients presenting to medical facilities often have any one of the four clinical signs of SIRS. However, many different conditions can present with one of the four clinical signs of SIRS and such patients need to be assessed to determine if they have InSIRS, and if so the extent of InSIRS, or BaSIRS, and if so the extent of BaSIRS, or VaSIRS, and if so the extent of VaSIRS, or PaSIRS, and if so the extent of PaSIRS, and to exclude other differential diagnoses. 
     By way of example, a patient with respiratory distress is likely to present with clinical signs of increased respiratory rate. Differential diagnoses could be (but not limited to) asthma, viral or bacterial pneumonia, respiratory distress due to malaria, congestive heart failure, physical blockage of airways, allergic reaction, collapsed lung, pneumothorax. In this instance it would be important to determine if there was a infection-negative systemic inflammatory response (InSIRS) or whether an infection (viral, bacterial, or protozoal) was contributing to the condition. The treatment and management of patients with and without systemic inflammation and/or viral, bacterial, protozoal infections are different. Because the biomarkers described herein can determine the degree of systemic involvement, the use of them will allow medical practitioners to determine the next medical procedure(s) to perform to satisfactorily resolve the patient issue. Patients with a collapsed lung, pneumothorax or a physical blockage are unlikely to have a systemic inflammatory response and patients with congestive heart failure, allergic reaction or asthma may have a large systemic inflammatory response but not due to infection. The extent of BaSIRS, VaSIRS, PaSIRS or InSIRS, as indicated by biomarkers presented herein, allows clinicians to determine a cause of the respiratory distress, to rule out other possible causes and provides them with information to assist in decision making on next treatment and management steps. For example, a patient with respiratory distress and a strong marker response indicating VaSIRS is likely to be hospitalized and specific viral diagnostic tests performed to ensure that appropriate anti-viral therapy is administered. 
     Antibiotic Stewardship 
     In patients suspected of having a systemic infection (InSIRS, BaSIRS, VaSIRS, PaSIRS) a clinical diagnosis and treatment regimen is provided by the physician(s) at the time the patient presents and often in the absence of any results from diagnostic tests. This is done in the interests of rapid treatment and positive patient outcomes. However, such an approach leads to over-prescribing of antibiotics irrespective of whether the patient has a bacterial infection or not. Clinician diagnosis of BaSIRS is reasonably reliable (0.88) in children but only with respect to differentiating between patients ultimately shown to be blood culture positive and those that were judged to be unlikely to have an infection at the time antibiotics were administered (Fischer, J. E. et al. Quantifying uncertainty: physicians&#39; estimates of infection in critically ill neonates and children. Clin. Infect. Dis. 38, 1383-1390 (2004)). In Fischer et al., (2004), 54% of critically ill children were put on antibiotics during their hospital stay, of which only 14% and 16% had proven systemic bacterial infection or localized infection respectively. In this study, 53% of antibiotic treatment courses for critically ill children were for those that had an unlikely infection and 38% were antibiotic treatment courses for critically ill children as a rule-out treatment episode. Clearly, pediatric physicians err on the side of caution with respect to treating critically ill patients by placing all patients suspected of an infection on antibiotics—38% of all antibiotics used in critically ill children are used on the basis of ruling out BaSIRS, that is, are used as a precaution. Antibiotics are also widely prescribed and overused in adult patients as reported in Braykov et al., 2014 (Braykov, N. P., Morgan, D. J., Schweizer, M. L., Uslan, D. Z., Kelesidis, T., Weisenberg, S. A., et al. (2014). Assessment of empirical antibiotic therapy optimisation in six hospitals: an observational cohort study. The Lancet Infectious Diseases, 14(12), 1220-1227). In this study, across six US hospitals over four days in 2009 and 2010, 60% of all patients admitted received antibiotics. Of those patients prescribed antibiotics 30% were afebrile and had a normal white blood cell count and where therefore prescribed antibiotics as a precaution. Further, in study of febrile children presenting to an African emergency department 70% were put on antibiotics despite approximately only 35% being diagnosed as having a bacterial infection (Ringo, F H., et al., (2013). Clinical presentation, diagnostic evaluation, treatment and diagnoses of febrile children presenting to the emergency department at Muhimbili national hospital in Dar es Salaam, Tanzania. African Journal of Emergency Medicine, 3(4), S21-S22). As such, an assay that can accurately diagnose BaSIRS, VaSIRS, PaSIRS or InSIRS in patients presenting with non-pathognomonic clinical signs of infection would be clinically useful and may lead to more appropriate use of antibiotics, anti-viral and anti-malarial therapies. 
     Controlling the Spread of Infectious Agents 
     Often the best method of limiting infectious disease spread is through a combination of accurate diagnosis, surveillance, patient isolation and practical measures to prevent transmission (e.g., hand washing) (Sydnor, E. R. M., &amp; Perl, T. M. (2011). Hospital Epidemiology and Infection Control in Acute-Care Settings. Clinical Microbiology Reviews, 24(1), 141-173; Chowell, G., Castillo-Chavez, C., Fenimore, P. W., Kribs-Zaleta, C. M., Arriola, L., &amp; Hyman, J. M. (2004). Model parameters and outbreak control for SARS. Emerging Infectious Diseases, 10(7), 1258-1263.; Centers for Disease Control, Interim U.S. Guidance for Monitoring and Movement of Persons with Potential Ebola Virus Exposure, Dec. 24, 2014; Fletcher, S. M., Stark, D., Harkness, J., &amp; Ellis, J. (2012). Enteric Protozoa in the Developed World: a Public Health Perspective. Clinical Microbiology Reviews, 25(3), 420-449). The BaSIRS, VaSIRS, PaSIRS and InSIRS biomarkers detailed herein can be used to identify those people with early clinical signs that actually have a BaSIRS, VaSIRS, PaSIRS or InSIRS. For those people identified as having a BaSIRS, VaSIRS, PaSIRS or InSIRS appropriate testing and procedures can then be performed to obtain an accurate and specific diagnosis and to limit infectious agent spread, if diagnosed, through isolation of patients and the use of appropriate protective measures. 
     Example 10 
     Example Applications of a Combination of Host Response Biomarker Profiles and/or Pathogen Specific Biomarkers 
     Combining host response biomarker profiles and pathogen specific biomarkers provides extra diagnostic power that is useful in a number of medical facility locations (e.g., clinics, emergency, ward, ICU) and infectious disease diagnostic situations. For the diagnosis of BaSIRS, typically blood and other body fluid samples are taken for culture. In comparison to a physician&#39;s retrospective diagnosis these culture results are often falsely positive or falsely negative. Possible causes of such false positive or negative results include: growth of a contaminant or commensal organism, overgrowth of a dominant non-pathogenic organism, organism not viable, organism will not grow in media, organism not present in the sample, not enough sample taken, antibiotics in the sample inhibit growth. TABLE 39 indicates possible interpretation of either positive or negative results using a combination of BaSIRS and BIP biomarkers. 
     For the diagnosis of VaSIRS, typically blood and other body fluid samples are taken for protein-based or molecular DNA testing (as either individual tests or a panel of tests). In comparison to a physician&#39;s retrospective diagnosis these test results are also often falsely positive or falsely negative. Possible causes of such false positive or negative results include; presence of a virus that is not contributing to pathology (latency, commensal), virus not present in the sample, not enough sample taken, assay not sensitive enough, wrong assay performed, specific antibodies have not yet been produced, residual antibodies from a previous non-relevant infection. TABLE 40 indicates possible interpretation of either positive or negative results using a combination of VaSIRS and VIP biomarkers. 
     For the diagnosis of PaSIRS, typically blood and other body fluid samples are taken for antibody or antigen testing (as either individual tests or a panel of tests). In comparison to a physician&#39;s retrospective diagnosis these test results are also often falsely positive or falsely negative. Possible causes of such false positive or negative results include; presence of a protozoan that is not contributing to pathology, protozoan not present in the sample, not enough sample taken, assay not sensitive enough, wrong assay performed, antibodies not yet produced, residual antibodies from a previous non-relevant infection. TABLE 41 indicates possible interpretation of either positive or negative results using a combination of PaSIRS and PIP biomarkers. 
     In some instances it would be useful to use BaSIRS and VaSIRS host response specific biomarkers in combination with bacterial and viral pathogen specific biomarkers. For example, children often present to first world emergency departments with fever. Interpretation of results would be along the same lines as described in the tables above. However, double positive results (for either bacterial or viral) would provide greater assurance to the clinician that a child had either a bacterial or viral infection. If all assays were positive then a mixed infection would be likely. If all assays were negative then it is likely the child has InSIRS. A positive BaSIRS host response in combination with a positive bacterial pathogen test would be the most life threatening and require immediate medical attention, administration of appropriate therapies (antibiotics) and appropriate interventions. A negative BaSIRS host response in combination with a negative bacterial pathogen test would provide clinicians with assurance that the cause of the fever was not bacterial.  FIGS. 34 and 35  show the use of a combination of BaSIRS and bacterial pathogen detection, and VaSIRS and viral pathogen detection respectively when using in-house clinical samples (Venus A study and MARS study). TABLES 38 and 39 demonstrate how the results of the use of such combinations may be interpreted. 
     In some instances it would be useful to use BaSIRS, VaSIRS, PaSIRS and InSIRS host response biomarkers in combination with bacterial, viral and protozoal pathogen specific biomarkers. For example, children often present to third world emergency departments with fever. Interpretation of results would be along the same lines as described in the tables above. However, double positive results (for either bacterial or viral or protozoal) would provide greater assurance to the clinician that a child had either a bacterial or viral or protozoal infection. If two or more assays were positive then a mixed infection would be likely. If BaSIRS, VaSIRS and PaSIRS assays and pathogen assays were negative then it is likely the child has InSIRS. A positive BaSIRS host response in combination with a positive bacterial pathogen test would be the most life threatening and require immediate medical attention, administration of appropriate therapies (antibiotics) and appropriate interventions. A negative BaSIRS host response in combination with a positive InSIRS host response and a negative bacterial pathogen test would provide clinicians with assurance that the cause of the fever was not bacterial. 
     In some instances it would be useful to use just host response biomarkers (BaSIRS, VaSIRS, PaSIRS, InSIRS, alone or in combination), especially in instances where it is known that growth and isolation of a causative organism has a low positive rate (e.g. blood culture in patients in a setting with a low prevalence of sepsis). 
     Examples of the use of multiple host response biomarkers are depicted in  FIGS. 26, 36 and 37 .  FIG. 26  shows a multi-dimensional scaling plot using random forest and BaSIRS and VaSIRS derived biomarkers on data associated with GSE63990. In this dataset patients with acute respiratory inflammation were retrospectively categorized by a clinician into the cohorts of: bacterial, viral or non-infectious. Separation of such patients into these three cohorts using BaSIRS and VaSIRS derived biomarkers can be seen clearly.  FIG. 36  shows the use of the BaSIRS and VaSIRS signature in a pediatric population with retrospectively diagnosed sepsis, InSIRS, viral infection and mixed infection. Some patients show host responses to both bacteria and viruses suggesting that co-infections can occur and/or one type of infection may predispose to another type of infection.  FIG. 37  demonstrates the specificity of the BaSIRS, VaSIRS, PaSIRS and InSIRS signatures in a number of GEO datasets covering a variety of conditions including sepsis, malaria, SIRS and influenza, and in healthy subjects. 
     Example 11 
     First Example Workflow for Determining Host Response 
     A first example workflow for measuring host response to BaSIRS, VaSIRS, PaSIRS and InSIRS will now be described. The workflow involves a number of steps depending upon availability of automated platforms. The assay uses quantitative, real-time determination of the amount of each host immune cell RNA transcript in the sample based on the detection of fluorescence on a qRT-PCR instrument (e.g., Applied Biosystems 7500 Fast Dx Real-Time PCR Instrument, Applied Biosystems, Foster City, Calif., catalogue number 440685; K082562). Transcripts are each reverse-transcribed, amplified, detected, and quantified in a separate reaction well for each target gene using a probe that is visualized in the FAM channel (by example). Such reactions can be run as single-plexes (one probe for one transcript per tube), multiplexed (multiple probes for multiple transcripts in one tube), one-step (reverse transcription and PCR are performed in the same tube), or two-step (reverse transcription and PCR performed as two separate reactions in two tubes). A score is calculated for each set of BaSIRS, VaSIRS, PaSIRS and InSIRS host response biomarkers using interpretive software provided separately to the kit but designed to integrate with RT-PCR machines. It is contemplated that a separate score is calculated that combines the results of BaSIRS, VaSIRS, PaSIRS and InSIRS host response specific biomarkers using interpretive software provided separately to the kit but designed to integrate with RT-PCR machines. Such a combined score aims to provide clinicians with information regarding the type(s) and degree(s) of systemic inflammation for each of BaSIRS, VaSIRS, PaSIRS and InSIRS. 
     The workflow below describes the use of manual processing and a pre-prepared kit. 
     Pre-Analytical 
     Blood collection 
     Total RNA isolation 
     Analytical 
     Reverse transcription (generation of cDNA) 
     qPCR preparation 
     qPCR 
     Software, Interpretation of Results and Quality Control 
     Output. 
     Kit Contents 
     Diluent 
     RT Buffer 
     RT Enzyme Mix 
     qPCR Buffer 
     Primer/Probe Mixes 
     AmpliTaq Gold® (or similar) 
     High Positive Control (one for each of BaSIRS, VaSIRS, PaSIRS and InSIRS) 
     Low Positive Control (one for each of BaSIRS, VaSIRS, PaSIRS and InSIRS) 
     Negative Control 
     Blood Collection 
     The specimen used is a 2.5 mL sample of blood collected by venipuncture using the PAXgene® collection tubes within the PAXgene® Blood RNA System (Qiagen, kit catalogue #762164; Becton Dickinson, Collection Tubes catalogue number 762165; K042613). An alternate collection tube is Tempus® (Life Technologies). 
     Total RNA Isolation 
     Blood (2.5 mL) collected into a PAXgene RNA tube is processed according to the manufacturer&#39;s instructions. Briefly, 2.5 mL sample of blood collected by venipuncture using the PAXgene™ collection tubes within the PAXgene™ Blood RNA System (Qiagen, kit catalogue #762164; Becton Dickinson, Collection Tubes catalogue number 762165; K042613). Total RNA isolation is performed using the procedures specified in the PAXgene™ Blood RNA kit (a component of the PAXgene™ Blood RNA System). The extracted RNA is then tested for purity and yield (for example by running an A 260/280  ratio using a Nanodrop® (Thermo Scientific)) for which a minimum quality must be (ratio &gt;1.6). RNA should be adjusted in concentration to allow for a constant input volume to the reverse transcription reaction (below). RNA should be processed immediately or stored in single-use volumes at or below −70° C. for later processing. 
     Reverse Transcription 
     Determine the appropriate number of reaction equivalents to be prepared (master mix formulation) based on a plate map and the information provided directly below. Each clinical specimen is run in singleton. 
     Each batch run desirably includes the following specimens:
         High Control (one for each of BaSIRS, VaSIRS, PaSIRS and InSIRS), Low Control (one for each of BaSIRS, VaSIRS, PaSIRS and InSIRS), Negative Control, and No Template Control (Test Diluent instead of sample) in singleton each       

     Program the ABI 7500 Fast Dx Instrument as detailed below.
         Launch the software.   Click Create New Document   In the New Document Wizard, select the following options:
           i. Assay: Standard Curve (Absolute Quantitation)   i. Container: 96-Well Clear   iii. Template: Blank Document (or select a laboratory-defined template)   iv. Run Mode: Standard 7500   v. Operator: Enter operator&#39;s initials   vi. Plate name: [default]   
           Click Finish   Select the Instrument tab in the upper left   In the Thermal Cycler Protocol area, Thermal Profile tab, enter the following times:
           i. 25° C. for 10 minutes   ii. 45° C. for 45 minutes   iii. 93° C. for 10 minutes   iv. Hold at 25° C. for 60 minutes   
               

     In a template-free area, remove the test Diluent and RT-qPCR Test RT Buffer to room temperature to thaw. Leave the RT-qPCR Test RT Enzyme mix in the freezer and/or on a cold block. 
     In a template-free area, assemble the master mix in the order listed below. 
     RT Master Mix—Calculation 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Per well 
                 ×N 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 RT-qPCR Test RT Buffer 
                 3.5 μL 
                 3.5 × N 
               
               
                   
                 RT-qPCR Test RT Enzyme mix 
                 1.5 μL 
                 1.5 × N 
               
               
                   
                 Total Volume 
                   5 μL 
                   5 × N 
               
               
                   
                   
               
            
           
         
       
     
     Gently vortex the master mix then pulse spin. Add the appropriate volume (5 μL) of the RT Master Mix into each well at room temperature. 
     Remove clinical specimens and control RNAs to thaw. (If the specimens routinely take longer to thaw, this step may be moved upstream in the validated method.) 
     Vortex the clinical specimens and control RNAs, then pulse spin. Add 10 μL of control RNA or RT-qPCR Test Diluent to each respective control or negative well. 
     Add 10 μL of sample RNA to each respective sample well (150 ng total input for RT; OD 260 /OD 280  ratio greater than 1.6). Add 10 μL of RT-qPCR Test Diluent to the respective NTC well. 
     Note: The final reaction volume per well is 15 μL. 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Samples 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 RT Master Mix 
                  5 μL 
               
               
                   
                 RNA sample 
                 10 μL 
               
               
                   
                 Total Volume (per well) 
                 15 μL 
               
               
                   
                   
               
            
           
         
       
     
     Mix by gentle pipetting. Avoid forming bubbles in the wells. 
     Cover wells with a seal. 
     Spin the plate to remove any bubbles (1 minute at 400×g). 
     Rapidly transfer to ABI 7500 Fast Dx Instrument pre-programmed as detailed above. 
     Click Start. Click Save and Continue. Before leaving the instrument, it is recommended to verify that the run started successfully by displaying a time under Estimated Time Remaining. 
     qPCR master mix may be prepared to coincide roughly with the end of the RT reaction. For example, start about 15 minutes before this time. See below. 
     When RT is complete (i.e. resting at 25° C.; stop the hold at any time before 60 minutes is complete), spin the plate to collect condensation (1 minute at 400×g). 
     qPCR Preparation 
     Determine the appropriate number of reaction equivalents to be prepared (master mix formulation) based on a plate map and the information provided in RT Preparation above. 
     Program the ABI 7500 Fast Dx with the settings below.
         a) Launch the software.   b) Click Create New Document   c) In the New Document Wizard, select the following options:
           i. Assay: Standard Curve (Absolute Quantitation)   ii. Container: 96-Well Clear   iii. Template: Blank Document (or select a laboratory-defined template)   iv. Run Mode: Standard 7500   v. Operator: Enter operator&#39;s initials   vi. Plate name: Enter desired file name   
           d) Click Next   e) In the Select Detectors dialog box:
           i. Select the detector for the first biomarker, and then click Add&gt;&gt;.   ii. Select the detector second biomarker, and then click Add&gt;&gt;, etc.   iii. Passive Reference: ROX   
           f) Click Next   g) Assign detectors to appropriate wells according to plate map.
           i. Highlight wells in which the first biomarker assay will be assigned   ii. Click use for the first biomarker detector   iii. Repeat the previous two steps for the other biomarkers   iv. Click Finish   
           h) Ensure that the Setup and Plate tabs are selected   i) Select the Instrument tab in the upper left   j) In the Thermal Cycler Protocol area, Thermal Profile tab, perform the following actions:
           i. Delete Stage 1 (unless this was completed in a laboratory-defined template).   ii. Enter sample volume of 25 μL.   iii. 95° C. 10 minutes   iv. 40 cycles of 95° C. for 15 seconds, 63° C. for 1 minute   v. Run Mode: Standard 7500   vi. Collect data using the “stage 2, step 2 (63.0@1:00)” setting   
           k) Label the wells as below using this process: Right click over the plate map, then select Well Inspector. With the Well Inspector open, select a well or wells. Click back into the Well Inspector and enter the Sample Name. Close the Well Inspector when completed.
           i. CONN for High Control   ii. CONL for Low Control   iii. CONN for Negative Control   iv. NTC for No Template Control   v. [Accession ID] for clinical specimens   
           l) Ensure that detectors and quenchers are selected as listed below (for singleplex reactions—one target per reaction).
           i. FAM for CEACAM4 biomarker 1; quencher=none   ii. FAM for LAMP1 biomarker 2; quencher=none   iii. FAM for PLAC8 biomarker 3; quencher=none   iv. FAM for PLA2G7 biomarker 4; quencher=none   v. FAM for ISG15 biomarker 1; quencher=none   vi. FAM for IL16 biomarker 2; quencher=none   vii. FAM for OASL; biomarker 3; quencher=none   viii. FAM for ADGRE5; biomarker 4; quencher=none   ix. FAM for TTC17 biomarker 1; quencher=none   x. FAM for G6PD biomarker 2; quencher=none   xi. FAM for HERC6 biomarker 3; quencher=none   xii. FAM for LAP3 biomarker 4; quencher=none   xiii. FAM for NUP160 biomarker 5; quencher=none   xiv. FAM for TPP1 biomarker 6; quencher=none   xv. FAM for ARL6IP5 biomarker 1; quencher=none   xvi. FAM for ENTPD1 biomarker 2; quencher=none   xvii. FAM for HEATR1 biomarker 3; quencher=none   xviii. FAM for TNFSF8 biomarker 4; quencher=none   xix. Select “ROX” for passive reference   
               

     qPCR 
     In a template-free area, remove the assay qPCR Buffer and assay Primer/Probe Mixes for each target to room temperature to thaw. Leave the assay AmpliTaq Gold in the freezer and/or on a cold block. 
     Still in a template-free area, prepare qPCR Master Mixes for each target in the listed order at room temperature. 
     
       
         
           
               
            
               
                   
               
               
                 qPCR Master Mixes - Calculation Per Sample 
               
            
           
           
               
               
               
            
               
                   
                 Per well 
                 ×N 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 qPCR Buffer 
                  11 μL 
                  11 × N 
               
               
                   
                 Primer/Probe Mix 
                 3.4 μL 
                 3.4 × N 
               
               
                   
                 AmpliTaq Gold ® 
                 0.6 μL 
                 0.6 × N 
               
               
                   
                 Total Volume 
                  15 μL 
                  15 × N 
               
               
                   
                   
               
            
           
         
       
     
     Example forward (F) and reverse (R) primers and probes (P) (in 5′-3′ orientation) and their final reaction concentration for measuring 14 host response transcripts to bacterial, viral and protozoal host response specific biomarkers are contained in TABLE H (F, forward; R, reverse; P, probe). The melting temperature for all primers and probes in this table is approximately 60° C. Primers are designed for best coverage of all transcripts and across an exon/intron border to reduce the likelihood of amplifying genomic DNA. 
     
       
         
           
               
               
               
               
             
               
                 TABLE H 
               
               
                   
               
               
                 Reagent 
                 5′-3′ Sequence 
                 Reactionr mM 
                 SEQ ID NO 
               
               
                   
               
             
            
               
                 OPLAH-F 
                 GCTGGACATCAACACCGTGGC 
                 360 
                 1666 
               
               
                   
               
               
                 OPLAH-R 
                 GTCCTGGGTGGGCTCCTGC 
                 360 
                 1667 
               
               
                   
               
               
                 OPLAH-P 
                 GGGGTTCCCGCCTCTTCTTCAG 
                  50 
                 1668 
               
               
                   
               
               
                 ZHX2-F 
                 GCGGCAGAAGGTGTGTCGGAA 
                 360 
                 1669 
               
               
                   
               
               
                 ZHX2-R 
                 GTCCCGTTGATCAGCACAGCAG 
                 360 
                 1670 
               
               
                   
               
               
                 ZHX2-P 
                 GCAGAGGCTGGCCAGGC 
                  50 
                 1671 
               
               
                   
               
               
                 TSPO-F 
                 CTGAACTGGGCATGGCCCCC 
                 360 
                 1672 
               
               
                   
               
               
                 TSPO-R 
                 CCCCACTGACCAGCAGGAGATC 
                 360 
                 1673 
               
               
                   
               
               
                 TSPO-P 
                 GGTGCCCGACAAATGGGCTG 
                  50 
                 1674 
               
               
                   
               
               
                 HCLS1-F 
                 GGTCGGTTTGGAGTAGAAAGAGACC 
                 360 
                 1675 
               
               
                   
               
               
                 HCLS1-R 
                 CCCTCTCAAGTCCGTACTTGCC 
                 360 
                 1676 
               
               
                   
               
               
                 HCLS1-P 
                 TGGGCCATGAGTATGTTGCC 
                  50 
                 1677 
               
               
                   
               
               
                 ISG15-F 
                 CTTCGAGGGGAAGCCCCTGGAG 
                 360 
                 1678 
               
               
                   
               
               
                 ISG15-R 
                 CCTGCTCGGATGCTGGTGGAGC 
                 360 
                 1679 
               
               
                   
               
               
                 ISG15-P 
                 CATGAATCTGCGCCTGCGGGG 
                  50 
                 1680 
               
               
                   
               
               
                 IL16-F 
                 GCCCAGTGACCCAAACATCCCC 
                 360 
                 1681 
               
               
                   
               
               
                 IL16-R 
                 CAAAGCTATAGTCCATCCGAGCCTCG 
                 360 
                 1682 
               
               
                   
               
               
                 IL16-P 
                 GATAAAACACCCACTGCTTAAG 
                  50 
                 1683 
               
               
                   
               
               
                 OASL-F 
                 CCCTGGGGCCTTCTCTTCCCA 
                 360 
                 1684 
               
               
                   
               
               
                 OASL-R 
                 CCGCAGGCCTTGATCAGGC 
                 360 
                 1685 
               
               
                   
               
               
                 OASL-P 
                 CCCAGCCACCCCCTGAGGTC 
                  50 
                 1686 
               
               
                   
               
               
                 ADGRE5-F 
                 CCATCCAGAATGTCATCAAATTGGTGGA 
                 360 
                 1687 
               
               
                   
               
               
                 ADGRE5-R 
                 GGACAGGTGGCGCCAGGG 
                 360 
                 1688 
               
               
                   
               
               
                 ADGRE5-P 
                 GAACTGATGGAAGCTCCTGGAGAC 
                  50 
                 1689 
               
               
                   
               
               
                 TTC17-F 
                 GGACGGAAAATCCAGCAGC 
                 360 
                 1690 
               
               
                   
               
               
                 TTC17-R 
                 CTTCTTGTCTCATTAATATGACTAGG 
                 360 
                 1691 
               
               
                   
               
               
                 TTC17-P 
                 CACCAATGAACTTGAAGCATCC 
                  50 
                 1692 
               
               
                   
               
               
                 G6PD-F 
                 GCGACGACGACGAAGCGC 
                 360 
                 1693 
               
               
                   
               
               
                 G6PD-R 
                 CGCAGGATCCCGCACACC 
                 360 
                 1694 
               
               
                   
               
               
                 G6PD-P 
                 GGCAGAGCAGGTGGCCCT 
                  50 
                 1695 
               
               
                   
               
               
                 HERC6-F 
                 GTTTCCTGCCAAGCCTAAACC 
                 360 
                 1696 
               
               
                   
               
               
                 HERC6-R 
                 GAGCCAGTGGGAAAGGAAGG 
                 360 
                 1697 
               
               
                   
               
               
                 HERC-P 
                 GAATGCTGTGTGGACTCTCC 
                  50 
                 1698 
               
               
                   
               
               
                 LAP3-F 
                 CTAGTAGTAAAACCGAGGTCCA 
                 360 
                 1699 
               
               
                   
               
               
                 LAP3-R 
                 GTGAATTTCCAAGAAGACTGGG 
                 360 
                 1700 
               
               
                   
               
               
                 LAP3-P 
                 GTCTTGGATTGAGGAAACAGGC 
                  50 
                 1701 
               
               
                   
               
               
                 NUP160-F 
                 TGATGGAGAATGCACAGCTGC 
                 360 
                 1702 
               
               
                   
               
               
                 NUP160-R 
                 ATGCGAGCCAAGGAACACTC 
                 360 
                 1703 
               
               
                   
               
               
                 NUP160-P 
                 TCCTGGAACTGGAAGATCTGG 
                  50 
                 1704 
               
               
                   
               
               
                 TPP1-F 
                 AATGTGTTCCCACGGCCTTC 
                 360 
                 1705 
               
               
                   
               
               
                 TPP1-R 
                 GTAGGCACGGCCACTGGC 
                 360 
                 1706 
               
               
                   
               
               
                 TPP-P 
                 GAGCTCTAGCCCCCACCT 
                  50 
                 1707 
               
               
                   
               
               
                 ARL6IP5-F 
                 GGAGGAGTCATGGTCTTTGTGTTTGG 
                 360 
                 1708 
               
               
                   
               
               
                 ARL6IP5-R 
                 ATGCCCATCGGTGTCCTCTTC 
                 360 
                 1709 
               
               
                   
               
               
                 ARL6IP5-P 
                 TGATGTTTATCCATGCATCGTTGAGAC 
                  50 
                 1710 
               
               
                   
               
               
                 ENTPD1-F 
                 GGAGCACATCCATTTCATTGGCA 
                 360 
                 1711 
               
               
                   
               
               
                 ENTPD1-R 
                 GCTGGGATCATGTTGGTCAGG 
                 360 
                 1712 
               
               
                   
               
               
                 ENTPD1-P 
                 ATCCAGGGCAGCGACGC 
                  50 
                 1713 
               
               
                   
               
               
                 HEATR1-F 
                 CCCACTGCTACAAAGATCTTGGATTC 
                 360 
                 1714 
               
               
                   
               
               
                 HEATR1-R 
                 CCAAGAGCACCCTCAACTGAG 
                 360 
                 1715 
               
               
                   
               
               
                 HEATR1-P 
                 CTGAGTACCCGGGCAGCT 
                  50 
                 1716 
               
               
                   
               
               
                 TNFSF8-F 
                 GGTGGCCACTATTATGGTGTTGG 
                 360 
                 1717 
               
               
                   
               
               
                 TNFSF8-R 
                 GAGCAATTTCCTCCTTTGAGGGG 
                 360 
                 1718 
               
               
                   
               
               
                 TNFSF8-P 
                 CATTCCCAACTCACCTGACAACG 
                  50 
                 1719 
               
               
                   
               
            
           
         
       
     
     Gently mix the master mixes by flicking or by vortexing, and then pulse spin. Add 15 μL of qPCR Master Mix to each well at room temperature. 
     In a template area, add 130 μL of Test Diluent to each cDNA product from the RT Reaction. Reseal the plate tightly and vortex the plate to mix thoroughly. 
     Add 10 μL of diluted cDNA product to each well according to the plate layout. 
     Mix by gentle pipetting. Avoid forming bubbles in the wells. 
     Cover wells with an optical seal. 
     Spin the plate to remove any bubbles (1 minute at 400×g). 
     Place on real-time thermal cycler pre-programmed with the settings above. 
     Click Start. Click Save and Continue. Before leaving the instrument, it is recommended to verify that the run started successfully by displaying a time under Estimated Time Remaining. 
     Note: Do not open the qPCR plate at any point after amplification has begun. 
     When amplification has completed, discard the unopened plate. 
     Software, Interpretation of Results and Quality Control 
     Software is specifically designed to integrate with the output of PCR machines and to apply an algorithm based on the use of multiple biomarkers. The software takes into account appropriate controls and reports results in a desired format. 
     When the run has completed on the ABI 7500 Fast Dx Instrument, complete the steps below in the application 7500 Fast System with 21 CFR Part 11 Software, ABI software SDS v1.4. 
     Click on the Results tab in the upper left corner. 
     Click on the Amplification Plot tab in the upper left corner. 
     In the Analysis Settings area, select an auto baseline and manual threshold for all targets. Enter 0.01 as the threshold. 
     Click on the Analyze button on the right in the Analysis Settings area. 
     From the menu bar in the upper left, select File then Close. 
     Complete the form in the dialog box that requests a reason for the change. Click 
     OK. 
     Transfer the data file (.sds) to a separate computer running the specific assay RT-qPCR Test Software. 
     Launch the assay RT-qPCR Test Software. Log in. 
     From the menu bar in the upper left, select File then Open. 
     Browse to the location of the transferred data file (.sds). Click OK. 
     The data file will then be analyzed using the assay&#39;s software application for interpretation of results. 
     Interpretation of Results and Quality Control 
     Results 
     Launch the interpretation software. Software application instructions are provided separately. 
     Following upload of the .sds file, the Software will automatically generate classifier scores for controls and clinical specimens. 
     Controls 
     The Software compares each CON (control) specimen (CONN, CONL, CONN) to its expected result. The controls are run in singleton. 
     
       
         
           
               
               
            
               
                   
               
               
                 Control specimen 
                   
               
            
           
           
               
               
               
            
               
                 Designation 
                 Name 
                 Expected result 
               
               
                   
               
               
                 CONH 
                 High Control 
                 Score range 
               
               
                 CONL 
                 Low Control 
                 Score range 
               
               
                 CONN 
                 Negative Control 
                 Score range 
               
               
                 NTC 
                 No Template Control 
                 Fail (no Ct for all targets) 
               
               
                   
               
            
           
         
       
     
     If CONN, CONL, and/or CONN fail the batch run is invalid and no data will be reported for the clinical specimens. This determination is made automatically by the interpretive software. The batch run should be repeated starting with either a new RNA preparation or starting at the RT reaction step. 
     If NTC yields a result other than Fail (no Ct for all targets), the batch run is invalid and no data may be reported for the clinical specimens. This determination is made by visual inspection of the run data. The batch run should be repeated starting with either a new RNA preparation or starting at the RT reaction step. 
     If a second batch run fails, please contact technical services. If both the calibrations and all controls are valid, then the batch run is valid and specimen results will be reported. 
     Specimens 
     Note that a valid batch run may contain both valid and invalid specimen results. 
     Analytical criteria (e.g., Ct values) that qualify each specimen as passing or failing (using pre-determined data) are called automatically by the software. 
     Scores out of range—reported. 
     Quality Control 
     Singletons each of the Negative Control, Low Positive Control, and High Positive Control must be included in each batch run. The batch is valid if no flags appear for any of these controls. 
     A singleton of the No Template Control is included in each batch run and Fail (no Ct for all targets) is a valid result indicating no amplifiable material was detectable in the well. 
     The negative control must yield a Negative result. If the negative control is flagged as Invalid, then the entire batch run is invalid. 
     The low positive and high positive controls must fall within the assigned ranges. If one or both of the positive controls are flagged as Invalid, then the entire batch run is invalid. 
     Example 12 
     Detection of Pathogen Specific Biomarkers 
     An example workflow for measuring pathogen (bacterial, viral, protozoal) nucleic acid in whole blood will now be described. The workflow is largely similar to that for detecting host response specific biomarkers but involves a number of unique steps. Specific enrichment of pathogens, especially from whole blood, may be required upstream of nucleic acid detection. Nucleic acid is amplified using specific or broad-range forward and reverse primers and the amplicon is detected using fluorescence-labelled probes and a qPCR instrument (e.g., Applied Biosystems 7500 Fast Dx Real-Time PCR Instrument, Applied Biosystems, Foster City, Calif., catalogue number 440685; K082562). Appropriate positive and negative controls need to be used to ensure that the assay has worked and that contamination has not occurred. In part, some steps depend upon availability of automated platforms and specific cartridges designed to enrich, isolate and amplify pathogen nucleic acids. 
     Bacterial DNA transcripts are each amplified, detected, and quantified in a single multiplexed reaction using a pair of forward and reverse primers and three probes. The forward and reverse primers are broad-range, designed to 16S rDNA and amplify a large number of bacterial species. The probes are designed to identify DNA sequences unique to Gram positive and Gram negative bacteria. Viral DNA transcripts are detected using assays designed specifically for viruses that cause a viremia and for which anti-viral medicines are available, including Influenza A and B, Hepatitis B virus, Hepatitis C virus, Human Immunodeficiency Virus 1 and 2 (HIV-1, -2), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV), Herpes Simplex Virus 1 and 2 (HSV-1 and -2), Epstein Barr Virus (EBV). Alternatively, and for detection of such viruses, commercially available kits could be used, for example, HBV Digene Hybrid Capture II Microplate assay (Digene/Qiagen), Luminex (12212 Technology Blvd. Austin, Tex. 78727 United States), xTAG® Respiratory Viral Panel, Seegene (Washingtonian Blvd. Suite 290 Gaithersburg, Md. 20878 U.S.A.) Respiratory Virus Detection Assay. Protozoal DNA transcripts are each amplified, detected, and quantified in a single multiplexed reaction using three pairs of forward and reverse primers and four probes. The forward and reverse primers are designed to known common protozoal pathogens and the probes are designed to differentiate key protozoal species. 
     Blood (approximately 0.5 mL) collected into anti-coagulant is processed using a proprietary method, a commercially available kit, or a cartridge designed for use on a point-of-care instrument, and according to the manufacturer&#39;s instructions. Microbial DNA may need to be enriched from whole blood prior to performing PCR because the amount of background host DNA in blood reduces the effectiveness and sensitivity of downstream assays designed to detect bacterial DNA. Proprietary methods or commercially available kits or cartridges associated with a point-of-care instrument can be used. A proprietary method could involve the steps of: 1). lysis of microbes through chemical or mechanical means 2). proteolytic digestion in the presence of chaotropic agents and detergents 3).addition of magnetic silicon beads 4). isolation and washing of the beads 5). elution of nucleic acid from the beads. An example bacterial DNA enrichment kit for use on whole blood is MolYsis® Pathogen DNA Isolation (Molzym Life Science, GmbH &amp; Co. KG Mary-Astell-Strasse 10 D-28359 Bremen, Germany) and an example automated machine is Polaris® by Biocartis (Biocartis N V, Generaal De Wittelaan 11 B3 2800 Mechelen Belgium). Other companies, such as Curetis AG and Enigma Limited provide sample preparation methodologies upstream of their proprietary testing cartridges. Kits and automated machines that enrich bacterial DNA from whole blood generally rely on selective lysis of mammalian host cells, digestion of host cell DNA using DNAse enzymes, and filtration and lysis of microbial cells. European patent 2333185 entitled “Selective Lysis of Cells” describes the general procedure. Example commercial kits that enrich for microbial and viral DNAs from whole blood are ApoH Captovir® and ApoH Captobac® (ApoH Technologies, 94, Allée des fauvettes 34 280 La Grande Motte FRANCE). Virus-specific DNA or RNA can be detected in plasma (HIV-1, -2, HBV, HCV, Influenza A and B), whole blood (HCV), or white-blood-cell-enriched fractions (HBV, HCV, herpes viruses). In some instances protozoan DNA needs to be enriched from whole blood ( Plasmodium, Babesia ), red blood cells ( Plasmodium, Babesia ), plasma ( Trypanosoma ), or white blood cells ( Toxoplasma, Leishmania ) so that it can be sensitively detected in the host DNA milieu. Example methods that enrich for malarial protozoa from whole blood are described in: Venkatesan M, Amaratunga C, Campino S, Auburn S, Koch O, et al. (2012) Using CF11 cellulose columns to inexpensively and effectively remove human DNA from  Plasmodium falciparum -infected whole blood samples. Malaria journal 11: 41 and; Trang D T X, Huy N T, Kariu T, Tajima K, Kamei K (2004) One-step concentration of malarial parasite-infected red blood cells and removal of contaminating white blood cells. Malar J 3: 7. An example method that enriches for  Trypanosoma  from plasma is described in: Nagarkatti R, Bist V, Sun S, Fortes de Araujo F, Nakhasi H L, et al. (2012) Development of an Aptamer-Based Concentration Method for the Detection of  Trypanosoma cruzi  in Blood. PLoS ONE 7: e43533. An example method that enriches for  Leishmania  from white blood cells in whole blood is described in: Mathis A, Deplazes P (1995) PCR and in vitro cultivation for detection of  Leishmania  spp. in diagnostic samples from humans and dogs. Journal of Clinical Microbiology 33: 1145-1149. An example method that enriches for  Toxoplasma  from white blood cells in whole blood is described in: Colombo F A, Vidal J E, Oliveira A C P D, Hernandez A V, Bonasser-Filho F, et al. (2005) Diagnosis of Cerebral Toxoplasmosis in AIDS Patients in Brazil: Importance of Molecular and Immunological Methods Using Peripheral Blood Samples. Journal of Clinical Microbiology 43: 5044-5047. An example method that enriches for  Babesia  from red blood cells in whole blood is described in: Persing D H, Mathiesen D, Marshall W F, Telford S R, Spielman A, et al. (1992) Detection of  Babesia microti  by polymerase chain reaction. Journal of Clinical Microbiology 30: 2097-2103. Once enriched, microbial, viral or protozoan DNA should be processed immediately or stored in single-use volumes at or below −70° C. for later processing. 
     The downstream amplification, detection and interpretation of qPCR for bacterial DNA is similar to that described in the first example host response workflow but without the need for reverse transcription. Some viruses (RNA viruses, e.g., Influenza) require a reverse transcription step prior to performing qPCR. 
     Example forward (F) and reverse (R) primers and probes (P) and their final reaction concentration for detecting bacterial DNA are contained in TABLE I. 
     
       
         
           
               
               
               
               
             
               
                 TABLE I 
               
               
                   
               
               
                   
                   
                 SEQ 
                 Reaction 
               
               
                 Reagent 
                 5′-3′ Sequence 
                 ID NO. 
                 nM 
               
               
                   
               
             
            
               
                 Bacterial-F 
                 ACTCCTACGGGAGGCAGCAGT 
                 1720 
                 800 nM 
               
               
                   
               
               
                 Bacterial-R 
                 GTATTACCGCGGCTGCTGGCA 
                 1721 
                 800 nM 
               
               
                   
               
               
                 G+/−P1 
                 AGCAACGCCGCGT 
                 1722 
                 250 nM 
               
               
                   
               
               
                 G+/−P2 
                 AGCGACGCCGCGT 
                 1723 
                 100 nM 
               
               
                   
               
               
                 G+/−P 
                 AGCCATGCCGCGT 
                 1724 
                 200 nM 
               
               
                   
               
            
           
         
       
     
     Example forward (F) and reverse (R) primers and probes (P) and the protozoan parasitic DNA detected are contained in TABLE G supra. 
     Example forward (F) and reverse (R) primers and probes for common human pathogenic viruses that cause systemic inflammation and viremia are listed in TABLE F supra, which are disclosed for example in the following references: Watzinger, F., Suda, M., Preuner, S., Baumgartinger, R., Ebner, K., Baskova, L., et al. (2004). Real-time quantitative PCR assays for detection and monitoring of pathogenic human viruses in immunosuppressed pediatric patients. Journal of Clinical Microbiology, 42(11), 5189-5198; Pripuzova N, Wang R, Tsai S, Li B, Hung G-C, et al. (2012) Development of Real-Time PCR Array for Simultaneous Detection of Eight Human Blood-Borne Viral Pathogens. PLoS ONE 7: e43246; van Elden L J R, Nijhuis M, Schipper P, Schuurman R, van Loon A M (2001) Simultaneous Detection of Influenza Viruses A and B Using Real-Time Quantitative PCR. Journal of Clinical Microbiology 39: 196-200; U.S. Pat. No. 5,962,665 (application Ser. No. 08/876,546); Pas S D, Fries E, De Man R A, Osterhaus A D, Niesters H G (2000) Development of a quantitative real-time detection assay for hepatitis B virus DNA and comparison with two commercial assays. Journal of Clinical Microbiology 38: 2897-2901; Namvar L, Olofsson S, Bergstrom T, Lindh M (2005) Detection and Typing of Herpes Simplex Virus (HSV) in Mucocutaneous Samples by TaqMan PCR Targeting a gB Segment Homologous for HSV Types 1 and 2. Journal of Clinical Microbiology 43: 2058-2064; Mentel, R. (2003). Real-time PCR to improve the diagnosis of respiratory syncytial virus infection. Journal of Medical Microbiology, 52(10), 893-896; Do, D. H., Laus, S., Leber, A., Marcon, M. J., Jordan, J. A., Martin, J. M., &amp; Wadowsky, R. M. (2010). A One-Step, Real-Time PCR Assay for Rapid Detection of Rhinovirus. The Journal of Molecular Diagnostics, 12(1), 102-108; Fellner, M. D., Durand, K., Rodriguez, M., Irazu, L., Alonio, V., &amp; Picconi, M. A. (2014). Duplex realtime PCR method for Epstein-Barr virus and human DNA quantification: its application for post-transplant lymphoproliferative disorders detection. The Brazilian Journal of Infectious Diseases, 18(3), 271-280; Sanchez, J. L., &amp; Storch, G. A. (2002). Multiplex, Quantitative, Real-Time PCR Assay for Cytomegalovirus and Human DNA. Journal of Clinical Microbiology, 40(7), 2381-2386; Collot, S., Petit, B., Bordessoule, D., Alain, S., Touati, M., Denis, F., &amp; Ranger-Rogez, S. (2002). Real-Time PCR for Quantification of Human Herpesvirus 6 DNA from Lymph Nodes and Saliva. Journal of Clinical Microbiology, 40(7), 2445-2451; Akiyama, M., Kimura, H., Tsukagoshi, H., Taira, K., Mizuta, K., Saitoh, M., et al. (2009). Development of an assay for the detection and quantification of the measles virus nucleoprotein (N) gene using real-time reverse transcriptase PCR. Journal of Medical Microbiology, 58(5), 638-643; Lanciotti, R. S., Kerst, A. J., Nasci, R. S., Godsey, M. S., Mitchell, C. J., Savage, H. M., et al. (2000). Rapid detection of west nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase-PCR assay. Journal of Clinical Microbiology, 38(11), 4066-4071; Moës, E., Vijgen, L., Keyaerts, E., Zlateva, K., Li, S., Maes, P., et al. (2005). BMC Infectious Diseases. BMC Infectious Diseases, 5(1), 6-10; Neske, F., Blessing, K., Tollmann, F., Schubert, J., Rethwilm, A., Kreth, H. W., &amp; Weissbrich, B. (2007). Real-time PCR for diagnosis of human bocavirus infections and phylogenetic analysis. Journal of Clinical Microbiology, 45(7), 2116-2122; Verstrepen, W. A., Kuhn, S., Kockx, M. M., Van De Vyvere, M. E., &amp; Mertens, A. H. (2001). Rapid Detection of Enterovirus RNA in Cerebrospinal Fluid Specimens with a Novel Single-Tube Real-Time Reverse Transcription-PCR Assay. Journal of Clinical Microbiology, 39(11), 4093-4096; Logan, C., O&#39;Leary, J. J., &amp; O&#39;Sullivan, N. (2006). Real-Time Reverse Transcription-PCR for Detection of Rotavirus and Adenovirus as Causative Agents of Acute Viral Gastroenteritis in Children. Journal of Clinical Microbiology, 44(9), 3189-3195; Chigor, V., &amp; Okoh, A. (2012). Quantitative RT-PCR Detection of Hepatitis A Virus, Rotaviruses and Enteroviruses in the Buffalo River and Source Water Dams in the Eastern Cape Province of South Africa. International Journal of Environmental Research and Public Health, 9(12), 4017-4032; Ito, M., Takasaki, T., Yamada, K. I., Nerome, R., Tajima, S., &amp; Kurane, I. (2004). Development and Evaluation of Fluorogenic TaqMan Reverse Transcriptase PCR Assays for Detection of Dengue Virus Types 1 to 4. Journal of Clinical Microbiology, 42(12), 5935-5937; Nix, W. A., Maher, K., Johansson, E. S., Niklasson, B., Lindberg, A. M., Pallansch, M. A., &amp; Oberste, M. S. (2008). Detection of all known parechoviruses by real-time PCR. Journal of Clinical Microbiology, 46(8), 2519-2524; McQuaig, S. M., Scott, T. M., Lukasik, J. O., Paul, J. H., &amp; Harwood, V. J. (2009). Quantification of Human Polyomaviruses JC Virus and BK Virus by TaqMan Quantitative PCR and Comparison to Other Water Quality Indicators in Water and Fecal Samples. Applied and Environmental Microbiology, 75(11), 3379-3388; Raymond, F., Carbonneau, J., Boucher, N., Robitaille, L., Boisvert, S., Wu, W. K., et al. (2009). Comparison of Automated Microarray Detection with Real-Time PCR Assays for Detection of Respiratory Viruses in Specimens Obtained from Children. Journal of Clinical Microbiology, 47(3), 743-750; Kato, T., Mizokami, M., Mukaide, M., Orito, E., Ohno, T., Nakano, T., et al. (2000). Development of a TT virus DNA quantification system using real-time detection PCR. Journal of Clinical Microbiology, 38(1), 94-98; Xiao, X.-L., He, Y.-Q., Yu, Y.-G., Yang, H., Chen, G., Li, H.-F., et al. (2008). Simultaneous detection of human enterovirus 71 and coxsackievirus A16 in clinical specimens by multiplex real-time PCR with an internal amplification control. Archives of Virology, 154(1), 121-125. 
     Important controls in pathogen detection assays, especially broad-range PCR assays, include the use of 1). a process control 2). a no-template control 3). internal amplification control. A process control added to the clinical sample and detection demonstrates successful pathogen enrichment, isolation and amplification. For the bacterial and protozoal assays described here an appropriate process control is  Stenotrophomonas nitritireducens , since it is a harmless soil organism and its 16S rDNA is not amplified by the described broad range forward and reverse primers. Specific forward and reverse primers and a probe are required to detect this organism. Armored RNA (Life Technologies) is an example of a process control that could be used in the viral assays described herein, and again, specific forward and reverse primers and a probe are required to detect this control. A no-template control (e.g., nucleic-acid-free phospate buffered saline) run in parallel demonstrates the level of contamination or background nucleic acid. Broad-range PCR detects many microorganisms commonly found in and on water, soil, human skin, material surfaces, reagents, Taq polymerase, blood collection tubes and chemical preparations. As such, it is almost impossible to eliminate contaminating bacterial nucleic acid. A known level of contaminating or background nucleic acid, determined by running a no-template control, can be subtracted from the results obtained for a clinical sample. An internal amplification control run as part of a PCR demonstrate successful amplification. A synthetic DNA (with no known homology to natural DNA sequence), specific primers and a probe spiked into the PCR reaction are required to detect this control. 
     Example 13 
     Host Response Example Outputs (BaSIRS, VaSIRS, PaSIRS) 
     Possible example outputs from the software for BaSIRS, VaSIRS, PaSIRS assays run and analyzed individually are presented in  FIGS. 27, 28 and 29 . The format of such reports depends on many factors including; quality control, regulatory authorities, cut-off values, the algorithm used, laboratory and clinician requirements, likelihood of misinterpretation. 
     The host response assays are called “SeptiCyte MICROBE”, “SeptiCyte VIRUS” and “SeptiCyte PROTOZOAN”. The results are reported as a number representing a position on a linear scale, and a probability of the patient having BaSIRS, VaSIRS or PaSIRS based on historical results and the use of pre-determined cut-offs (using results from clinical studies). Results of controls within the assays may also be reported. Other information that could be reported might include: previous results and date and time of such results, a prognosis, a scale that provides cut-off values for historical testing results that separate the conditions of healthy, BaSIRS, VaSIRS, PaSIRS and InSIRS such that those patients with higher scores are considered to have more severe BaSIRS, VaSIRS or PaSIRS. 
     Example 14 
     Combining Host Response Signatures and Example Outputs 
     One method of combining the four host response signatures is to calculate a probability of a subject, or subjects, having each of the conditions, as described below. 
     Additional datasets independent of the discovery process were used including; GSE70311 (Trauma patients that developed bacterial sepsis), GSE34205 (Influenza), GSE5418 (Malaria-infection) and GSE76293 (Bacterial). These datasets included at least one clinical group from each of the pathologies of interest, i.e. bacterial, protozoal and viral infections and a similar control group (InSIRS). 
     Each of the datasets was log 2  transformed and then the final score was linearly shifted to align each of the control groups across all of the datasets. This latter approach was required because the data were produced on different machines under different study conditions. Because the discovery process for each of the signatures (BaSIRS, VaSIRS, PaSIRS, InSIRS) involved a subtraction step to ensure specificity (signal for conditions other than the one of interest were subtracted), displacing the score in this manner controlled for this variability without losing biological signal. 
     Probabilities were then calculated by mapping the raw scores through a logit function via a logistic regression model. A one-vs-all response label was set because each of the signatures (BaSIRS, VaSIRS, PaSIRS, InSIRS) had been developed and designed to force non-specific infections into the control group (e.g., for the BaSIRS all non-BaSIRS conditions (VaSIRS, PaSIRS, InSIRS) were treated as controls). Each of the signatures were then applied to each sample and probabilities for each individual sample were calculated using a leave-one-out cross validation (LOO-CV).  FIG. 37  demonstrates the use of this approach, through box and whisker plots, for the four host response signatures when using various datasets representing the four conditions. 
     Possible example patient report outputs from the software for BaSIRS, VaSIRS, PaSIRS and InSIRS assays combined are presented in  FIGS. 30, 31, 32 and 33 . The format of such reports depends on many factors including; quality control, regulatory authorities, cut-off values, the algorithm used, laboratory and clinician requirements, likelihood of misinterpretation. 
     The combined host response assay is called “SeptiCyte SPECTRUM”. The result is reported as numbers representing positions on linear scales, and a probability of the patient having BaSIRS, VaSIRS, PaSIRS or InSIRS based on historical results and the use of pre-determined cut-offs (using results from clinical studies). Results of controls within the assays may also be reported. Other information that could be reported might include: previous results and date and time of such results, a prognosis, a scale that provides cut-off values for historical testing results that separate the conditions of healthy, InSIRS, BaSIRS, VaSIRS, PaSIRS and InSIRS such that those patients with higher scores are considered to have more severe BaSIRS, VaSIRS, PaSIRS or InSIRS. 
     Example 15 
     Combination of Host Response Specific Biomarkers Assay Output and Pathogen Specific Biomarkers Assay Output—Example Output (BaSIRS and BIP Combined) 
     Possible example output from software that combines the results for a host response specific biomarker assay (e.g., BaSIRS) and a pathogen specific biomarker assay (e.g., BIP) for over 50 patients suspected of sepsis and over 50 healthy volunteers is presented in  FIG. 34 . A similar output is envisaged for a single patient. In this instance, SeptiScore (results of a BaSIRS host response specific biomarker assay) on a scale of −2-12 are plotted on the Y axis, and SeptID (results of a BIP pathogen specific biomarker assay on a reverse scale of 40-20, representing the output of a real-time PCR assay in Ct values) are plotted on the X axis. The higher the SeptiScore the higher the likelihood that a particular patient has BaSIRS. The lower the SeptID score the higher the concentration of bacterial DNA in the sample taken from a patient. Thus, patients with a high SeptiScore and a low SeptID score have a higher probability (or “likelihood”) of BaSIRS compared to patients with a low SeptiScore and a high SeptID score. In  FIG. 34 , those patients that were ultimately shown to be blood culture positive are circled in the top right of the plot—that is, such patients had a high SeptiScore and low SeptID score. Healthy volunteers had low SeptiScore values and a range (27-&gt;40) of SeptID scores. 
     In this instance the value of combining host response specific biomarkers with pathogen specific biomarkers is; 1) increased positive predictive value in those samples that are positive for both assays, 2) increased negative predictive value in those samples that are negative for both assays, 3) capturing those patients that were retrospectively diagnosed as sepsis and had high SeptiScores, but were blood culture negative, 4) indicating which samples might be contaminated (low SeptiScore, high pathogen detection), and 5) confirmation of blood culture results in a shorter time frame. 
     Similar outputs are envisaged for: the combination of VaSIRS biomarker assay results and VIP biomarker assay results, and the combination of PaSIRS biomarker assay results and PIP biomarker assay results. A report may contain individual plots for each of the conditions (bacterial, viral and protozoal) or a plot that combines the results for each of these conditions. The format of such reports therefore depends on many factors including; the suspected conditions that the patient has (e.g., bacterial, viral, protozoal), the number and type of assays that are run, quality control, regulatory authority requirements, pre-determined cut-off values, the algorithm used, laboratory and clinician requirements, likelihood of misinterpretation. 
     In a patient report other information could be conveyed, including: probability of a patient having a particular condition based on historical results, results of controls run, previous results and date and time of such results, a prognosis, a scale that provides cut-off values for historical testing results that separate the conditions of healthy, BaSIRS, VaSIRS, PaSIRS and InSIRS such that those patients with higher scores are considered to have more severe BaSIRS, VaSIRS, PaSIRS or InSIRS. 
     Example 16 
     Combination of Host Response Specific Biomarkers Assay Output and Pathogen Specific Biomarkers Assay Output—Example Output (VaSIRS and VIP Combined) 
     Possible example output from software that combines the results for a host response specific biomarker assay (e.g., VaSIRS) and a pathogen specific biomarker assay (e.g., VIP) for over 200 patients suspected of sepsis for which some were concurrently tested for the presence of virus antigen is shown in  FIG. 35 . A similar output is envisaged for a single patient. In this instance, the VaSIRS signature result is plotted on the Y axis and patients with positive viral pathogen results are circled (with varying sized circles for different virus types). In particular, those patients positive for influenza and RSV virus antigens are also strongly positive for VaSIRS signature. The value of combining host response specific biomarkers (VaSIRS signature) with pathogen specific biomarkers is; 1) increased positive predictive value in those samples that are positive for both assays, 2) increased negative predictive value in those samples that are negative for both assays, and 3) confirmation of virus pathogen detection assay results (not an incidental finding or commensal virus). 
     Example 17 
     Example Workflow on Automated Machines 
     A second example automated workflow will now be described. Machines have been, and are being, developed that are capable of processing a patient sample at point-of-care, or near point-of-care. Such machines require few molecular biology skills to run and are aimed at non-technical users. The idea is that the sample would be pipetted directly into a disposable cartridge(s) that is/are then inserted into the machine. One cartridge may be able to run a host response assay and pathogen assay in combination, or separate cartridges may be required to run each assay separately. In both instances the results of each assay will be combined algorithmically following completion of the assay. For determining host response specific biomarkers the cartridge will need to extract high quality RNA from the host cells in the sample for use in reverse transcription followed by RT-PCR. For determining pathogen specific biomarkers the cartridge will need to extract high quality pathogen nucleic acid from the cells in the sample, and away from potentially interfering host nucleic acid, for use in RT-PCR, or reverse transcription followed by RT-PCR. The machines are designed for minimum user interaction such that the user presses “Start” and within 1-3 hours results are generated. The cartridges contains all of the required reagents to perform host cell and pathogen nucleic acid extraction (RNA and/or DNA), reverse transcription, and qRT-PCR, and the machine has appropriate software incorporated to allow use of algorithms to interpret each result and combine results, and final interpretation and printing of results. 
     Fresh, whole, anti-coagulated blood can be pipetted into a specialized cartridge (e.g., cartridges designed for Enigma ML machine by Enigma Diagnostics Limited (Enigma Diagnostics Limited, Building 224, Tetricus Science Park, DstI, Porton Down, Salisbury, Wiltshire SP4 0JQ) or similar (Unyvero, Curetis A G, Max-Eyth-Str. 42 71088 Holzgerlingen, Germany) (Biocartis N V, Generaal De Wittelaan 11 B3, 2800 Mechelen, Belgium)), and on-screen instructions followed to test for differentiating a BaSIRS, VaSIRS, PaSIRS or InSIRS. For determining host response specific biomarkers, inside the machine RNA is first extracted from the whole blood and is then converted into cDNA. The cDNA is then used in qRT-PCR reactions. For determining pathogen specific biomarkers, inside the machine pathogen nucleic acid is first extracted (possibly selectively) from the whole blood and is then used directly in qRT-PCR reactions, or converted into cDNA and then used in qRT-PCR reactions. The reactions are followed in real time and Ct values calculated. On-board software generates a result output (see,  FIGS. 30-33 ). Appropriate quality control measures for RNA and DNA quality, a process control, no template controls, high and low template controls and expected Ct ranges ensure that results are not reported erroneously. 
     Example 18 
     Example Algorithms Combining Derived Biomarkers for Assessing SIRS 
     Derived biomarkers can be used in combination to increase the diagnostic power for separating various conditions. Determining which markers to use, and how many, for separating various conditions can be achieved by calculating Area Under Curve (AUC). 
     As such, and by example, immune host response biomarker profiles using four to six biomarkers can offer the appropriate balance between simplicity, practicality and commercial risk for diagnosing BaSIRS, VaSIRS, PaSIRS or InSIRS. Further, equations using four to six biomarkers weighs each biomarker equally which provides robustness in cases of analytical or clinical variability. 
     One example equation (amongst others) that provides good diagnostic power for diagnosing a BaSIRS is: 
       Diagnostic Score=(TSPO−HCLS1)+(OPLAH−ZHX2)
         Note: each marker in the Diagnostic Score above is the Log 2 transformed concentration of the marker in the sample.       

     One example equation (amongst others) that provides good diagnostic power for diagnosing a VaSIRS is: 
       Diagnostic Score=(IL16−ISG15)+(ADGRE5−OASL)
         Note: each marker in the Diagnostic Score above is the Log 2 transformed concentration of the marker in the sample.       

     One example equation (amongst others) that provides good diagnostic power for diagnosing a PaSIRS is: 
       Diagnostic Score=(TTC17−G6PD)+(HERC6−LAP3)+(NUP160−TPP1)
         Note: each marker in the Diagnostic Score above is the Log 2 transformed concentration of the marker in the sample.       

     One example equation (amongst others) that provides good diagnostic power for diagnosing a INSIRS is: 
       Diagnostic Score=(ARL6IIP5−ENTPD1)+(HEATR1−TNFSF8)
         Note: each marker in the Diagnostic Score above is the Log 2 transformed concentration of the marker in the sample.       

     Example 19 
     Validation of Derived Biomarkers for BaSIRS and VaSIRS on a Pediatric Patient Sample Set 
     The best performing pairs of host response derived biomarkers for BaSIRS and VaSIRS (TSPO/HCLS1+OPLAH/ZHX2 and IL16/ISG15+ADGRE5/OASL) were further validated on an independent pediatric patient sample set. In this study, samples were collected from three groups of patients including 1). SIRS following cardiopulmonary bypass surgery (n=12) (“Control” in  FIG. 36 ), 2). Sepsis (SIRS+confirmed or strongly suspected bacterial infection) (n=28) (“Sepsis” in  FIG. 36 ), 3). Severe respiratory virus-infected (n=6) (“Virus” in  FIG. 36 ). For SIRS patients, samples were taken within the first 24 hours following surgery and when the patient had at least two clinical signs of SIRS. Sepsis patients were retrospectively diagnosed by a panel of clinicians using all available clinical and diagnostic data. Virus-infected patients were also retrospectively diagnosed by a panel of clinicians using all available clinical and diagnostic data including the use of a viral PCR panel used on nasal or nasal/pharyngeal swabs (Biofire, FilmArray, Respiratory Panel, Biomerieux, 390 Wakara Way Salt Lake City, Utah 84108 USA). The respiratory viruses detected in these patients were: rhinovirus/enterovirus, parainfluenza 3, respiratory syncytial virus and coronavirus HKU1. Three of the six patients with a confirmed virus infection also had a confirmed or suspected bacterial infection. It should be noted that sepsis patients that were not suspected of having a viral infection were also tested with the Biofire FilmArray and nine of the 28 sepsis patients had a positive viral PCR. Thus, there is some overlapping etiologies/pathologies in the sepsis and viral groups which is illustrated in  FIG. 36 . 
     The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety. 
     The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application. 
     Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims. 
     TABLES 
       
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 NON-LIMITING HUMAN PATHOGENS THAT ARE KNOWN 
               
               
                 TO CAUSE SYSTEMIC INFLAMMATION AND BACTEREMIA, 
               
               
                 VIREMIA OR PROTOZOAN PARASITEMIA 
               
            
           
           
               
               
               
            
               
                 Bacteria/Fungi 
                 Viruses 
                 Protozoans 
               
               
                   
               
               
                 Coagulase-negative 
                 Respiratory Clinical Signs 
                 
                   Plasmodium falciparum 
                 
               
               
                   Staphylococcus  (CoNS consist 
                 Respiratory Syncytial Virus (RSV) 
                 
                   Plasmodium ovale 
                 
               
               
                 mainly of  S. epidemidis , 
                 Influenza A and B 
                 
                   Plasmodium malariae 
                 
               
               
                   saprophyticus  and  hominus ) 
                 Adenovirus 
                 
                   Plasmodium vivax 
                 
               
               
                   Staphylococcus ,  aureus   
                 Parainfluenza virus 1, 2, 3 and 4 
                 
                   Leishmania donovani 
                 
               
               
                 
                   Enterococcus faecalis 
                 
                 Human Coronavirus types 229e, 
                 
                   Trypanosoma brucei 
                 
               
               
                 
                   Escherichia coli 
                 
                 OC43, HKU1, NL-63 
                 
                   Trypanosoma cruzi 
                 
               
               
                 
                   Klebsiella pneumoniae 
                 
                 Rhinovirus 
                 
                   Toxoplasma gondii 
                 
               
               
                 
                   Enterococcus faecium 
                 
                 SARS Coronavirus 
                 
                   Babesia microti 
                 
               
               
                   Streptococcus viridans  group 
                 Enterovirus 
               
               
                 ( Streptococcus viridans  group 
                 BK virus 
               
               
                 includes:  mitis ,  mutans , 
                 Respiratory/Gastrointestinal 
               
               
                   oralis ,  sanginus ,  sobrinus  and 
                 Bocavirus 
               
               
                   milleri  ( anginosus , 
                 Fever/Rash/Aches/Generalised 
               
               
                   constellatus ,  intermedius ) 
                 Measles 
               
               
                 
                   Pseudomonas aeruginosa 
                 
                 Hantavirus 
               
               
                 
                   Streptococcus pneumoniae 
                 
                 Cytomegalovirus 
               
               
                 
                   Enterobacter cloacae 
                 
                 Varicella Zoster Virus 
               
               
                 
                   Serratia marcescens 
                 
                 Herpes Simplex Virus 
               
               
                 
                   Acinetobacter baumammii 
                 
                 Epstein Barr Virus 
               
               
                 
                   Proteus mirabilis 
                 
                 Parechovirus 
               
               
                 
                   Streptococcus agalactiae 
                 
                 Human immunodeficiency virus 
               
               
                 
                   Klebsiella oxytoca 
                 
                 Hepatitis B virus 
               
               
                 
                   Enterobacter aerogenes 
                 
                 HTLV1 and 2 
               
               
                 
                   Stenotrophomonas 
                 
                 Vaccinia virus 
               
               
                 
                   maltophilia 
                 
                 West Nile Virus 
               
               
                 
                   Citrobacter freundii 
                 
                 Coxsackie virus 
               
               
                 
                   Streptococcus pyogenes 
                 
                 Parvovirus B19 
               
               
                 
                   Enterococcus avium 
                 
                 Dengue 
               
               
                 
                   Bacteroides fragilis 
                 
                 Few Clinical Signs 
               
               
                 
                   Bacteroides vulgatus 
                 
                 TTV (torque teno virus) 
               
               
                   
                 Hepatitis C virus 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 COMMON HUMAN VIRUSES THAT CAUSE SIRS AS 
               
               
                 PART OF THEIR PATHOGENESIS AND FOR WHICH 
               
               
                 THERE ARE SPECIFIC ANTI-VIRAL TREATMENTS 
               
            
           
           
               
               
            
               
                 Virus 
                 Reference 
               
               
                   
               
               
                 Influenza A and B 
                 Wootton SH, Aguilera EA, Wanger A, 
               
               
                   
                 Jewell A, Patel K, et al. (2014) 
               
               
                   
                 Detection of NH1N1 influenza virus in 
               
               
                   
                 nonrespiratory sites among children. 
               
               
                   
                 Pediatr Infect Dis J 33: 95-96. 
               
               
                 Hepatitis B virus 
                 Pripuzova N, Wang R, Tsai S, Li B, 
               
               
                 Hepatitis C virus 
                 Hung G-C, et al. (2012) Development 
               
               
                 Human immunodeficiency 
                 of Real-Time PCR Array for Simulta- 
               
               
                 virus 1 and 2 
                 neous Detection of Eight Human Blood- 
               
               
                   
                 Borne Viral Pathogens. PLoS ONE 7: 
               
               
                   
                 e43246. 
               
               
                 Cytomegalovirus 
                 Johnson G, Nelson S, Petric M, Tellier 
               
               
                 Varicella Zoster Virus 
                 R (2000) Comprehensive PCR-based assay 
               
               
                 Herpes Simplex Virus 
                 for detection and species identification 
               
               
                 Epstein Barr Virus 
                 of human herpesviruses. Journal of 
               
               
                   
                 Clinical Microbiology 38: 3274-3279. 
               
               
                 Respiratory Syncytial 
                 Najarro, P., Angell, R., &amp; Powell, K. 
               
               
                 Virus 
                 (2012). The prophylaxis and treatment 
               
               
                   
                 with antiviral agents of respiratory 
               
               
                   
                 syncytial virus infections. Antiviral 
               
               
                   
                 Chemistry &amp; Chemotherapy, 22(4), 
               
               
                   
                 139-150. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 BASIRS BIOMARKER DETAILS INCLUDING; 
               
               
                 SEQUENCE IDENTIFICATION NUMBER,  
               
               
                 GENE SYMBOL, ENSEMBL TRANSCRIPT 
               
               
                 ID AND DNA SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID 
                 Gene 
                 Ensembl Transcript 
               
               
                   
                 # DNA 
                 Symbol 
                 ID 
               
               
                   
                   
               
               
                   
                  1 
                 ADAM19 
                 ENST00000257527 
               
               
                   
                  2 
                 ADM 
                 ENST00000278175 
               
               
                   
                  3 
                 ALPL 
                 ENST00000374840 
               
               
                   
                  4 
                 CAMK1D 
                 ENST00000378845 
               
               
                   
                  5 
                 CASS4 
                 ENST00000360314 
               
               
                   
                  6 
                 CBLL1 
                 ENST00000440859 
               
               
                   
                  7 
                 CCNK 
                 ENST00000389879 
               
               
                   
                  8 
                 CD82 
                 ENST00000227155 
               
               
                   
                  9 
                 CLEC7A 
                 ENST00000353231 
               
               
                   
                 10 
                 CNNM3 
                 ENST00000305510 
               
               
                   
                 11 
                 COX15 
                 ENST00000370483 
               
               
                   
                 12 
                 CR1 
                 ENST00000400960 
               
               
                   
                 13 
                 DENND3 
                 ENST00000262585 
               
               
                   
                 14 
                 DOCK5 
                 ENST00000276440 
               
               
                   
                 15 
                 ENTPD7 
                 ENST00000370489 
               
               
                   
                 16 
                 EPHB4 
                 ENST00000358173 
               
               
                   
                 17 
                 EXTL3 
                 ENST00000220562 
               
               
                   
                 18 
                 FAM129A 
                 ENST00000367511 
               
               
                   
                 19 
                 FBXO28 
                 ENST00000366862 
               
               
                   
                 20 
                 FIG4 
                 ENST00000230124 
               
               
                   
                 21 
                 FOXJ3 
                 ENST00000361346 
               
               
                   
                 22 
                 GAB2 
                 ENST00000340149 
               
               
                   
                 23 
                 GALNT2 
                 ENST00000366672 
               
               
                   
                 24 
                 GAS7 
                 ENST00000580865 
               
               
                   
                 25 
                 GCC2 
                 ENST00000309863 
               
               
                   
                 26 
                 GRK5 
                 ENST00000392870 
               
               
                   
                 27 
                 HAL 
                 ENST00000261208 
               
               
                   
                 28 
                 HCLS1 
                 ENST00000314583 
               
               
                   
                 29 
                 HK3 
                 ENST00000292432 
               
               
                   
                 30 
                 ICK 
                 ENST00000350082 
               
               
                   
                 31 
                 IGFBP7 
                 ENST00000295666 
               
               
                   
                 32 
                 IK 
                 ENST00000417647 
               
               
                   
                 33 
                 IKZF5 
                 ENST00000617859 
               
               
                   
                 34 
                 IL2RB 
                 ENST00000216223 
               
               
                   
                 35 
                 IMPDH1 
                 ENST00000338791 
               
               
                   
                 36 
                 INPP5D 
                 ENST00000359570 
               
               
                   
                 37 
                 ITGA7 
                 ENST00000257879 
               
               
                   
                 38 
                 JARID2 
                 ENST00000341776 
               
               
                   
                 39 
                 KIAA0101 
                 ENST00000300035 
               
               
                   
                 40 
                 KIAA0355 
                 ENST00000299505 
               
               
                   
                 41 
                 KIAA0907 
                 ENST00000368321 
               
               
                   
                 42 
                 KLRD1 
                 ENST00000336164 
               
               
                   
                 43 
                 KLRF1 
                 ENST00000617889 
               
               
                   
                 44 
                 LAG3 
                 ENST00000203629 
               
               
                   
                 45 
                 LEPROTL1 
                 ENST00000321250 
               
               
                   
                 46 
                 LPIN2 
                 ENST00000261596 
               
               
                   
                 47 
                 MBIP 
                 ENST00000416007 
               
               
                   
                 48 
                 MCTP1 
                 ENST00000515393 
               
               
                   
                 49 
                 MGAM 
                 ENST00000549489 
               
               
                   
                 50 
                 MME 
                 ENST00000460393 
               
               
                   
                 51 
                 NCOA6 
                 ENST00000359003 
               
               
                   
                 52 
                 NFIC 
                 ENST00000341919 
               
               
                   
                 53 
                 NLRP1 
                 ENST00000269280 
               
               
                   
                 54 
                 NMUR1 
                 ENST00000305141 
               
               
                   
                 55 
                 NOV 
                 ENST00000259526 
               
               
                   
                 56 
                 NPAT 
                 ENST00000278612 
               
               
                   
                 57 
                 OPLAH 
                 ENST00000618853 
               
               
                   
                 58 
                 PARP8 
                 ENST00000281631 
               
               
                   
                 59 
                 PCOLCE2 
                 ENST00000295992 
               
               
                   
                 60 
                 PDGFC 
                 ENST00000502773 
               
               
                   
                 61 
                 PDS5B 
                 ENST00000315596 
               
               
                   
                 62 
                 PHF3 
                 ENST00000393387 
               
               
                   
                 63 
                 PIK3C2A 
                 ENST00000265970 
               
               
                   
                 64 
                 PLA2G7 
                 ENST00000274793 
               
               
                   
                 65 
                 POGZ 
                 ENST00000271715 
               
               
                   
                 66 
                 PRKD2 
                 ENST00000433867 
               
               
                   
                 67 
                 PRKDC 
                 ENST00000314191 
               
               
                   
                 68 
                 PRPF38B 
                 ENST00000370025 
               
               
                   
                 69 
                 PRSS23 
                 ENST00000280258 
               
               
                   
                 70 
                 PYHIN1 
                 ENST00000368140 
               
               
                   
                 71 
                 QRICH1 
                 ENST00000357496 
               
               
                   
                 72 
                 RAB32 
                 ENST00000367495 
               
               
                   
                 73 
                 RBM15 
                 ENST00000618772 
               
               
                   
                 74 
                 RBM23 
                 ENST00000399922 
               
               
                   
                 75 
                 RFC1 
                 ENST00000349703 
               
               
                   
                 76 
                 RNASE6 
                 ENST00000304677 
               
               
                   
                 77 
                 RUNX2 
                 ENST00000371432 
               
               
                   
                 78 
                 RYK 
                 ENST00000623711 
               
               
                   
                 79 
                 SAP130 
                 ENST00000259235 
               
               
                   
                 80 
                 SEMA4D 
                 ENST00000438547 
               
               
                   
                 81 
                 SIDT1 
                 ENST00000264852 
               
               
                   
                 82 
                 SMPDL3A 
                 ENST00000368440 
               
               
                   
                 83 
                 SPIN1 
                 ENST00000375859 
               
               
                   
                 84 
                 ST3GAL2 
                 ENST00000342907 
               
               
                   
                 85 
                 SYTL2 
                 ENST00000389960 
               
               
                   
                 86 
                 TGFBR3 
                 ENST00000212355 
               
               
                   
                 87 
                 TLE3 
                 ENST00000558939 
               
               
                   
                 88 
                 TLR5 
                 ENST00000366881 
               
               
                   
                 89 
                 TMEM165 
                 ENST00000381334 
               
               
                   
                 90 
                 TSPO 
                 ENST00000337554 
               
               
                   
                 91 
                 UTRN 
                 ENST00000367545 
               
               
                   
                 92 
                 YPEL1 
                 ENST00000339468 
               
               
                   
                 93 
                 ZFP36L2 
                 ENST00000282388 
               
               
                   
                 94 
                 ZHX2 
                 ENST00000314393 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 BASIRS BIOMARKER DETAILS INCLUDING;  
               
               
                 SEQUENCE IDENTIFICATION NUMBER, 
               
               
                 GENE SYMBOL, GENBANK ACCESSION 
               
               
                 AND AMINO ACID SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID 
                 Gene 
                 GenBank 
               
               
                   
                 # AA 
                 Symbol 
                 Accession 
               
               
                   
                   
               
               
                   
                  95 
                 ADAM19 
                 NP_150377 
               
               
                   
                  96 
                 ADM 
                 NP_001115 
               
               
                   
                  97 
                 ALPL 
                 NP_000469 
               
               
                   
                  98 
                 CAMK1D 
                 NP_065130 
               
               
                   
                  99 
                 CASS4 
                 NP_065089 
               
               
                   
                 100 
                 CBLL1 
                 NP_079090 
               
               
                   
                 101 
                 CCNK 
                 NP_001092872 
               
               
                   
                 102 
                 CD82 
                 NP_002222 
               
               
                   
                 103 
                 CLEC7A 
                 NP_072092 
               
               
                   
                 104 
                 CNNM3 
                 NP_060093 
               
               
                   
                 105 
                 COX15 
                 NP_004367 
               
               
                   
                 106 
                 CR1 
                 NP_000564 
               
               
                   
                 107 
                 DENND3 
                 NP_055772 
               
               
                   
                 108 
                 DOCK5 
                 NP_079216 
               
               
                   
                 109 
                 ENTPD7 
                 NP_065087 
               
               
                   
                 110 
                 EPHB4 
                 NP_004435 
               
               
                   
                 111 
                 EXTL3 
                 NP_001431 
               
               
                   
                 112 
                 FAM129A 
                 NP_443198 
               
               
                   
                 113 
                 FBXO28 
                 NP_055991 
               
               
                   
                 114 
                 FIG4 
                 NP_055660 
               
               
                   
                 115 
                 FOXJ3 
                 NP_055762 
               
               
                   
                 116 
                 GAB2 
                 NP_036428 
               
               
                   
                 117 
                 GALNT2 
                 NP_004472 
               
               
                   
                 118 
                 GAS7 
                 NP_003635 
               
               
                   
                 119 
                 GCC2 
                 NP_852118 
               
               
                   
                 120 
                 GRK5 
                 NP_005299 
               
               
                   
                 121 
                 HAL 
                 NP_002099 
               
               
                   
                 122 
                 HCLS1 
                 NP_005326 
               
               
                   
                 123 
                 HK3 
                 NP_002106 
               
               
                   
                 124 
                 ICK 
                 NP_055735 
               
               
                   
                 125 
                 IGFBP7 
                 NP_001544 
               
               
                   
                 126 
                 IK 
                 NP_006074 
               
               
                   
                 127 
                 IKZF5 
                 NP_001258769 
               
               
                   
                 128 
                 IL2RB 
                 NP_000869 
               
               
                   
                 129 
                 IMPDH1 
                 NP_000874 
               
               
                   
                 130 
                 INPP5D 
                 NP_005532 
               
               
                   
                 131 
                 ITGA7 
                 NP_002197 
               
               
                   
                 132 
                 JARID2 
                 NP_004964 
               
               
                   
                 133 
                 KIAA0101 
                 NP_055551 
               
               
                   
                 134 
                 KIAA0355 
                 NP_055501 
               
               
                   
                 135 
                 KIAA0907 
                 NP_055764 
               
               
                   
                 136 
                 KLRD1 
                 NP_002253 
               
               
                   
                 137 
                 KLRF1 
                 NP_057607 
               
               
                   
                 138 
                 LAG3 
                 NP_002277 
               
               
                   
                 139 
                 LEPROTL1 
                 NP_056159 
               
               
                   
                 140 
                 LPIN2 
                 NP_055461 
               
               
                   
                 141 
                 MBIP 
                 NP_057670 
               
               
                   
                 142 
                 MCTP1 
                 NP_078993 
               
               
                   
                 143 
                 MGAM 
                 NP_004659 
               
               
                   
                 144 
                 MME 
                 NP_000893 
               
               
                   
                 145 
                 NCOA6 
                 NP_054790 
               
               
                   
                 146 
                 NFIC 
                 NP_005588 
               
               
                   
                 147 
                 NLRP1 
                 NP_055737 
               
               
                   
                 148 
                 NMUR1 
                 NP_006047 
               
               
                   
                 149 
                 NOV 
                 NP_002505 
               
               
                   
                 150 
                 NPAT 
                 NP_002510 
               
               
                   
                 151 
                 OPLAH 
                 NP_060040 
               
               
                   
                 152 
                 PARP8 
                 NP_078891 
               
               
                   
                 153 
                 PCOLCE2 
                 NP_037495 
               
               
                   
                 154 
                 PDGFC 
                 NP_057289 
               
               
                   
                 155 
                 PDS5B 
                 NP_055847 
               
               
                   
                 156 
                 PHF3 
                 NP_055968 
               
               
                   
                 157 
                 PIK3C2A 
                 NP_002636 
               
               
                   
                 158 
                 PLA2G7 
                 NP_005075 
               
               
                   
                 159 
                 POGZ 
                 NP_055915 
               
               
                   
                 160 
                 PRKD2 
                 NP_057541 
               
               
                   
                 161 
                 PRKDC 
                 NP_008835 
               
               
                   
                 162 
                 PRPF38B 
                 NP_060531 
               
               
                   
                 163 
                 PRSS23 
                 NP_009104 
               
               
                   
                 164 
                 PYHIN1 
                 NP_689714 
               
               
                   
                 165 
                 QRICH1 
                 NP_060200 
               
               
                   
                 166 
                 RAB32 
                 NP_006825 
               
               
                   
                 167 
                 RBM15 
                 NP_073605 
               
               
                   
                 168 
                 RBM23 
                 NP_060577 
               
               
                   
                 169 
                 RFC1 
                 NP_002904 
               
               
                   
                 170 
                 RNASE6 
                 NP_005606 
               
               
                   
                 171 
                 RUNX2 
                 NP_001015051 
               
               
                   
                 172 
                 RYK 
                 NP_002949 
               
               
                   
                 173 
                 SAP130 
                 NP_078821 
               
               
                   
                 174 
                 SEMA4D 
                 NP_006369 
               
               
                   
                 175 
                 SIDT1 
                 NP_060169 
               
               
                   
                 176 
                 SMPDL3A 
                 NP_006705 
               
               
                   
                 177 
                 SPIN1 
                 NP_006708 
               
               
                   
                 178 
                 ST3GAL2 
                 NP_008858 
               
               
                   
                 179 
                 SYTL2 
                 NP_116561 
               
               
                   
                 180 
                 TGFBR3 
                 NP_003234 
               
               
                   
                 181 
                 TLE3 
                 NP_005069 
               
               
                   
                 182 
                 TLR5 
                 NP_003259 
               
               
                   
                 183 
                 TMEM165 
                 NP_060945 
               
               
                   
                 184 
                 TSPO 
                 NP_000705 
               
               
                   
                 185 
                 UTRN 
                 NP_009055 
               
               
                   
                 186 
                 YPEL1 
                 NP_037445 
               
               
                   
                 187 
                 ZFP36L2 
                 NP_008818 
               
               
                   
                 188 
                 ZHX2 
                 NP_055758 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 VASIRS BIOMARKER DETAILS INCLUDING;  
               
               
                 SEQUENCE IDENTIFICATION NUMBER, 
               
               
                 GENE SYMBOL, ENSEMBL TRANSCRIPT 
               
               
                 ID AND DNA SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID 
                 Gene  
                 Ensembl Transcript 
               
               
                   
                 # (DNA) 
                 Symbol 
                 ID 
               
               
                   
                   
               
               
                   
                 189 
                 ABAT 
                 ENST00000396600 
               
               
                   
                 190 
                 ABHD2 
                 ENST00000565973 
               
               
                   
                 191 
                 ABI1 
                 ENST00000376142 
               
               
                   
                 192 
                 ABLIM1 
                 ENST00000277895 
               
               
                   
                 193 
                 ACAA1 
                 ENST00000333167 
               
               
                   
                 194 
                 ACAP2 
                 ENST00000326793 
               
               
                   
                 195 
                 ACVR1B 
                 ENST00000257963 
               
               
                   
                 196 
                 AIF1 
                 ENST00000413349 
               
               
                   
                 197 
                 ALDH3A2 
                 ENST00000579855 
               
               
                   
                 198 
                 ANKRD49 
                 ENST00000544612 
               
               
                   
                 199 
                 AOAH 
                 ENST00000617537 
               
               
                   
                 200 
                 APBB1IP 
                 ENST00000376236 
               
               
                   
                 201 
                 APLP2 
                 ENST00000263574 
               
               
                   
                 202 
                 ARAP1 
                 ENST00000334211 
               
               
                   
                 203 
                 ARHGAP15 
                 ENST00000295095 
               
               
                   
                 204 
                 ARHGAP25 
                 ENST00000409030 
               
               
                   
                 205 
                 ARHGAP26 
                 ENST00000274498 
               
               
                   
                 206 
                 ARHGEF2 
                 ENST00000313695 
               
               
                   
                 207 
                 ARRB1 
                 ENST00000420843 
               
               
                   
                 208 
                 ARRB2 
                 ENST00000269260 
               
               
                   
                 209 
                 ASAP1 
                 ENST00000518721 
               
               
                   
                 210 
                 ATAD2B 
                 ENST00000238789 
               
               
                   
                 211 
                 ATF7IP2 
                 ENST00000396560 
               
               
                   
                 212 
                 ATM 
                 ENST00000278616 
               
               
                   
                 213 
                 ATP6V1B2 
                 ENST00000276390 
               
               
                   
                 214 
                 BACH1 
                 ENST00000286800 
               
               
                   
                 215 
                 BANP 
                 ENST00000355022 
               
               
                   
                 216 
                 BAZ2B 
                 ENST00000392783 
               
               
                   
                 217 
                 BCL2 
                 ENST00000398117 
               
               
                   
                 218 
                 BEX4 
                 ENST00000372695 
               
               
                   
                 219 
                 BMP2K 
                 ENST00000502871 
               
               
                   
                 220 
                 BRD1 
                 ENST00000216267 
               
               
                   
                 221 
                 BRD4 
                 ENST00000371835 
               
               
                   
                 222 
                 BTG1 
                 ENST00000256015 
               
               
                   
                 223 
                 C19orf66 
                 ENST00000253110 
               
               
                   
                 224 
                 C2orf68 
                 ENST00000306336 
               
               
                   
                 225 
                 CAMK1D 
                 ENST00000378845 
               
               
                   
                 226 
                 CAMK2G 
                 ENST00000351293 
               
               
                   
                 227 
                 CAP1 
                 ENST00000372797 
               
               
                   
                 228 
                 CASC3 
                 ENST00000264645 
               
               
                   
                 229 
                 CASP8 
                 ENST00000264275 
               
               
                   
                 230 
                 CBX7 
                 ENST00000216133 
               
               
                   
                 231 
                 CCND3 
                 ENST00000372991 
               
               
                   
                 232 
                 CCNG2 
                 ENST00000316355 
               
               
                   
                 233 
                 CCNT2 
                 ENST00000295238 
               
               
                   
                 234 
                 CCR7 
                 ENST00000246657 
               
               
                   
                 235 
                 CD37 
                 ENST00000323906 
               
               
                   
                 236 
                 CD93 
                 ENST00000246006 
               
               
                   
                 237 
                 ADGRE5 (CD97) 
                 ENST00000358600 
               
               
                   
                 238 
                 CDIPT 
                 ENST00000219789 
               
               
                   
                 239 
                 CEP170 
                 ENST00000612450 
               
               
                   
                 240 
                 CEP68 
                 ENST00000377990 
               
               
                   
                 241 
                 CHD3 
                 ENST00000358181 
               
               
                   
                 242 
                 CHMP1B 
                 ENST00000526991 
               
               
                   
                 243 
                 CHMP7 
                 ENST00000397677 
               
               
                   
                 244 
                 CHST11 
                 ENST00000303694 
               
               
                   
                 245 
                 CIAPIN1 
                 ENST00000394391 
               
               
                   
                 246 
                 CLEC4A 
                 ENST00000229332 
               
               
                   
                 247 
                 CLK4 
                 ENST00000316308 
               
               
                   
                 248 
                 CNPY3 
                 ENST00000372836 
               
               
                   
                 249 
                 CREB1 
                 ENST00000353267 
               
               
                   
                 250 
                 CREBBP 
                 ENST00000262367 
               
               
                   
                 251 
                 CRLF3 
                 ENST00000324238 
               
               
                   
                 252 
                 CRTC3 
                 ENST00000268184 
               
               
                   
                 253 
                 CSAD 
                 ENST00000267085 
               
               
                   
                 254 
                 CSF2RB 
                 ENST00000403662 
               
               
                   
                 255 
                 CSNK1D 
                 ENST00000314028 
               
               
                   
                 256 
                 CST3 
                 ENST00000376925 
               
               
                   
                 257 
                 CTBP2 
                 ENST00000337195 
               
               
                   
                 258 
                 CTDSP2 
                 ENST00000398073 
               
               
                   
                 259 
                 CUL1 
                 ENST00000325222 
               
               
                   
                 260 
                 CYLD 
                 ENST00000311559 
               
               
                   
                 261 
                 CYTH4 
                 ENST00000248901 
               
               
                   
                 262 
                 DCP2 
                 ENST00000389063 
               
               
                   
                 263 
                 DDX60 
                 ENST00000393743 
               
               
                   
                 264 
                 DGCR2 
                 ENST00000263196 
               
               
                   
                 265 
                 DGKA 
                 ENST00000331886 
               
               
                   
                 266 
                 DHX58 
                 ENST00000251642 
               
               
                   
                 267 
                 DIDO1 
                 ENST00000370371 
               
               
                   
                 268 
                 DOCK9 
                 ENST00000376460 
               
               
                   
                 269 
                 DOK3 
                 ENST00000357198 
               
               
                   
                 270 
                 DPEP2 
                 ENST00000393847 
               
               
                   
                 271 
                 DPF2 
                 ENST00000528416 
               
               
                   
                 272 
                 EIF2AK2 
                 ENST00000395127 
               
               
                   
                 273 
                 EIF3H 
                 ENST00000521861 
               
               
                   
                 274 
                 EMR2 
                 ENST00000315576 
               
               
                   
                 275 
                 ERBB2IP 
                 ENST00000380943 
               
               
                   
                 276 
                 ETS2 
                 ENST00000360938 
               
               
                   
                 277 
                 FAIM3 
                 ENST00000367091 
               
               
                   
                 278 
                 FAM134A 
                 ENST00000430297 
               
               
                   
                 279 
                 FAM65B 
                 ENST00000259698 
               
               
                   
                 280 
                 FBXO11 
                 ENST00000402508 
               
               
                   
                 281 
                 FBXO9 
                 ENST00000244426 
               
               
                   
                 282 
                 FCGRT 
                 ENST00000426395 
               
               
                   
                 283 
                 FES 
                 ENST00000328850 
               
               
                   
                 284 
                 FGR 
                 ENST00000374005 
               
               
                   
                 285 
                 FLOT2 
                 ENST00000394908 
               
               
                   
                 286 
                 FNBP1 
                 ENST00000446176 
               
               
                   
                 287 
                 FOXJ2 
                 ENST00000162391 
               
               
                   
                 288 
                 FOXO1 
                 ENST00000379561 
               
               
                   
                 289 
                 FOXO3 
                 ENST00000406360 
               
               
                   
                 290 
                 FRY 
                 ENST00000542859 
               
               
                   
                 291 
                 FYB 
                 ENST00000505428 
               
               
                   
                 292 
                 GABARAP 
                 ENST00000302386 
               
               
                   
                 293 
                 GCC2 
                 ENST00000309863 
               
               
                   
                 294 
                 GMIP 
                 ENST00000203556 
               
               
                   
                 295 
                 GNA12 
                 ENST00000275364 
               
               
                   
                 296 
                 GNAQ 
                 ENST00000286548 
               
               
                   
                 297 
                 GOLGA7 
                 ENST00000520817 
               
               
                   
                 298 
                 GPBP1L1 
                 ENST00000355105 
               
               
                   
                 299 
                 GPR97 
                 ENST00000333493 
               
               
                   
                 300 
                 GPS2 
                 ENST00000389167 
               
               
                   
                 301 
                 GPSM3 
                 ENST00000383269 
               
               
                   
                 302 
                 GRB2 
                 ENST00000316804 
               
               
                   
                 303 
                 GSK3B 
                 ENST00000316626 
               
               
                   
                 304 
                 GYPC 
                 ENST00000259254 
               
               
                   
                 305 
                 HAL 
                 ENST00000261208 
               
               
                   
                 306 
                 HCK 
                 ENST00000534862 
               
               
                   
                 307 
                 HERC5 
                 ENST00000264350 
               
               
                   
                 308 
                 HERC6 
                 ENST00000264346 
               
               
                   
                 309 
                 HGSNAT 
                 ENST00000379644 
               
               
                   
                 310 
                 HHEX 
                 ENST00000282728 
               
               
                   
                 311 
                 HIP1 
                 ENST00000336926 
               
               
                   
                 312 
                 HPCAL1 
                 ENST00000307845 
               
               
                   
                 313 
                 HPS1 
                 ENST00000325103 
               
               
                   
                 314 
                 ICAM3 
                 EN5T00000160262 
               
               
                   
                 315 
                 IFI44 
                 ENST00000370747 
               
               
                   
                 316 
                 IFI6 
                 ENST00000361157 
               
               
                   
                 317 
                 IFIH1 
                 ENST00000263642 
               
               
                   
                 318 
                 IGSF6 
                 ENST00000268389 
               
               
                   
                 319 
                 IKBKB 
                 ENST00000520810 
               
               
                   
                 320 
                 IL10RB 
                 ENST00000290200 
               
               
                   
                 321 
                 IL13RA1 
                 ENST00000371666 
               
               
                   
                 322 
                 IL16 
                 ENST00000394652 
               
               
                   
                 323 
                 IL1RAP 
                 ENST00000447382 
               
               
                   
                 324 
                 IL27RA 
                 ENST00000263379 
               
               
                   
                 325 
                 IL4R 
                 ENST00000395762 
               
               
                   
                 326 
                 IL6R 
                 ENST00000368485 
               
               
                   
                 327 
                 IL6ST 
                 ENST00000381298 
               
               
                   
                 328 
                 INPP5D 
                 ENST00000359570 
               
               
                   
                 329 
                 IQSEC1 
                 ENST00000273221 
               
               
                   
                 330 
                 ISG15 
                 ENST00000379389 
               
               
                   
                 331 
                 ITGAX 
                 ENST00000268296 
               
               
                   
                 332 
                 ITGB2 
                 ENST00000302347 
               
               
                   
                 333 
                 ITPKB 
                 ENST00000429204 
               
               
                   
                 334 
                 ITSN2 
                 ENST00000355123 
               
               
                   
                 335 
                 JAK1 
                 ENST00000342505 
               
               
                   
                 336 
                 KBTBD2 
                 ENST00000304056 
               
               
                   
                 337 
                 KIAA0232 
                 ENST00000307659 
               
               
                   
                 338 
                 KIAA0247 
                 ENST00000342745 
               
               
                   
                 339 
                 KIAA0513 
                 ENST00000258180 
               
               
                   
                 340 
                 KLF3 
                 ENST00000261438 
               
               
                   
                 341 
                 KLF6 
                 ENST00000497571 
               
               
                   
                 342 
                 KLF7 
                 ENST00000309446 
               
               
                   
                 343 
                 KLHL2 
                 ENST00000226725 
               
               
                   
                 344 
                 LAP3 
                 ENST00000618908 
               
               
                   
                 345 
                 LAPTM5 
                 ENST00000294507 
               
               
                   
                 346 
                 LAT2 
                 ENST00000344995 
               
               
                   
                 347 
                 LCP2 
                 ENST00000046794 
               
               
                   
                 348 
                 LDLRAP1 
                 ENST00000374338 
               
               
                   
                 349 
                 LEF1 
                 ENST00000265165 
               
               
                   
                 350 
                 LILRA2 
                 ENST00000251376 
               
               
                   
                 351 
                 LILRB3 
                 ENST00000617251 
               
               
                   
                 352 
                 LIMK2 
                 ENST00000331728 
               
               
                   
                 353 
                 LPAR2 
                 ENST00000407877 
               
               
                   
                 354 
                 LPIN2 
                 ENST00000261596 
               
               
                   
                 355 
                 LRMP 
                 ENST00000354454 
               
               
                   
                 356 
                 LRP10 
                 ENST00000359591 
               
               
                   
                 357 
                 LST1 
                 ENST00000376093 
               
               
                   
                 358 
                 LTB 
                 ENST00000429299 
               
               
                   
                 359 
                 LYL1 
                 ENST00000264824 
               
               
                   
                 360 
                 LYN 
                 ENST00000519728 
               
               
                   
                 361 
                 LYST 
                 ENST00000389793 
               
               
                   
                 362 
                 MAML1 
                 ENST00000292599 
               
               
                   
                 363 
                 MANSC1 
                 ENST00000535902 
               
               
                   
                 364 
                 MAP1LC3B 
                 ENST00000268607 
               
               
                   
                 365 
                 MAP3K11 
                 ENST00000309100 
               
               
                   
                 366 
                 MAP3K3 
                 ENST00000361733 
               
               
                   
                 367 
                 MAP3K5 
                 ENST00000359015 
               
               
                   
                 368 
                 MAP4K4 
                 ENST00000350198 
               
               
                   
                 369 
                 MAPK1 
                 ENST00000215832 
               
               
                   
                 370 
                 MAPK14 
                 ENST00000229795 
               
               
                   
                 371 
                 MAPRE2 
                 ENST00000300249 
               
               
                   
                 372 
                 MARCH7 
                 ENST00000259050 
               
               
                   
                 373 
                 MARCH8 
                 ENST00000319836 
               
               
                   
                 374 
                 MARK3 
                 ENST00000303622 
               
               
                   
                 375 
                 MAST3 
                 ENST00000262811 
               
               
                   
                 376 
                 MAX 
                 ENST00000358664 
               
               
                   
                 377 
                 MBP 
                 ENST00000359645 
               
               
                   
                 378 
                 MCTP2 
                 ENST00000357742 
               
               
                   
                 379 
                 MED13 
                 ENST00000397786 
               
               
                   
                 380 
                 MEF2A 
                 ENST00000354410 
               
               
                   
                 381 
                 METTL3 
                 ENST00000298717 
               
               
                   
                 382 
                 MKLN1 
                 ENST00000352689 
               
               
                   
                 383 
                 MKRN1 
                 ENST00000255977 
               
               
                   
                 384 
                 MMP25 
                 ENST00000336577 
               
               
                   
                 385 
                 MORC3 
                 ENST00000400485 
               
               
                   
                 386 
                 MOSPD2 
                 ENST00000380492 
               
               
                   
                 387 
                 MPPE1 
                 ENST00000588072 
               
               
                   
                 388 
                 MSL1 
                 ENST00000579565 
               
               
                   
                 389 
                 MTMR3 
                 ENST00000401950 
               
               
                   
                 390 
                 MX1 
                 ENST00000398598 
               
               
                   
                 391 
                 MXI1 
                 ENST00000239007 
               
               
                   
                 392 
                 MYC 
                 ENST00000613283 
               
               
                   
                 393 
                 N4BP1 
                 ENST00000262384 
               
               
                   
                 394 
                 NAB1 
                 ENST00000337386 
               
               
                   
                 395 
                 NACA 
                 ENST00000356769 
               
               
                   
                 396 
                 NCBP2 
                 ENST00000321256 
               
               
                   
                 397 
                 NCOA1 
                 ENST00000348332 
               
               
                   
                 398 
                 NCOA4 
                 ENST00000585132 
               
               
                   
                 399 
                 NDE1 
                 ENST00000396354 
               
               
                   
                 400 
                 NDEL1 
                 ENST00000334527 
               
               
                   
                 401 
                 NDFIP1 
                 ENST00000253814 
               
               
                   
                 402 
                 NECAP2 
                 ENST00000337132 
               
               
                   
                 403 
                 NEK7 
                 ENST00000367385 
               
               
                   
                 404 
                 NFKB1 
                 ENST00000226574 
               
               
                   
                 405 
                 NFYA 
                 ENST00000341376 
               
               
                   
                 406 
                 NLRP1 
                 ENST00000269280 
               
               
                   
                 407 
                 NOD2 
                 ENST00000300589 
               
               
                   
                 408 
                 NOSIP 
                 ENST00000596358 
               
               
                   
                 409 
                 NPL 
                 ENST00000367553 
               
               
                   
                 410 
                 NR3C1 
                 ENST00000394464 
               
               
                   
                 411 
                 NRBF2 
                 ENST00000277746 
               
               
                   
                 412 
                 NSUN3 
                 ENST00000314622 
               
               
                   
                 413 
                 NUMB 
                 ENST00000557597 
               
               
                   
                 414 
                 OAS2 
                 ENST00000392583 
               
               
                   
                 415 
                 OASL 
                 ENST00000257570 
               
               
                   
                 416 
                 OGFRL1 
                 ENST00000370435 
               
               
                   
                 417 
                 OSBPL11 
                 ENST00000296220 
               
               
                   
                 418 
                 OSBPL2 
                 ENST00000358053 
               
               
                   
                 419 
                 PACSIN2 
                 ENST00000403744 
               
               
                   
                 420 
                 PAFAH1B1 
                 ENST00000397195 
               
               
                   
                 421 
                 PARP12 
                 ENST00000263549 
               
               
                   
                 422 
                 PBX3 
                 ENST00000373489 
               
               
                   
                 423 
                 PCBP2 
                 ENST00000359462 
               
               
                   
                 424 
                 PCF11 
                 ENST00000298281 
               
               
                   
                 425 
                 PCNX 
                 ENST00000304743 
               
               
                   
                 426 
                 PDCD6IP 
                 ENST00000307296 
               
               
                   
                 427 
                 PDE3B 
                 ENST00000282096 
               
               
                   
                 428 
                 PECAM1 
                 ENST00000563924 
               
               
                   
                 429 
                 PFDN5 
                 ENST00000551018 
               
               
                   
                 430 
                 PGS1 
                 ENST00000262764 
               
               
                   
                 431 
                 PHC2 
                 ENST00000373418 
               
               
                   
                 432 
                 PHF11 
                 ENST00000378319 
               
               
                   
                 433 
                 PHF2 
                 ENST00000359246 
               
               
                   
                 434 
                 PHF20 
                 ENST00000374012 
               
               
                   
                 435 
                 PHF20L1 
                 ENST00000395386 
               
               
                   
                 436 
                 PHF3 
                 ENST00000393387 
               
               
                   
                 437 
                 PIAS1 
                 ENST00000249636 
               
               
                   
                 438 
                 PIK3IP1 
                 ENST00000215912 
               
               
                   
                 439 
                 PINK1 
                 ENST00000321556 
               
               
                   
                 440 
                 PISD 
                 ENST00000266095 
               
               
                   
                 441 
                 PITPNA 
                 ENST00000313486 
               
               
                   
                 442 
                 PLEKHO1 
                 ENST00000369124 
               
               
                   
                 443 
                 PLEKHO2 
                 ENST00000323544 
               
               
                   
                 444 
                 PLXNC1 
                 ENST00000258526 
               
               
                   
                 445 
                 POLB 
                 ENST00000265421 
               
               
                   
                 446 
                 POLD4 
                 ENST00000312419 
               
               
                   
                 447 
                 POLR1D 
                 ENST00000302979 
               
               
                   
                 448 
                 PPARD 
                 ENST00000360694 
               
               
                   
                 449 
                 PPM1F 
                 ENST00000263212 
               
               
                   
                 450 
                 PPP1R11 
                 ENST00000448378 
               
               
                   
                 451 
                 PPP1R2 
                 ENST00000618156 
               
               
                   
                 452 
                 PPP2R5A 
                 ENST00000261461 
               
               
                   
                 453 
                 PPP3R1 
                 ENST00000234310 
               
               
                   
                 454 
                 PPP4R1 
                 ENST00000400555 
               
               
                   
                 455 
                 PRKAA1 
                 ENST00000397128 
               
               
                   
                 456 
                 PRKAG2 
                 ENST00000287878 
               
               
                   
                 457 
                 PRKCD 
                 ENST00000330452 
               
               
                   
                 458 
                 PRMT2 
                 ENST00000397638 
               
               
                   
                 459 
                 PRUNE 
                 ENST00000271620 
               
               
                   
                 460 
                 PSAP 
                 ENST00000394936 
               
               
                   
                 461 
                 PSEN1 
                 ENST00000324501 
               
               
                   
                 462 
                 PSTPIP1 
                 ENST00000558012 
               
               
                   
                 463 
                 PTAFR 
                 ENST00000373857 
               
               
                   
                 464 
                 PTEN 
                 ENST00000371953 
               
               
                   
                 465 
                 PTGER4 
                 ENST00000302472 
               
               
                   
                 466 
                 PTPN6 
                 ENST00000318974 
               
               
                   
                 467 
                 PTPRE 
                 ENST00000254667 
               
               
                   
                 468 
                 PUM2 
                 ENST00000338086 
               
               
                   
                 469 
                 R3HDM2 
                 ENST00000358907 
               
               
                   
                 470 
                 RAB11FIP1 
                 ENST00000287263 
               
               
                   
                 471 
                 RAB14 
                 ENST00000373840 
               
               
                   
                 472 
                 RAB31 
                 ENST00000578921 
               
               
                   
                 473 
                 RAB4B 
                 ENST00000357052 
               
               
                   
                 474 
                 RAB7A 
                 ENST00000265062 
               
               
                   
                 475 
                 RAF1 
                 ENST00000251849 
               
               
                   
                 476 
                 RALB 
                 ENST00000272519 
               
               
                   
                 477 
                 RARA 
                 ENST00000254066 
               
               
                   
                 478 
                 RASSF2 
                 ENST00000379400 
               
               
                   
                 479 
                 RBM23 
                 ENST00000399922 
               
               
                   
                 480 
                 RBMS1 
                 ENST00000348849 
               
               
                   
                 481 
                 RC3H2 
                 ENST00000423239 
               
               
                   
                 482 
                 RERE 
                 ENST00000337907 
               
               
                   
                 483 
                 RGS14 
                 ENST00000408923 
               
               
                   
                 484 
                 RGS19 
                 ENST00000395042 
               
               
                   
                 485 
                 RHOG 
                 ENST00000351018 
               
               
                   
                 486 
                 RIN3 
                 ENST00000216487 
               
               
                   
                 487 
                 RNASET2 
                 ENST00000508775 
               
               
                   
                 488 
                 RNF130 
                 EN5T00000521389 
               
               
                   
                 489 
                 RNF141 
                 ENST00000265981 
               
               
                   
                 490 
                 RNF146 
                 ENST00000608991 
               
               
                   
                 491 
                 RNF19B 
                 ENST00000373456 
               
               
                   
                 492 
                 RPL10A 
                 ENST00000322203 
               
               
                   
                 493 
                 RPL22 
                 ENST00000234875 
               
               
                   
                 494 
                 RPS6KA1 
                 ENST00000374168 
               
               
                   
                 495 
                 RPS6KA3 
                 ENST00000379565 
               
               
                   
                 496 
                 RSAD2 
                 ENST00000382040 
               
               
                   
                 497 
                 RTN3 
                 ENST00000537981 
               
               
                   
                 498 
                 RTP4 
                 ENST00000259030 
               
               
                   
                 499 
                 RXRA 
                 ENST00000481739 
               
               
                   
                 500 
                 RYBP 
                 ENST00000477973 
               
               
                   
                 501 
                 SAFB2 
                 ENST00000252542 
               
               
                   
                 502 
                 SATB1 
                 ENST00000338745 
               
               
                   
                 503 
                 SEC62 
                 ENST00000337002 
               
               
                   
                 504 
                 SEMA4D 
                 ENST00000438547 
               
               
                   
                 505 
                 SERINC3 
                 ENST00000342374 
               
               
                   
                 506 
                 SERINC5 
                 ENST00000509193 
               
               
                   
                 507 
                 SERTAD2 
                 ENST00000313349 
               
               
                   
                 508 
                 SESN1 
                 ENST00000436639 
               
               
                   
                 509 
                 SETD2 
                 ENST00000409792 
               
               
                   
                 510 
                 SH2B3 
                 ENST00000341259 
               
               
                   
                 511 
                 SH2D3C 
                 ENST00000373277 
               
               
                   
                 512 
                 SIRPA 
                 ENST00000356025 
               
               
                   
                 513 
                 SIRPB1 
                 ENST00000381605 
               
               
                   
                 514 
                 SLCO3A1 
                 ENST00000318445 
               
               
                   
                 515 
                 SMAD4 
                 ENST00000342988 
               
               
                   
                 516 
                 SNN 
                 ENST00000329565 
               
               
                   
                 517 
                 SNRK 
                 ENST00000296088 
               
               
                   
                 518 
                 SNX27 
                 ENST00000368843 
               
               
                   
                 519 
                 SOATI 
                 ENST00000367619 
               
               
                   
                 520 
                 SORL1 
                 ENST00000260197 
               
               
                   
                 521 
                 SOS2 
                 ENST00000216373 
               
               
                   
                 522 
                 SP3 
                 ENST00000310015 
               
               
                   
                 523 
                 SSBP2 
                 ENST00000320672 
               
               
                   
                 524 
                 SSFA2 
                 ENST00000320370 
               
               
                   
                 525 
                 ST13 
                 ENST00000216218 
               
               
                   
                 526 
                 ST3GAL1 
                 ENST00000521180 
               
               
                   
                 527 
                 STAM2 
                 ENST00000263904 
               
               
                   
                 528 
                 STAT1 
                 ENST00000361099 
               
               
                   
                 529 
                 STAT5A 
                 ENST00000345506 
               
               
                   
                 530 
                 STAT5B 
                 ENST00000293328 
               
               
                   
                 531 
                 STK38L 
                 ENST00000389032 
               
               
                   
                 532 
                 STX10 
                 ENST00000587230 
               
               
                   
                 533 
                 STX3 
                 ENST00000337979 
               
               
                   
                 534 
                 STX6 
                 ENST00000258301 
               
               
                   
                 535 
                 SYPL1 
                 ENST00000011473 
               
               
                   
                 536 
                 TAP1 
                 ENST00000428324 
               
               
                   
                 537 
                 TFE3 
                 ENST00000315869 
               
               
                   
                 538 
                 TFEB 
                 ENST00000230323 
               
               
                   
                 539 
                 TGFBI 
                 ENST00000442011 
               
               
                   
                 540 
                 TGFBR2 
                 ENST00000295754 
               
               
                   
                 541 
                 TGOLN2 
                 ENST00000377386 
               
               
                   
                 542 
                 TIAM1 
                 ENST00000286827 
               
               
                   
                 543 
                 TLE3 
                 ENST00000558939 
               
               
                   
                 544 
                 TLE4 
                 ENST00000376552 
               
               
                   
                 545 
                 TLR2 
                 ENST00000260010 
               
               
                   
                 546 
                 TM2D3 
                 ENST00000347970 
               
               
                   
                 547 
                 TMBIM1 
                 ENST00000258412 
               
               
                   
                 548 
                 TMEM127 
                 ENST00000258439 
               
               
                   
                 549 
                 TMEM204 
                 ENST00000566264 
               
               
                   
                 550 
                 TNFRSF1A 
                 ENST00000162749 
               
               
                   
                 551 
                 TNFSF13 
                 ENST00000338784 
               
               
                   
                 552 
                 TNIP1 
                 ENST00000521591 
               
               
                   
                 553 
                 TNK2 
                 ENST00000333602 
               
               
                   
                 554 
                 TNRC6B 
                 ENST00000335727 
               
               
                   
                 555 
                 TOPORS 
                 ENST00000360538 
               
               
                   
                 556 
                 TRAK1 
                 ENST00000341421 
               
               
                   
                 557 
                 TREM1 
                 ENST00000244709 
               
               
                   
                 558 
                 TRIB2 
                 ENST00000155926 
               
               
                   
                 559 
                 TRIM8 
                 ENST00000302424 
               
               
                   
                 560 
                 TRIOBP 
                 ENST00000403663 
               
               
                   
                 561 
                 TSC22D3 
                 ENST00000372397 
               
               
                   
                 562 
                 TYK2 
                 ENST00000525621 
               
               
                   
                 563 
                 TYROBP 
                 ENST00000262629 
               
               
                   
                 564 
                 UBE2D2 
                 ENST00000398733 
               
               
                   
                 565 
                 UBE2L6 
                 ENST00000287156 
               
               
                   
                 566 
                 UBN1 
                 ENST00000262376 
               
               
                   
                 567 
                 UBQLN2 
                 ENST00000338222 
               
               
                   
                 568 
                 UBXN2B 
                 ENST00000399598 
               
               
                   
                 569 
                 USP10 
                 ENST00000219473 
               
               
                   
                 570 
                 USP15 
                 ENST00000353364 
               
               
                   
                 571 
                 USP18 
                 ENST00000215794 
               
               
                   
                 572 
                 USP4 
                 ENST00000265560 
               
               
                   
                 573 
                 UTP14A 
                 ENST00000394422 
               
               
                   
                 574 
                 VAMP3 
                 ENST00000054666 
               
               
                   
                 575 
                 VAV3 
                 EN5T00000370056 
               
               
                   
                 576 
                 VEZF1 
                 ENST00000581208 
               
               
                   
                 577 
                 VPS8 
                 ENST00000436792 
               
               
                   
                 578 
                 WASF2 
                 ENST00000618852 
               
               
                   
                 579 
                 WBP2 
                 ENST00000254806 
               
               
                   
                 580 
                 WDR37 
                 ENST00000263150 
               
               
                   
                 581 
                 WDR47 
                 ENST00000369965 
               
               
                   
                 582 
                 XAF1 
                 ENST00000361842 
               
               
                   
                 583 
                 XPC 
                 ENST00000285021 
               
               
                   
                 584 
                 XPO6 
                 ENST00000304658 
               
               
                   
                 585 
                 YPEL5 
                 ENST00000261353 
               
               
                   
                 586 
                 YTHDF3 
                 ENST00000539294 
               
               
                   
                 588 
                 ZBTB18 
                 ENST00000622512 
               
               
                   
                 589 
                 ZC3HAV1 
                 ENST00000242351 
               
               
                   
                 590 
                 ZDHHC17 
                 ENST00000426126 
               
               
                   
                 591 
                 ZDHHC18 
                 ENST00000374142 
               
               
                   
                 592 
                 ZFAND5 
                 ENST00000376960 
               
               
                   
                 593 
                 ZFC3H1 
                 ENST00000378743 
               
               
                   
                 594 
                 ZFYVE16 
                 ENST00000338008 
               
               
                   
                 595 
                 ZMIZ1 
                 ENST00000334512 
               
               
                   
                 596 
                 ZNF143 
                 ENST00000396602 
               
               
                   
                 597 
                 ZNF148 
                 ENST00000360647 
               
               
                   
                 598 
                 ZNF274 
                 ENST00000424679 
               
               
                   
                 599 
                 ZNF292 
                 ENST00000369577 
               
               
                   
                 600 
                 ZXDC 
                 ENST00000389709 
               
               
                   
                 601 
                 ZYX 
                 ENST00000322764 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 VASIRS BIOMARKER DETAILS INCLUDING;  
               
               
                 SEQUENCE IDENTIFICATION NUMBER, 
               
               
                 GENE SYMBOL, GENBANK ACCESSION  
               
               
                 AND AMINO ACID SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID 
                 Gene 
                 GenBank 
               
               
                   
                 # (AA) 
                 Symbol 
                 Accession 
               
               
                   
                   
               
               
                   
                  602 
                 ABAT 
                 NP_000654 
               
               
                   
                  603 
                 ABHD2 
                 NP_008942 
               
               
                   
                  604 
                 ABI1 
                 NP_005461 
               
               
                   
                  605 
                 ABLIM1 
                 NP_002304 
               
               
                   
                  606 
                 ACAA1 
                 NP_001598 
               
               
                   
                  607 
                 ACAP2 
                 NP_036419 
               
               
                   
                  608 
                 ACVR1B 
                 NP_004293 
               
               
                   
                  609 
                 AIF1 
                 NP_001614 
               
               
                   
                  610 
                 ALDH3A2 
                 NP_000373 
               
               
                   
                  611 
                 ANKRD49 
                 NP_060174 
               
               
                   
                  612 
                 AOAH 
                 NP_001628 
               
               
                   
                  613 
                 APBB1IP 
                 NP_061916 
               
               
                   
                  614 
                 APLP2 
                 NP_001633 
               
               
                   
                  615 
                 ARAP1 
                 NP_056057 
               
               
                   
                  616 
                 ARHGAP15 
                 NP_060930 
               
               
                   
                  617 
                 ARHGAP25 
                 NP_055697 
               
               
                   
                  618 
                 ARHGAP26 
                 NP_055886 
               
               
                   
                  619 
                 ARHGEF2 
                 NP_004714 
               
               
                   
                  620 
                 ARRB1 
                 NP_004032 
               
               
                   
                  621 
                 ARRB2 
                 NP_004304 
               
               
                   
                  622 
                 ASAP1 
                 NP_060952 
               
               
                   
                  623 
                 ATAD2B 
                 NP_060022 
               
               
                   
                  624 
                 ATF7IP2 
                 NP_079273 
               
               
                   
                  625 
                 ATM 
                 NP_000042 
               
               
                   
                  626 
                 ATP6V1B2 
                 NP_001684 
               
               
                   
                  627 
                 BACH1 
                 NP_001177 
               
               
                   
                  628 
                 BANP 
                 NP_060339 
               
               
                   
                  629 
                 BAZ2B 
                 NP_038478 
               
               
                   
                  630 
                 BCL2 
                 NP_000624 
               
               
                   
                  631 
                 BEX4 
                 NP_001073894 
               
               
                   
                  632 
                 BMP2K 
                 NP_060063 
               
               
                   
                  633 
                 BRD1 
                 NP_055392 
               
               
                   
                  634 
                 BRD4 
                 NP_055114 
               
               
                   
                  635 
                 BTG1 
                 NP_001722 
               
               
                   
                  636 
                 C19orf66 
                 NP_060851 
               
               
                   
                  637 
                 C2orf68 
                 NP_001013671 
               
               
                   
                  638 
                 CAMK1D 
                 NP_065130 
               
               
                   
                  639 
                 CAMK2G 
                 NP_001213 
               
               
                   
                  640 
                 CAP1 
                 NP_006358 
               
               
                   
                  641 
                 CASC3 
                 NP_031385 
               
               
                   
                  642 
                 CASP8 
                 NP_001219 
               
               
                   
                  643 
                 CBX7 
                 NP_783640 
               
               
                   
                  644 
                 CCND3 
                 NP_001751 
               
               
                   
                  645 
                 CCNG2 
                 NP_004345 
               
               
                   
                  646 
                 CCNT2 
                 NP_001232 
               
               
                   
                  647 
                 CCR7 
                 NP_001829 
               
               
                   
                  648 
                 CD37 
                 NP_001765 
               
               
                   
                  649 
                 CD93 
                 NP_036204 
               
               
                   
                  650 
                 ADGRE5 (CD97) 
                 NP_001775 
               
               
                   
                  651 
                 CDIPT 
                 NP_006310 
               
               
                   
                  652 
                 CEP170 
                 NP_055627 
               
               
                   
                  653 
                 CEP68 
                 NP_055962 
               
               
                   
                  654 
                 CHD3 
                 NP_005843 
               
               
                   
                  655 
                 CHMP1B 
                 NP_065145 
               
               
                   
                  656 
                 CHMP7 
                 NP_689485 
               
               
                   
                  657 
                 CHST11 
                 NP_060883 
               
               
                   
                  658 
                 CIAPIN1 
                 NP_064709 
               
               
                   
                  659 
                 CLEC4A 
                 NP_057268 
               
               
                   
                  660 
                 CLK4 
                 NP_065717 
               
               
                   
                  661 
                 CNPY3 
                 NP_006577 
               
               
                   
                  662 
                 CREB1 
                 NP_004370 
               
               
                   
                  663 
                 CREBBP 
                 NP_004371 
               
               
                   
                  664 
                 CRLF3 
                 NP_057070 
               
               
                   
                  665 
                 CRTC3 
                 NP_073606 
               
               
                   
                  666 
                 CSAD 
                 NP_057073 
               
               
                   
                  667 
                 CSF2RB 
                 NP_000386 
               
               
                   
                  668 
                 CSNK1D 
                 NP_001884 
               
               
                   
                  669 
                 CST3 
                 NP_000090 
               
               
                   
                  670 
                 CTBP2 
                 NP_001320 
               
               
                   
                  671 
                 CTDSP2 
                 NP_005721 
               
               
                   
                  672 
                 CUL1 
                 NP_003583 
               
               
                   
                  673 
                 CYLD 
                 NP_056062 
               
               
                   
                  674 
                 CYTH4 
                 NP_037517 
               
               
                   
                  675 
                 DCP2 
                 NP_689837 
               
               
                   
                  676 
                 DDX60 
                 NP_060101 
               
               
                   
                  677 
                 DGCR2 
                 NP_005128 
               
               
                   
                  678 
                 DGKA 
                 NP_001336 
               
               
                   
                  679 
                 DHX58 
                 NP_077024 
               
               
                   
                  680 
                 DIDO1 
                 NP_071388 
               
               
                   
                  681 
                 DOCK9 
                 NP_056111 
               
               
                   
                  682 
                 DOK3 
                 NP_079148 
               
               
                   
                  683 
                 DPEP2 
                 NP_071750 
               
               
                   
                  684 
                 DPF2 
                 NP_006259 
               
               
                   
                  685 
                 EIF2AK2 
                 NP_002750 
               
               
                   
                  686 
                 EIF3H 
                 NP_003747 
               
               
                   
                  687 
                 EMR2 
                 NP_038475 
               
               
                   
                  688 
                 ERBB2IP 
                 NP_061165 
               
               
                   
                  689 
                 ETS2 
                 NP_005230 
               
               
                   
                  690 
                 FAIM3 
                 NP_005440 
               
               
                   
                  691 
                 FAM134A 
                 NP_077269 
               
               
                   
                  692 
                 FAM65B 
                 NP_055537 
               
               
                   
                  693 
                 FBXO11 
                 NP_079409 
               
               
                   
                  694 
                 FBXO9 
                 NP_036479 
               
               
                   
                  695 
                 FCGRT 
                 NP_004098 
               
               
                   
                  696 
                 FES 
                 NP_001996 
               
               
                   
                  697 
                 FGR 
                 NP_005239 
               
               
                   
                  698 
                 FLOT2 
                 NP_004466 
               
               
                   
                  699 
                 FNBP1 
                 NP_055848 
               
               
                   
                  700 
                 FOXJ2 
                 NP_060886 
               
               
                   
                  701 
                 FOXO1 
                 NP_002006 
               
               
                   
                  702 
                 FOXO3 
                 NP_001446 
               
               
                   
                  703 
                 FRY 
                 NP_075463 
               
               
                   
                  704 
                 FYB 
                 NP_001456 
               
               
                   
                  705 
                 GABARAP 
                 NP_009209 
               
               
                   
                  706 
                 GCC2 
                 NP_852118 
               
               
                   
                  707 
                 GMIP 
                 NP_057657 
               
               
                   
                  708 
                 GNA12 
                 NP_031379 
               
               
                   
                  709 
                 GNAQ 
                 NP_002063 
               
               
                   
                  710 
                 GOLGA7 
                 NP_057183 
               
               
                   
                  711 
                 GPBP1L1 
                 NP_067652 
               
               
                   
                  712 
                 GPR97 
                 NP_740746 
               
               
                   
                  713 
                 GPS2 
                 NP_004480 
               
               
                   
                  714 
                 GPSM3 
                 NP_071390 
               
               
                   
                  715 
                 GRB2 
                 NP_002077 
               
               
                   
                  716 
                 GSK3B 
                 NP_002084 
               
               
                   
                  717 
                 GYPC 
                 NP_002092 
               
               
                   
                  718 
                 HAL 
                 NP_002099 
               
               
                   
                  719 
                 HCK 
                 NP_002101 
               
               
                   
                  720 
                 HERC5 
                 NP_057407 
               
               
                   
                  721 
                 HERC6 
                 NP_060382 
               
               
                   
                  722 
                 HGSNAT 
                 NP_689632 
               
               
                   
                  723 
                 HHEX 
                 NP_002720 
               
               
                   
                  724 
                 HIP1 
                 NP_005329 
               
               
                   
                  725 
                 HPCAL1 
                 NP_002140 
               
               
                   
                  726 
                 HPS1 
                 NP_000186 
               
               
                   
                  727 
                 ICAM3 
                 NP_002153 
               
               
                   
                  728 
                 IFI44 
                 NP_006408 
               
               
                   
                  729 
                 IFI6 
                 NP_002029 
               
               
                   
                  730 
                 IFIH1 
                 NP_071451 
               
               
                   
                  731 
                 IGSF6 
                 NP_005840 
               
               
                   
                  732 
                 IKBKB 
                 NP_001547 
               
               
                   
                  733 
                 IL10RB 
                 NP_000619 
               
               
                   
                  734 
                 IL13RA1 
                 NP_001551 
               
               
                   
                  735 
                 IL16 
                 NP_004504 
               
               
                   
                  736 
                 IL1RAP 
                 NP_002173 
               
               
                   
                  737 
                 IL27RA 
                 NP_004834 
               
               
                   
                  738 
                 IL4R 
                 NP_000409 
               
               
                   
                  739 
                 IL6R 
                 NP_000556 
               
               
                   
                  740 
                 IL6ST 
                 NP_002175 
               
               
                   
                  741 
                 INPP5D 
                 NP_005532 
               
               
                   
                  742 
                 IQSEC1 
                 NP_055684 
               
               
                   
                  743 
                 ISG15 
                 NP_005092 
               
               
                   
                  744 
                 ITGAX 
                 NP_000878 
               
               
                   
                  745 
                 ITGB2 
                 NP_000202 
               
               
                   
                  746 
                 ITPKB 
                 NP_002212 
               
               
                   
                  747 
                 ITSN2 
                 NP_006268 
               
               
                   
                  748 
                 JAK1 
                 NP_002218 
               
               
                   
                  749 
                 KBTBD2 
                 NP_056298 
               
               
                   
                  750 
                 KIAA0232 
                 NP_055558 
               
               
                   
                  751 
                 KIAA0247 
                 NP_055549 
               
               
                   
                  752 
                 KIAA0513 
                 NP_055547 
               
               
                   
                  753 
                 KLF3 
                 NP_057615 
               
               
                   
                  754 
                 KLF6 
                 NP_001291 
               
               
                   
                  755 
                 KLF7 
                 NP_003700 
               
               
                   
                  756 
                 KLHL2 
                 NP_009177 
               
               
                   
                  757 
                 LAP3 
                 NP_056991 
               
               
                   
                  758 
                 LAPTM5 
                 NP_006753 
               
               
                   
                  759 
                 LAT2 
                 NP_054865 
               
               
                   
                  760 
                 LCP2 
                 NP_005556 
               
               
                   
                  761 
                 LDLRAP1 
                 NP_056442 
               
               
                   
                  762 
                 LEF1 
                 NP_057353 
               
               
                   
                  763 
                 LILRA2 
                 NP_006857 
               
               
                   
                  764 
                 LILRB3 
                 NP_006855 
               
               
                   
                  765 
                 LIMK2 
                 NP_005560 
               
               
                   
                  766 
                 LPAR2 
                 NP_004711 
               
               
                   
                  767 
                 LPIN2 
                 NP_055461 
               
               
                   
                  768 
                 LRMP 
                 NP_006143 
               
               
                   
                  769 
                 LRP10 
                 NP_054764 
               
               
                   
                  770 
                 LST1 
                 NP_009092 
               
               
                   
                  771 
                 LTB 
                 NP_002332 
               
               
                   
                  772 
                 LYL1 
                 NP_005574 
               
               
                   
                  773 
                 LYN 
                 NP_002341 
               
               
                   
                  774 
                 LYST 
                 NP_000072 
               
               
                   
                  775 
                 MAML1 
                 NP_055572 
               
               
                   
                  776 
                 MANSC1 
                 NP_060520 
               
               
                   
                  777 
                 MAP1LC3B 
                 NP_073729 
               
               
                   
                  778 
                 MAP3K11 
                 NP_002410 
               
               
                   
                  779 
                 MAP3K3 
                 NP_002392 
               
               
                   
                  780 
                 MAP3K5 
                 NP_005914 
               
               
                   
                  781 
                 MAP4K4 
                 NP_004825 
               
               
                   
                  782 
                 MAPK1 
                 NP_002736 
               
               
                   
                  783 
                 MAPK14 
                 NP_001306 
               
               
                   
                  784 
                 MAPRE2 
                 NP_055083 
               
               
                   
                  785 
                 MARCH7 
                 NP_073737 
               
               
                   
                  786 
                 MARCH8 
                 NP_659458 
               
               
                   
                  787 
                 MARK3 
                 NP_002367 
               
               
                   
                  788 
                 MAST3 
                 NP_055831 
               
               
                   
                  789 
                 MAX 
                 NP_002373 
               
               
                   
                  790 
                 MBP 
                 NP_002376 
               
               
                   
                  791 
                 MCTP2 
                 NP_060819 
               
               
                   
                  792 
                 MED13 
                 NP_005112 
               
               
                   
                  793 
                 MEF2A 
                 NP_005578 
               
               
                   
                  794 
                 METTL3 
                 NP_062826 
               
               
                   
                  795 
                 MKLN1 
                 NP_037387 
               
               
                   
                  796 
                 MKRN1 
                 NP_038474 
               
               
                   
                  797 
                 MMP25 
                 NP_071913 
               
               
                   
                  798 
                 MORC3 
                 NP_056173 
               
               
                   
                  799 
                 MOSPD2 
                 NP_689794 
               
               
                   
                  800 
                 MPPE1 
                 NP_075563 
               
               
                   
                  801 
                 MSL1 
                 NP_001012241 
               
               
                   
                  802 
                 MTMR3 
                 NP_066576 
               
               
                   
                  803 
                 MX1 
                 NP_002453 
               
               
                   
                  804 
                 MXI1 
                 NP_005953 
               
               
                   
                  805 
                 MYC 
                 NP_002458 
               
               
                   
                  806 
                 N4BP1 
                 NP_694574 
               
               
                   
                  807 
                 NAB1 
                 NP_005957 
               
               
                   
                  808 
                 NACA 
                 NP_001106673 
               
               
                   
                  809 
                 NCBP2 
                 NP_031388 
               
               
                   
                  810 
                 NCOA1 
                 NP_003734 
               
               
                   
                  811 
                 NCOA4 
                 NP_005428 
               
               
                   
                  812 
                 NDE1 
                 NP_060138 
               
               
                   
                  813 
                 NDEL1 
                 NP_110435 
               
               
                   
                  814 
                 NDFIP1 
                 NP_085048 
               
               
                   
                  815 
                 NECAP2 
                 NP_060560 
               
               
                   
                  816 
                 NEK7 
                 NP_598001 
               
               
                   
                  817 
                 NFKB1 
                 NP_003989 
               
               
                   
                  818 
                 NFYA 
                 NP_002496 
               
               
                   
                  819 
                 NLRP1 
                 NP_055737 
               
               
                   
                  820 
                 NOD2 
                 NP_071445 
               
               
                   
                  821 
                 NOSIP 
                 NP_057037 
               
               
                   
                  822 
                 NPL 
                 NP_110396 
               
               
                   
                  823 
                 NR3C1 
                 NP_000167 
               
               
                   
                  824 
                 NRBF2 
                 NP_110386 
               
               
                   
                  825 
                 NSUN3 
                 NP_071355 
               
               
                   
                  826 
                 NUMB 
                 NP_003735 
               
               
                   
                  827 
                 OAS2 
                 NP_002526 
               
               
                   
                  828 
                 OASL 
                 NP_003724 
               
               
                   
                  829 
                 OGFRL1 
                 NP_078852 
               
               
                   
                  830 
                 OSBPL11 
                 NP_073613 
               
               
                   
                  831 
                 OSBPL2 
                 NP_055650 
               
               
                   
                  832 
                 PACSIN2 
                 NP_009160 
               
               
                   
                  833 
                 PAFAH1B1 
                 NP_000421 
               
               
                   
                  834 
                 PARP12 
                 NP_073587 
               
               
                   
                  835 
                 PBX3 
                 NP_006186 
               
               
                   
                  836 
                 PCBP2 
                 NP_005007 
               
               
                   
                  837 
                 PCF11 
                 NP_056969 
               
               
                   
                  838 
                 PCNX 
                 NP_055797 
               
               
                   
                  839 
                 PDCD6IP 
                 NP_037506 
               
               
                   
                  840 
                 PDE3B 
                 NP_000913 
               
               
                   
                  841 
                 PECAM1 
                 NP_000433 
               
               
                   
                  842 
                 PFDN5 
                 NP_002615 
               
               
                   
                  843 
                 PGS1 
                 NP_077733 
               
               
                   
                  844 
                 PHC2 
                 NP_004418 
               
               
                   
                  845 
                 PHF11 
                 NP_001035533 
               
               
                   
                  846 
                 PHF2 
                 NP_005383 
               
               
                   
                  847 
                 PHF20 
                 NP_057520 
               
               
                   
                  848 
                 PHF20L1 
                 NP_057102 
               
               
                   
                  849 
                 PHF3 
                 NP_055968 
               
               
                   
                  850 
                 PIAS1 
                 NP_057250 
               
               
                   
                  851 
                 PIK3IP1 
                 NP_443112 
               
               
                   
                  852 
                 PINK1 
                 NP_115785 
               
               
                   
                  853 
                 PISD 
                 NP_055153 
               
               
                   
                  854 
                 PITPNA 
                 NP_006215 
               
               
                   
                  855 
                 PLEKHO1 
                 NP_057358 
               
               
                   
                  856 
                 PLEKHO2 
                 NP_079477 
               
               
                   
                  857 
                 PLXNC1 
                 NP_005752 
               
               
                   
                  858 
                 POLB 
                 NP_002681 
               
               
                   
                  859 
                 POLD4 
                 NP_066996 
               
               
                   
                  860 
                 POLR1D 
                 NP_057056 
               
               
                   
                  861 
                 PPARD 
                 NP_006229 
               
               
                   
                  862 
                 PPM1F 
                 NP_055449 
               
               
                   
                  863 
                 PPP1R11 
                 NP_068778 
               
               
                   
                  864 
                 PPP1R2 
                 NP_006232 
               
               
                   
                  865 
                 PPP2R5A 
                 NP_006234 
               
               
                   
                  866 
                 PPP3R1 
                 NP_000936 
               
               
                   
                  867 
                 PPP4R1 
                 NP_005125 
               
               
                   
                  868 
                 PRKAA1 
                 NP_006242 
               
               
                   
                  869 
                 PRKAG2 
                 NP_057287 
               
               
                   
                  870 
                 PRKCD 
                 NP_006245 
               
               
                   
                  871 
                 PRMT2 
                 NP_001526 
               
               
                   
                  872 
                 PRUNE 
                 NP_067045 
               
               
                   
                  873 
                 PSAP 
                 NP_002769 
               
               
                   
                  874 
                 PSEN1 
                 NP_000012 
               
               
                   
                  875 
                 PSTPIP1 
                 NP_003969 
               
               
                   
                  876 
                 PTAFR 
                 NP_000943 
               
               
                   
                  877 
                 PTEN 
                 NP_000305 
               
               
                   
                  878 
                 PTGER4 
                 NP_000949 
               
               
                   
                  879 
                 PTPN6 
                 NP_002822 
               
               
                   
                  880 
                 PTPRE 
                 NP_006495 
               
               
                   
                  881 
                 PUM2 
                 NP_056132 
               
               
                   
                  882 
                 R3HDM2 
                 NP_055740 
               
               
                   
                  883 
                 RAB11FIP1 
                 NP_079427 
               
               
                   
                  884 
                 RAB14 
                 NP_057406 
               
               
                   
                  885 
                 RAB31 
                 NP_006859 
               
               
                   
                  886 
                 RAB4B 
                 NP_057238 
               
               
                   
                  887 
                 RAB7A 
                 NP_004628 
               
               
                   
                  888 
                 RAF1 
                 NP_002871 
               
               
                   
                  889 
                 RALB 
                 NP_002872 
               
               
                   
                  890 
                 RARA 
                 NP_000955 
               
               
                   
                  891 
                 RASSF2 
                 NP_055552 
               
               
                   
                  892 
                 RBM23 
                 NP_060577 
               
               
                   
                  893 
                 RBMS1 
                 NP_002888 
               
               
                   
                  894 
                 RC3H2 
                 NP_061323 
               
               
                   
                  895 
                 RERE 
                 NP_036234 
               
               
                   
                  896 
                 RGS14 
                 NP_006471 
               
               
                   
                  897 
                 RGS19 
                 NP_005864 
               
               
                   
                  898 
                 RHOG 
                 NP_001656 
               
               
                   
                  899 
                 RIN3 
                 NP_079108 
               
               
                   
                  900 
                 RNASET2 
                 NP_003721 
               
               
                   
                  901 
                 RNF130 
                 NP_060904 
               
               
                   
                  902 
                 RNF141 
                 NP_057506 
               
               
                   
                  903 
                 RNF146 
                 NP_112225 
               
               
                   
                  904 
                 RNF19B 
                 NP_699172 
               
               
                   
                  905 
                 RPL10A 
                 NP_009035 
               
               
                   
                  906 
                 RPL22 
                 NP_000974 
               
               
                   
                  907 
                 RPS6KA1 
                 NP_002944 
               
               
                   
                  908 
                 RPS6KA3 
                 NP_004577 
               
               
                   
                  909 
                 RSAD2 
                 NP_542388 
               
               
                   
                  910 
                 RTN3 
                 NP_006045 
               
               
                   
                  911 
                 RTP4 
                 NP_071430 
               
               
                   
                  912 
                 RXRA 
                 NP_002948 
               
               
                   
                  913 
                 RYBP 
                 NP_036366 
               
               
                   
                  914 
                 SAFB2 
                 NP_055464 
               
               
                   
                  915 
                 SATB1 
                 NP_002962 
               
               
                   
                  916 
                 SEC62 
                 NP_003253 
               
               
                   
                  917 
                 SEMA4D 
                 NP_006369 
               
               
                   
                  918 
                 SERINC3 
                 NP_006802 
               
               
                   
                  919 
                 SERINC5 
                 NP_840060 
               
               
                   
                  920 
                 SERTAD2 
                 NP_055570 
               
               
                   
                  921 
                 SESN1 
                 NP_055269 
               
               
                   
                  922 
                 SETD2 
                 NP_054878 
               
               
                   
                  923 
                 SH2B3 
                 NP_005466 
               
               
                   
                  924 
                 SH2D3C 
                 NP_005480 
               
               
                   
                  925 
                 SIRPA 
                 NP_542970 
               
               
                   
                  926 
                 SIRPB1 
                 NP_006056 
               
               
                   
                  927 
                 SLCO3A1 
                 NP_037404 
               
               
                   
                  928 
                 SMAD4 
                 NP_005350 
               
               
                   
                  929 
                 SNN 
                 NP_003489 
               
               
                   
                  930 
                 SNRK 
                 NP_060189 
               
               
                   
                  931 
                 SNX27 
                 NP_112180 
               
               
                   
                  932 
                 SOAT1 
                 NP_003092 
               
               
                   
                  933 
                 SORL1 
                 NP_003096 
               
               
                   
                  934 
                 SOS2 
                 NP_008870 
               
               
                   
                  935 
                 SP3 
                 NP_003102 
               
               
                   
                  936 
                 SSBP2 
                 NP_036578 
               
               
                   
                  937 
                 SSFA2 
                 NP_006742 
               
               
                   
                  938 
                 ST13 
                 NP_003923 
               
               
                   
                  939 
                 ST3GAL1 
                 NP_003024 
               
               
                   
                  940 
                 STAM2 
                 NP_005834 
               
               
                   
                  941 
                 STAT1 
                 NP_009330 
               
               
                   
                  942 
                 STAT5A 
                 NP_003143 
               
               
                   
                  943 
                 STAT5B 
                 NP_036580 
               
               
                   
                  944 
                 STK38L 
                 NP_055815 
               
               
                   
                  945 
                 STX10 
                 NP_003756 
               
               
                   
                  946 
                 STX3 
                 NP_004168 
               
               
                   
                  947 
                 STX6 
                 NP_005810 
               
               
                   
                  948 
                 SYPL1 
                 NP_006745 
               
               
                   
                  949 
                 TAP1 
                 NP_000584 
               
               
                   
                  950 
                 TFE3 
                 NP_006512 
               
               
                   
                  951 
                 TFEB 
                 NP_009093 
               
               
                   
                  952 
                 TGFBI 
                 NP_000349 
               
               
                   
                  953 
                 TGFBR2 
                 NP_003233 
               
               
                   
                  954 
                 TGOLN2 
                 NP_006455 
               
               
                   
                  955 
                 TIAM1 
                 NP_003244 
               
               
                   
                  956 
                 TLE3 
                 NP_005069 
               
               
                   
                  957 
                 TLE4 
                 NP_008936 
               
               
                   
                  958 
                 TLR2 
                 NP_003255 
               
               
                   
                  959 
                 TM2D3 
                 NP_079417 
               
               
                   
                  960 
                 TMBIM1 
                 NP_071435 
               
               
                   
                  961 
                 TMEM127 
                 NP_060319 
               
               
                   
                  962 
                 TMEM204 
                 NP_078876 
               
               
                   
                  963 
                 TNFRSF1A 
                 NP_001056 
               
               
                   
                  964 
                 TNFSF13 
                 NP_003799 
               
               
                   
                  965 
                 TNIP1 
                 NP_006049 
               
               
                   
                  966 
                 TNK2 
                 NP_005772 
               
               
                   
                  967 
                 TNRC6B 
                 NP_055903 
               
               
                   
                  968 
                 TOPORS 
                 NP_005793 
               
               
                   
                  969 
                 TRAK1 
                 NP_055780 
               
               
                   
                  970 
                 TREM1 
                 NP_061113 
               
               
                   
                  971 
                 TRIB2 
                 NP_067675 
               
               
                   
                  972 
                 TRIM8 
                 NP_112174 
               
               
                   
                  973 
                 TRIOBP 
                 NP_008963 
               
               
                   
                  974 
                 TSC22D3 
                 NP_004080 
               
               
                   
                  975 
                 TYK2 
                 NP_003322 
               
               
                   
                  976 
                 TYROBP 
                 NP_003323 
               
               
                   
                  977 
                 UBE2D2 
                 NP_003330 
               
               
                   
                  978 
                 UBE2L6 
                 NP_004214 
               
               
                   
                  979 
                 UBN1 
                 NP_001072982 
               
               
                   
                  980 
                 UBQLN2 
                 NP_038472 
               
               
                   
                  981 
                 UBXN2B 
                 NP_001071087 
               
               
                   
                  982 
                 USP10 
                 NP_005144 
               
               
                   
                  983 
                 USP15 
                 NP_006304 
               
               
                   
                  984 
                 USP18 
                 NP_059110 
               
               
                   
                  985 
                 USP4 
                 NP_003354 
               
               
                   
                  986 
                 UTP14A 
                 NP_006640 
               
               
                   
                  987 
                 VAMP3 
                 NP_004772 
               
               
                   
                  988 
                 VAV3 
                 NP_006104 
               
               
                   
                  989 
                 VEZF1 
                 NP_009077 
               
               
                   
                  990 
                 VPS8 
                 NP_056118 
               
               
                   
                  991 
                 WASF2 
                 NP_008921 
               
               
                   
                  992 
                 WBP2 
                 NP_036610 
               
               
                   
                  993 
                 WDR37 
                 NP_054742 
               
               
                   
                  994 
                 WDR47 
                 NP_055784 
               
               
                   
                  995 
                 XAF1 
                 NP_059993 
               
               
                   
                  996 
                 XPC 
                 NP_004619 
               
               
                   
                  997 
                 XPO6 
                 NP_055986 
               
               
                   
                  998 
                 YPEL5 
                 NP_057145 
               
               
                   
                  999 
                 YTHDF3 
                 NP_689971 
               
               
                   
                 1000 
                 ZBTB18 
                 NP_006343 
               
               
                   
                 1001 
                 ZC3HAV1 
                 NP_064504 
               
               
                   
                 1002 
                 ZDHHC17 
                 NP_056151 
               
               
                   
                 1003 
                 ZDHHC18 
                 NP_115659 
               
               
                   
                 1004 
                 ZFAND5 
                 NP_005998 
               
               
                   
                 1005 
                 ZFC3H1 
                 NP_659419 
               
               
                   
                 1006 
                 ZFYVE16 
                 NP_055548 
               
               
                   
                 1007 
                 ZMIZ1 
                 NP_065071 
               
               
                   
                 1008 
                 ZNF143 
                 NP_003433 
               
               
                   
                 1009 
                 ZNF148 
                 NP_068799 
               
               
                   
                 1010 
                 ZNF274 
                 NP_057408 
               
               
                   
                 1011 
                 ZNF292 
                 NP_055836 
               
               
                   
                 1012 
                 ZXDC 
                 NP_079388 
               
               
                   
                 1013 
                 ZVX 
                 NP_003452 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 PASIRS BIOMARKER DETAILS  
               
               
                 INCLUDING; SEQUENCE IDENTIFICATION  
               
               
                 NUMBER, GENE SYMBOL, ENSEMBL  
               
               
                 TRANSCRIPT ID AND DNA SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 Seq ID 
                 Gene  
                 Ensembl Transcript 
               
               
                   
                 # DNA 
                 Symbol 
                 ID 
               
               
                   
                   
               
               
                   
                 1014 
                 ACSL4 
                 ENST00000348502 
               
               
                   
                 1015 
                 ADK 
                 ENST00000372734 
               
               
                   
                 1016 
                 ADSL 
                 ENST00000623063 
               
               
                   
                 1017 
                 AHCTF1 
                 ENST00000326225 
               
               
                   
                 1018 
                 APEX1 
                 ENST00000216714 
               
               
                   
                 1019 
                 ARHGAP17 
                 ENST00000303665 
               
               
                   
                 1020 
                 ARID1A 
                 ENST00000324856 
               
               
                   
                 1021 
                 ARIH2 
                 ENST00000356401 
               
               
                   
                 1022 
                 ASXL2 
                 ENST00000435504 
               
               
                   
                 1023 
                 ATOX1 
                 ENST00000313115 
               
               
                   
                 1024 
                 ATP2A2 
                 ENST00000308664 
               
               
                   
                 1025 
                 ATP6V1B2 
                 ENST00000276390 
               
               
                   
                 1026 
                 BCL11A 
                 ENST00000356842 
               
               
                   
                 1027 
                 BCL3 
                 ENST00000164227 
               
               
                   
                 1028 
                 BCL6 
                 ENST00000406870 
               
               
                   
                 1029 
                 C3AR1 
                 ENST00000307637 
               
               
                   
                 1030 
                 CAMK2G 
                 ENST00000351293 
               
               
                   
                 1031 
                 CCND3 
                 ENST00000372991 
               
               
                   
                 1032 
                 CCR7 
                 ENST00000246657 
               
               
                   
                 1033 
                 CD52 
                 ENST00000374213 
               
               
                   
                 1034 
                 CD55 
                 ENST00000367064 
               
               
                   
                 1035 
                 CD63 
                 ENST00000257857 
               
               
                   
                 1036 
                 CEBPB 
                 ENST00000303004 
               
               
                   
                 1037 
                 CEP192 
                 ENST00000506447 
               
               
                   
                 1038 
                 CHN2 
                 ENST00000222792 
               
               
                   
                 1039 
                 CLIP4 
                 ENST00000320081 
               
               
                   
                 1040 
                 CNOT7 
                 ENST00000361272 
               
               
                   
                 1041 
                 CSNK1G2 
                 ENST00000255641 
               
               
                   
                 1042 
                 CSTB 
                 ENST00000291568 
               
               
                   
                 1043 
                 DNAJC10 
                 ENST00000264065 
               
               
                   
                 1044 
                 ENO1 
                 ENST00000234590 
               
               
                   
                 1045 
                 ERLIN1 
                 ENST00000421367 
               
               
                   
                 1046 
                 ETV6 
                 ENST00000396373 
               
               
                   
                 1047 
                 EXOSC10 
                 ENST00000304457 
               
               
                   
                 1048 
                 EXOSC2 
                 ENST00000372358 
               
               
                   
                 1049 
                 EXOSC9 
                 ENST00000243498 
               
               
                   
                 1050 
                 FBL 
                 ENST00000221801 
               
               
                   
                 1051 
                 FBXO11 
                 ENST00000402508 
               
               
                   
                 1052 
                 FCER1G 
                 ENST00000289902 
               
               
                   
                 1053 
                 FGR 
                 ENST00000374005 
               
               
                   
                 1054 
                 FLII 
                 ENST00000327031 
               
               
                   
                 1055 
                 FLOT1 
                 ENST00000383382 
               
               
                   
                 1056 
                 FNTA 
                 ENST00000302279 
               
               
                   
                 1057 
                 G6PD 
                 ENST00000393562 
               
               
                   
                 1058 
                 GLG1 
                 ENST00000205061 
               
               
                   
                 1059 
                 GNG5 
                 ENST00000370645 
               
               
                   
                 1060 
                 GPI 
                 ENST00000356487 
               
               
                   
                 1061 
                 GRINA 
                 ENST00000313269 
               
               
                   
                 1062 
                 HCK 
                 ENST00000534862 
               
               
                   
                 1063 
                 HERC6 
                 ENST00000264346 
               
               
                   
                 1064 
                 HLA-DPA1 
                 ENST00000383224 
               
               
                   
                 1065 
                 IL10RA 
                 ENST00000227752 
               
               
                   
                 1066 
                 IMP3 
                 ENST00000403490 
               
               
                   
                 1067 
                 IRF1 
                 ENST00000245414 
               
               
                   
                 1068 
                 IRF8 
                 ENST00000268638 
               
               
                   
                 1069 
                 JUNB 
                 ENST00000302754 
               
               
                   
                 1070 
                 KIF1B 
                 ENST00000263934 
               
               
                   
                 1071 
                 LAP3 
                 ENST00000618908 
               
               
                   
                 1072 
                 LDHA 
                 ENST00000422447 
               
               
                   
                 1073 
                 LY9 
                 ENST00000263285 
               
               
                   
                 1074 
                 METAP1 
                 ENST00000296411 
               
               
                   
                 1075 
                 MGEA5 
                 ENST00000361464 
               
               
                   
                 1076 
                 MLLT10 
                 ENST00000377072 
               
               
                   
                 1077 
                 MYD88 
                 ENST00000396334 
               
               
                   
                 1078 
                 NFIL3 
                 ENST00000297689 
               
               
                   
                 1079 
                 NFKBIA 
                 ENST00000216797 
               
               
                   
                 1080 
                 NOSIP 
                 ENST00000596358 
               
               
                   
                 1081 
                 NUMB 
                 ENST00000557597 
               
               
                   
                 1082 
                 NUP160 
                 ENST00000378460 
               
               
                   
                 1083 
                 PCBP1 
                 ENST00000303577 
               
               
                   
                 1084 
                 PCID2 
                 ENST00000375479 
               
               
                   
                 1085 
                 PCMT1 
                 ENST00000464889 
               
               
                   
                 1086 
                 PGD 
                 ENST00000270776 
               
               
                   
                 1087 
                 PLAUR 
                 ENST00000340093 
               
               
                   
                 1088 
                 PLSCR1 
                 ENST00000342435 
               
               
                   
                 1089 
                 POMP 
                 ENST00000380842 
               
               
                   
                 1090 
                 PREPL 
                 ENST00000260648 
               
               
                   
                 1091 
                 PRKCD 
                 ENST00000330452 
               
               
                   
                 1092 
                 RAB27A 
                 ENST00000396307 
               
               
                   
                 1093 
                 RAB7A 
                 ENST00000265062 
               
               
                   
                 1094 
                 RALB 
                 ENST00000272519 
               
               
                   
                 1095 
                 RBMS1 
                 ENST00000348849 
               
               
                   
                 1096 
                 RIT1 
                 ENST00000368323 
               
               
                   
                 1097 
                 RPL15 
                 ENST00000611050 
               
               
                   
                 1098 
                 RPL22 
                 ENST00000234875 
               
               
                   
                 1099 
                 RPL9 
                 ENST00000295955 
               
               
                   
                 1100 
                 RPS14 
                 ENST00000407193 
               
               
                   
                 1101 
                 RP54X 
                 ENST00000316084 
               
               
                   
                 1102 
                 RTN4 
                 ENST00000394609 
               
               
                   
                 1103 
                 SEH1L 
                 ENST00000262124 
               
               
                   
                 1104 
                 SERBP1 
                 ENST00000370994 
               
               
                   
                 1105 
                 SERPINB1 
                 ENST00000380739 
               
               
                   
                 1106 
                 SERTAD2 
                 ENST00000313349 
               
               
                   
                 1107 
                 SETX 
                 ENST00000224140 
               
               
                   
                 1108 
                 SH3GLB1 
                 ENST00000370558 
               
               
                   
                 1109 
                 SLAMF7 
                 ENST00000368043 
               
               
                   
                 1110 
                 SOCS3 
                 ENST00000330871 
               
               
                   
                 1111 
                 SORT1 
                 ENST00000256637 
               
               
                   
                 1112 
                 SPI1 
                 ENST00000378538 
               
               
                   
                 1113 
                 SQRDL 
                 ENST00000260324 
               
               
                   
                 1114 
                 STAT3 
                 ENST00000404395 
               
               
                   
                 1115 
                 SUCLG2 
                 ENST00000307227 
               
               
                   
                 1116 
                 TANK 
                 ENST00000259075 
               
               
                   
                 1117 
                 TAPI 
                 ENST00000424897 
               
               
                   
                 1118 
                 TCF4 
                 ENST00000356073 
               
               
                   
                 1119 
                 TCIRG1 
                 ENST00000265686 
               
               
                   
                 1120 
                 TIMP2 
                 ENST00000262768 
               
               
                   
                 1121 
                 TMEM106B 
                 ENST00000396667 
               
               
                   
                 1122 
                 TMEM50B 
                 ENST00000573374 
               
               
                   
                 1123 
                 TNIP1 
                 ENST00000521591 
               
               
                   
                 1124 
                 TOP2B 
                 ENST00000435706 
               
               
                   
                 1125 
                 TPP1 
                 ENST00000299427 
               
               
                   
                 1126 
                 TRAF3IP3 
                 ENST00000367025 
               
               
                   
                 1127 
                 TRIB1 
                 ENST00000311922 
               
               
                   
                 1128 
                 TRIT1 
                 ENST00000316891 
               
               
                   
                 1129 
                 TROVE2 
                 ENST00000367446 
               
               
                   
                 1130 
                 TRPC4AP 
                 ENST00000252015 
               
               
                   
                 1131 
                 TSPO 
                 ENST00000337554 
               
               
                   
                 1132 
                 TTC17 
                 ENST00000039989 
               
               
                   
                 1133 
                 TUBA1B 
                 ENST00000336023 
               
               
                   
                 1134 
                 UBE2L6 
                 ENST00000287156 
               
               
                   
                 1135 
                 UFM1 
                 ENST00000239878 
               
               
                   
                 1136 
                 UPP1 
                 ENST00000395564 
               
               
                   
                 1137 
                 USP34 
                 ENST00000398571 
               
               
                   
                 1138 
                 VAMP3 
                 ENST00000054666 
               
               
                   
                 1139 
                 WARS 
                 ENST00000392882 
               
               
                   
                 1140 
                 WAS 
                 ENST00000376701 
               
               
                   
                 1141 
                 ZBED5 
                 ENST00000432999 
               
               
                   
                 1142 
                 ZMYND11 
                 ENST00000397962 
               
               
                   
                 1143 
                 ZNF266 
                 ENST00000590306 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 PASIRS BIOMARKER DETAILS 
               
               
                 INCLUDING; SEQUENCE IDENTIFICATION 
               
               
                 NUMBER, GENE SYMBOL, GENBANK  
               
               
                 ACCESSION AND AMINO ACID SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 Seq ID 
                 Gene  
                 GenBank 
               
               
                   
                 # AA 
                 Symbol 
                 Accession 
               
               
                   
                   
               
               
                   
                 1144 
                 ACSL4 
                 NP_004449 
               
               
                   
                 1145 
                 ADK 
                 NP_001114 
               
               
                   
                 1146 
                 ADSL 
                 NP_000017 
               
               
                   
                 1147 
                 AHCTF1 
                 NP_056261 
               
               
                   
                 1148 
                 APEX1 
                 NP_001632 
               
               
                   
                 1149 
                 ARHGAP17 
                 NP_060524 
               
               
                   
                 1150 
                 ARID1A 
                 NP_006006 
               
               
                   
                 1151 
                 ARIH2 
                 NP_006312 
               
               
                   
                 1152 
                 ASXL2 
                 NP_060733 
               
               
                   
                 1153 
                 ATOX1 
                 NP_004036 
               
               
                   
                 1154 
                 ATP2A2 
                 NP_001672 
               
               
                   
                 1155 
                 ATP6V1B2 
                 NP_001684 
               
               
                   
                 1156 
                 BCL11A 
                 NP_060484 
               
               
                   
                 1157 
                 BCL3 
                 NP_005169 
               
               
                   
                 1158 
                 BCL6 
                 NP_001697 
               
               
                   
                 1159 
                 C3AR1 
                 NP_004045 
               
               
                   
                 1160 
                 CAMK2G 
                 NP_001213 
               
               
                   
                 1161 
                 CCND3 
                 NP_001751 
               
               
                   
                 1162 
                 CCR7 
                 NP_001829 
               
               
                   
                 1163 
                 CD52 
                 NP_001794 
               
               
                   
                 1164 
                 CD55 
                 NP_000565 
               
               
                   
                 1165 
                 CD63 
                 NP_001771 
               
               
                   
                 1166 
                 CEBPB 
                 NP_005185 
               
               
                   
                 1167 
                 CEP192 
                 NP_115518 
               
               
                   
                 1168 
                 CHN2 
                 NP_004058 
               
               
                   
                 1169 
                 CLIP4 
                 NP_078968 
               
               
                   
                 1170 
                 CNOT7 
                 NP_037486 
               
               
                   
                 1171 
                 CSNK1G2 
                 NP_001310 
               
               
                   
                 1172 
                 CSTB 
                 NP_000091 
               
               
                   
                 1173 
                 DNAJC10 
                 NP_061854 
               
               
                   
                 1174 
                 ENO1 
                 NP_001419 
               
               
                   
                 1175 
                 ERLIN1 
                 NP_006450 
               
               
                   
                 1176 
                 ETV6 
                 NP_001978 
               
               
                   
                 1177 
                 EXOSC1O 
                 NP_002676 
               
               
                   
                 1178 
                 EXOSC2 
                 NP_055100 
               
               
                   
                 1179 
                 EXOSC9 
                 NP_005024 
               
               
                   
                 1180 
                 FBL 
                 NP_001427 
               
               
                   
                 1181 
                 FBXO11 
                 NP_079409 
               
               
                   
                 1182 
                 FCER1G 
                 NP_004097 
               
               
                   
                 1183 
                 FGR 
                 NP_005239 
               
               
                   
                 1184 
                 FLII 
                 NP_002009 
               
               
                   
                 1185 
                 FLOT1 
                 NP_005794 
               
               
                   
                 1186 
                 FNTA 
                 NP_002018 
               
               
                   
                 1187 
                 G6PD 
                 NP_000393 
               
               
                   
                 1188 
                 GLG1 
                 NP_036333 
               
               
                   
                 1189 
                 GNG5 
                 NP_005265 
               
               
                   
                 1190 
                 GPI 
                 NP_000166 
               
               
                   
                 1191 
                 GRINA 
                 NP_000828 
               
               
                   
                 1192 
                 HCK 
                 NP_002101 
               
               
                   
                 1193 
                 HERC6 
                 NP_060382 
               
               
                   
                 1194 
                 HLA-DPA1 
                 NP_291032 
               
               
                   
                 1195 
                 IL10RA 
                 NP_001549 
               
               
                   
                 1196 
                 IMP3 
                 NP_060755 
               
               
                   
                 1197 
                 IRF1 
                 NP_002189 
               
               
                   
                 1198 
                 IRF8 
                 NP_002154 
               
               
                   
                 1199 
                 JUNB 
                 NP_002220 
               
               
                   
                 1200 
                 KIF1B 
                 NP_055889 
               
               
                   
                 1201 
                 LAP3 
                 NP_056991 
               
               
                   
                 1202 
                 LDHA 
                 NP_005557 
               
               
                   
                 1203 
                 LY9 
                 NP_002339 
               
               
                   
                 1204 
                 METAP1 
                 NP_055958 
               
               
                   
                 1205 
                 MGEA5 
                 NP_036347 
               
               
                   
                 1206 
                 MLLT10 
                 NP_004632 
               
               
                   
                 1207 
                 MYD88 
                 NP_002459 
               
               
                   
                 1208 
                 NFIL3 
                 NP_005375 
               
               
                   
                 1209 
                 NFKBIA 
                 NP_065390 
               
               
                   
                 1210 
                 NOSIP 
                 NP_057037 
               
               
                   
                 1211 
                 NUMB 
                 NP_003735 
               
               
                   
                 1212 
                 NUP160 
                 NP_056046 
               
               
                   
                 1213 
                 PCBP1 
                 NP_006187 
               
               
                   
                 1214 
                 PCID2 
                 NP_060856 
               
               
                   
                 1215 
                 PCMT1 
                 NP_005380 
               
               
                   
                 1216 
                 PGD 
                 NP_002622 
               
               
                   
                 1217 
                 PLAUR 
                 NP_002650 
               
               
                   
                 1218 
                 PLSCR1 
                 NP_066928 
               
               
                   
                 1219 
                 POMP 
                 NP_057016 
               
               
                   
                 1220 
                 PREPL 
                 NP_006027 
               
               
                   
                 1221 
                 PRKCD 
                 NP_006245 
               
               
                   
                 1222 
                 RAB27A 
                 NP_004571 
               
               
                   
                 1223 
                 RAB7A 
                 NP_004628 
               
               
                   
                 1224 
                 RALB 
                 NP_002872 
               
               
                   
                 1225 
                 RBMS1 
                 NP_002888 
               
               
                   
                 1226 
                 RIT1 
                 NP_008843 
               
               
                   
                 1227 
                 RPL15 
                 NP_002939 
               
               
                   
                 1228 
                 RPL22 
                 NP_000974 
               
               
                   
                 1229 
                 RPL9 
                 NP_000652 
               
               
                   
                 1230 
                 RPS14 
                 NP_005608 
               
               
                   
                 1231 
                 RPS4X 
                 NP_000998 
               
               
                   
                 1232 
                 RTN4 
                 NP_008939 
               
               
                   
                 1233 
                 SEH1L 
                 NP_112493 
               
               
                   
                 1234 
                 SERBP1 
                 NP_056455 
               
               
                   
                 1235 
                 SERPINB1 
                 NP_109591 
               
               
                   
                 1236 
                 SERTAD2 
                 NP_055570 
               
               
                   
                 1237 
                 SETX 
                 NP_055861 
               
               
                   
                 1238 
                 SH3GLB1 
                 NP_057093 
               
               
                   
                 1239 
                 SLAMF7 
                 NP_067004 
               
               
                   
                 1240 
                 SOCS3 
                 NP_003946 
               
               
                   
                 1241 
                 SORT1 
                 NP_002950 
               
               
                   
                 1242 
                 SPI1 
                 NP_003111 
               
               
                   
                 1243 
                 SQRDL 
                 NP_057022 
               
               
                   
                 1244 
                 STAT3 
                 NP_003141 
               
               
                   
                 1245 
                 SUCLG2 
                 NP_003839 
               
               
                   
                 1245 
                 TANK 
                 NP_004171 
               
               
                   
                 1247 
                 TAP1 
                 NP_000584 
               
               
                   
                 1248 
                 TCF4 
                 NP_003190 
               
               
                   
                 1249 
                 TCIRG1 
                 NP_006010 
               
               
                   
                 1250 
                 TIMP2 
                 NP_003246 
               
               
                   
                 1251 
                 TMEM106B 
                 NP_060844 
               
               
                   
                 1252 
                 TMEM50B 
                 NP_006125 
               
               
                   
                 1253 
                 TNIP1 
                 NP_006049 
               
               
                   
                 1254 
                 TOP2B 
                 NP_001059 
               
               
                   
                 1255 
                 TPP1 
                 NP_000382 
               
               
                   
                 1256 
                 TRAF3IP3 
                 NP_079504 
               
               
                   
                 1257 
                 TRIB1 
                 NP_079471 
               
               
                   
                 1258 
                 TRIT1 
                 NP_060116 
               
               
                   
                 1259 
                 TROVE2 
                 NP_004591 
               
               
                   
                 1260 
                 TRPC4AP 
                 NP_056453 
               
               
                   
                 1261 
                 TSPO 
                 NP_000705 
               
               
                   
                 1262 
                 TTC17 
                 NP_060729 
               
               
                   
                 1263 
                 TUBA1B 
                 NP_006073 
               
               
                   
                 1264 
                 UBE2L6 
                 NP_004214 
               
               
                   
                 1265 
                 UFM1 
                 NP_057701 
               
               
                   
                 1266 
                 UPP1 
                 NP_003355 
               
               
                   
                 1267 
                 USP34 
                 NP_055524 
               
               
                   
                 1268 
                 VAMP3 
                 NP_004772 
               
               
                   
                 1269 
                 WARS 
                 NP_004175 
               
               
                   
                 1270 
                 WAS 
                 NP_000368 
               
               
                   
                 1271 
                 ZBED5 
                 NP_067034 
               
               
                   
                 1272 
                 ZMYND11 
                 NP_006615 
               
               
                   
                 1273 
                 ZNF266 
                 NP_006622 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 INSIRS BIOMARKER DETAILS INCLUDING; 
               
               
                 SEQUENCE IDENTIFICATION NUMBER,  
               
               
                 GENE SYMBOL, ENSEMBL TRANSCRIPT 
               
               
                 ID AND DNA SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 Seq ID 
                 Gene 
                 Ensembl Transcript 
               
               
                   
                 # DNA 
                 Symbol 
                 ID 
               
               
                   
                   
               
               
                   
                 1274 
                 ADAM19 
                 ENST00000257527 
               
               
                   
                 1275 
                 ADRBK2 
                 ENST00000324198 
               
               
                   
                 1276 
                 ADSL 
                 ENST00000623063 
               
               
                   
                 1277 
                 AGA 
                 ENST00000264595 
               
               
                   
                 1278 
                 AGPAT5 
                 ENST00000285518 
               
               
                   
                 1279 
                 ANK3 
                 ENST00000355288 
               
               
                   
                 1280 
                 ARHGAP5 
                 ENST00000556611 
               
               
                   
                 1281 
                 ARHGEF6 
                 ENST00000250617 
               
               
                   
                 1282 
                 ARL6IP5 
                 ENST00000273258 
               
               
                   
                 1283 
                 ASCC3 
                 ENST00000369162 
               
               
                   
                 1284 
                 ATP8A1 
                 ENST00000381668 
               
               
                   
                 1285 
                 ATXN3 
                 ENST00000558190 
               
               
                   
                 1286 
                 BCKDHB 
                 ENST00000356489 
               
               
                   
                 1287 
                 BRCC3 
                 ENST00000369462 
               
               
                   
                 1288 
                 BTN2A1 
                 ENST00000312541 
               
               
                   
                 1289 
                 BZW2 
                 ENST00000258761 
               
               
                   
                 1290 
                 C14orf1 
                 ENST00000256319 
               
               
                   
                 1291 
                 CD28 
                 ENST00000324106 
               
               
                   
                 1292 
                 CD40LG 
                 ENST00000370629 
               
               
                   
                 1293 
                 CD84 
                 ENST00000368054 
               
               
                   
                 1294 
                 CDA 
                 ENST00000375071 
               
               
                   
                 1295 
                 CDK6 
                 ENST00000265734 
               
               
                   
                 1296 
                 CDKN1B 
                 ENST00000228872 
               
               
                   
                 1297 
                 CKAP2 
                 ENST00000258607 
               
               
                   
                 1298 
                 CLEC4E 
                 ENST00000299663 
               
               
                   
                 1299 
                 CLOCK 
                 ENST00000309964 
               
               
                   
                 1300 
                 CLUAP1 
                 ENST00000576634 
               
               
                   
                 1301 
                 CPA3 
                 ENST00000296046 
               
               
                   
                 1302 
                 CREB1 
                 ENST00000353267 
               
               
                   
                 1303 
                 CYP4F3 
                 ENST00000221307 
               
               
                   
                 1304 
                 CYSLTR1 
                 ENST00000373304 
               
               
                   
                 1305 
                 DIAPH2 
                 ENST00000324765 
               
               
                   
                 1306 
                 EFHD2 
                 ENST00000375980 
               
               
                   
                 1307 
                 EFTUD1 
                 ENST00000268206 
               
               
                   
                 1308 
                 EIF5B 
                 ENST00000289371 
               
               
                   
                 1309 
                 ENOSF1 
                 ENST00000251101 
               
               
                   
                 1310 
                 ENTPD1 
                 ENST00000371205 
               
               
                   
                 1311 
                 ERCC4 
                 ENST00000311895 
               
               
                   
                 1312 
                 ESF1 
                 ENST00000202816 
               
               
                   
                 1313 
                 EXOC7 
                 ENST00000332065 
               
               
                   
                 1314 
                 EXTL3 
                 ENST00000220562 
               
               
                   
                 1315 
                 FASTKD2 
                 ENST00000236980 
               
               
                   
                 1316 
                 FCF1 
                 ENST00000341162 
               
               
                   
                 1317 
                 FUT8 
                 ENST00000557164 
               
               
                   
                 1318 
                 G3BP1 
                 ENST00000356245 
               
               
                   
                 1319 
                 GAB2 
                 ENST00000340149 
               
               
                   
                 1320 
                 GGPS1 
                 ENST00000358966 
               
               
                   
                 1321 
                 GOLPH3L 
                 ENST00000271732 
               
               
                   
                 1322 
                 HAL 
                 ENST00000261208 
               
               
                   
                 1323 
                 HEATR1 
                 ENST00000366582 
               
               
                   
                 1324 
                 HEBP2 
                 ENST00000607197 
               
               
                   
                 1325 
                 HIBCH 
                 ENST00000359678 
               
               
                   
                 1326 
                 HLTF 
                 ENST00000310053 
               
               
                   
                 1327 
                 HRH4 
                 ENST00000256906 
               
               
                   
                 1328 
                 IDE 
                 ENST00000265986 
               
               
                   
                 1329 
                 IGF2R 
                 ENST00000356956 
               
               
                   
                 1330 
                 IKBKAP 
                 ENST00000374647 
               
               
                   
                 1331 
                 IPO7 
                 ENST00000379719 
               
               
                   
                 1332 
                 IQCB1 
                 ENST00000310864 
               
               
                   
                 1333 
                 IQSEC1 
                 ENST00000273221 
               
               
                   
                 1334 
                 KCMF1 
                 ENST00000409785 
               
               
                   
                 1335 
                 KIAA0391 
                 ENST00000534898 
               
               
                   
                 1336 
                 KLHL20 
                 ENST00000209884 
               
               
                   
                 1337 
                 KLHL24 
                 ENST00000454652 
               
               
                   
                 1338 
                 KRIT1 
                 ENST00000340022 
               
               
                   
                 1339 
                 LANCL1 
                 ENST00000450366 
               
               
                   
                 1340 
                 LARP1 
                 ENST00000336314 
               
               
                   
                 1341 
                 LARP4 
                 ENST00000398473 
               
               
                   
                 1342 
                 LRRC8D 
                 ENST00000394593 
               
               
                   
                 1343 
                 MACF1 
                 ENST00000361689 
               
               
                   
                 1344 
                 MANEA 
                 ENST00000358812 
               
               
                   
                 1345 
                 MDH1 
                 ENST00000233114 
               
               
                   
                 1346 
                 METTL5 
                 ENST00000260953 
               
               
                   
                 1347 
                 MLLT10 
                 ENST00000377072 
               
               
                   
                 1348 
                 MRPS10 
                 ENST00000053468 
               
               
                   
                 1349 
                 MTO1 
                 ENST00000498286 
               
               
                   
                 1350 
                 MTRR 
                 ENST00000440940 
               
               
                   
                 1351 
                 MXD1 
                 ENST00000264444 
               
               
                   
                 1352 
                 MYH9 
                 ENST00000216181 
               
               
                   
                 1353 
                 MYO9A 
                 ENST00000356056 
               
               
                   
                 1354 
                 NCBP1 
                 ENST00000375147 
               
               
                   
                 1355 
                 NEK1 
                 ENST00000439128 
               
               
                   
                 1356 
                 NFX1 
                 ENST00000379540 
               
               
                   
                 1357 
                 NGDN 
                 ENST00000397154 
               
               
                   
                 1358 
                 NIP7 
                 ENST00000254940 
               
               
                   
                 1359 
                 NOL10 
                 ENST00000381685 
               
               
                   
                 1360 
                 NOL8 
                 ENST00000442668 
               
               
                   
                 1361 
                 NOTCH2 
                 ENST00000256646 
               
               
                   
                 1362 
                 NR2C1 
                 ENST00000333003 
               
               
                   
                 1363 
                 PELI1 
                 ENST00000358912 
               
               
                   
                 1364 
                 PEX1 
                 ENST00000248633 
               
               
                   
                 1365 
                 PHC3 
                 ENST00000495893 
               
               
                   
                 1366 
                 PLCL2 
                 ENST00000432376 
               
               
                   
                 1367 
                 POLR2A 
                 ENST00000621442 
               
               
                   
                 1368 
                 PRKAB2 
                 ENST00000254101 
               
               
                   
                 1369 
                 PRPF39 
                 ENST00000355765 
               
               
                   
                 1370 
                 PRUNE 
                 ENST00000271620 
               
               
                   
                 1371 
                 PSMD5 
                 ENST00000210313 
               
               
                   
                 1372 
                 PTGS1 
                 ENST00000362012 
               
               
                   
                 1373 
                 PWP1 
                 ENST00000412830 
               
               
                   
                 1374 
                 RAB11FIP2 
                 ENST00000355624 
               
               
                   
                 1375 
                 RABGAP1L 
                 ENST00000251507 
               
               
                   
                 1376 
                 RAD50 
                 ENST00000378823 
               
               
                   
                 1377 
                 RBM26 
                 ENST00000267229 
               
               
                   
                 1378 
                 RCBTB2 
                 ENST00000344532 
               
               
                   
                 1379 
                 RDX 
                 ENST00000343115 
               
               
                   
                 1380 
                 REPS1 
                 ENST00000258062 
               
               
                   
                 1381 
                 RFC1 
                 ENST00000349703 
               
               
                   
                 1382 
                 RGS2 
                 ENST00000235382 
               
               
                   
                 1383 
                 RIOK2 
                 ENST00000283109 
               
               
                   
                 1384 
                 RMND1 
                 ENST00000367303 
               
               
                   
                 1385 
                 RNF170 
                 ENST00000527424 
               
               
                   
                 1386 
                 RNMT 
                 ENST00000383314 
               
               
                   
                 1387 
                 RRAGC 
                 ENST00000373001 
               
               
                   
                 1388 
                 S100PBP 
                 ENST00000373475 
               
               
                   
                 1389 
                 SIDT2 
                 ENST00000324225 
               
               
                   
                 1390 
                 SLC35A3 
                 ENST00000370155 
               
               
                   
                 1391 
                 SLC35D1 
                 ENST00000235345 
               
               
                   
                 1392 
                 SLCO3A1 
                 ENST00000318445 
               
               
                   
                 1393 
                 SMC3 
                 ENST00000361804 
               
               
                   
                 1394 
                 SMC6 
                 ENST00000351948 
               
               
                   
                 1395 
                 STK17B 
                 ENST00000263955 
               
               
                   
                 1396 
                 SUPT7L 
                 ENST00000337768 
               
               
                   
                 1397 
                 SYNE2 
                 ENST00000344113 
               
               
                   
                 1398 
                 SYT11 
                 ENST00000368324 
               
               
                   
                 1399 
                 TBCE 
                 ENST00000366601 
               
               
                   
                 1400 
                 TCF12 
                 ENST00000267811 
               
               
                   
                 1401 
                 TCF7L2 
                 ENST00000369397 
               
               
                   
                 1402 
                 TFIP11 
                 ENST00000407690 
               
               
                   
                 1403 
                 TGS1 
                 ENST00000260129 
               
               
                   
                 1404 
                 THOC2 
                 ENST00000245838 
               
               
                   
                 1405 
                 TIA1 
                 ENST00000415783 
               
               
                   
                 1406 
                 TLK1 
                 ENST00000431350 
               
               
                   
                 1407 
                 TMEM87A 
                 ENST00000389834 
               
               
                   
                 1408 
                 TNFSF8 
                 ENST00000223795 
               
               
                   
                 1409 
                 TRAPPC2 
                 ENST00000359680 
               
               
                   
                 1410 
                 TRIP11 
                 ENST00000267622 
               
               
                   
                 1411 
                 TTC17 
                 ENST00000039989 
               
               
                   
                 1412 
                 TTC27 
                 ENST00000317907 
               
               
                   
                 1413 
                 VEZT 
                 ENST00000436874 
               
               
                   
                 1414 
                 VNN3 
                 ENST00000207771 
               
               
                   
                 1415 
                 VPS13A 
                 ENST00000357409 
               
               
                   
                 1416 
                 VPS13B 
                 ENST00000355155 
               
               
                   
                 1417 
                 VPS13C 
                 ENST00000249837 
               
               
                   
                 1418 
                 WDR70 
                 ENST00000265107 
               
               
                   
                 1419 
                 XPO4 
                 ENST00000255305 
               
               
                   
                 1420 
                 YEATS4 
                 ENST00000247843 
               
               
                   
                 1421 
                 YTHDC2 
                 ENST00000161863 
               
               
                   
                 1422 
                 ZMYND11 
                 ENST00000397962 
               
               
                   
                 1423 
                 ZNF507 
                 ENST00000311921 
               
               
                   
                 1424 
                 ZNF562 
                 ENST00000293648 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 INSIRS BIOMARKER DETAILS INCLUDING;  
               
               
                 SEQUENCE IDENTIFICATION NUMBER,  
               
               
                 GENE SYMBOL, GENBANK ACCESSION  
               
               
                 AND AMINO ACID SEQUENCE 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID  
                 Gene  
                 GenBank 
               
               
                   
                 # AA 
                 Symbol  
                 Accession 
               
               
                   
                   
               
               
                   
                 1425 
                 ADAM19 
                 NP_150377 
               
               
                   
                 1426 
                 ADRBK2 
                 NP_005151 
               
               
                   
                 1427 
                 ADSL 
                 NP_000017 
               
               
                   
                 1428 
                 AGA 
                 NP_000018 
               
               
                   
                 1429 
                 AGPAT5 
                 NP_060831 
               
               
                   
                 1430 
                 ANK3 
                 NP_001140 
               
               
                   
                 1431 
                 ARHGAP5 
                 NP_001164 
               
               
                   
                 1432 
                 ARHGEF6 
                 NP_004831 
               
               
                   
                 1433 
                 ARL6IP5 
                 NP_006398 
               
               
                   
                 1434 
                 ASCC3 
                 NP_006819 
               
               
                   
                 1435 
                 ATP8A1 
                 NP_006086 
               
               
                   
                 1436 
                 ATXN3 
                 NP_004984 
               
               
                   
                 1437 
                 BCKDHB 
                 NP_000047 
               
               
                   
                 1438 
                 BRCC3 
                 NP_077308 
               
               
                   
                 1439 
                 BTN2A1 
                 NP_008980 
               
               
                   
                 1440 
                 BZW2 
                 NP_054757 
               
               
                   
                 1441 
                 C14orf1 
                 NP_009107 
               
               
                   
                 1442 
                 CD28 
                 NP_006130 
               
               
                   
                 1443 
                 CD40LG 
                 NP_000065 
               
               
                   
                 1444 
                 CD84 
                 NP_003865 
               
               
                   
                 1445 
                 CDA 
                 NP_001776 
               
               
                   
                 1446 
                 CDK6 
                 NP_001250 
               
               
                   
                 1447 
                 CDKN1B 
                 NP_004055 
               
               
                   
                 1448 
                 CKAP2 
                 NP_060674 
               
               
                   
                 1449 
                 CLEC4E 
                 NP_055173 
               
               
                   
                 1450 
                 CLOCK 
                 NP_004889 
               
               
                   
                 1451 
                 CLUAP1 
                 NP_055856 
               
               
                   
                 1452 
                 CPA3 
                 NP_001861 
               
               
                   
                 1453 
                 CREB1 
                 NP_004370 
               
               
                   
                 1454 
                 CYP4F3 
                 NP_000887 
               
               
                   
                 1455 
                 CYSLTR1 
                 NP_006630 
               
               
                   
                 1456 
                 DIAPH2 
                 NP_006720 
               
               
                   
                 1457 
                 EFHD2 
                 NP_077305 
               
               
                   
                 1458 
                 EFTUD1 
                 NP_078856 
               
               
                   
                 1459 
                 EIF5B 
                 NP_056988 
               
               
                   
                 1460 
                 ENOSF1 
                 NP_059982 
               
               
                   
                 1461 
                 ENTPD1 
                 NP_001767 
               
               
                   
                 1462 
                 ERCC4 
                 NP_005227 
               
               
                   
                 1463 
                 ESF1 
                 NP_057733 
               
               
                   
                 1464 
                 EXOC7 
                 NP_056034 
               
               
                   
                 1465 
                 EXTL3 
                 NP_001431 
               
               
                   
                 1466 
                 FASTKD2 
                 NP_055744 
               
               
                   
                 1467 
                 FCF1 
                 NP_057046 
               
               
                   
                 1468 
                 FUT8 
                 NP_004471 
               
               
                   
                 1469 
                 G3BP1 
                 NP_005745 
               
               
                   
                 1470 
                 GAB2 
                 NP_036428 
               
               
                   
                 1471 
                 GGPS1 
                 NP_001032354 
               
               
                   
                 1472 
                 GOLPH3L 
                 NP_060648 
               
               
                   
                 1473 
                 HAL 
                 NP_002099 
               
               
                   
                 1474 
                 HEATR1 
                 NP_060542 
               
               
                   
                 1475 
                 HEBP2 
                 NP_055135 
               
               
                   
                 1476 
                 HIBCH 
                 NP_055177 
               
               
                   
                 1477 
                 HLTF 
                 NP_003062 
               
               
                   
                 1478 
                 HRH4 
                 NP_067637 
               
               
                   
                 1479 
                 IDE 
                 NP_004960 
               
               
                   
                 1480 
                 IGF2R 
                 NP_000867 
               
               
                   
                 1481 
                 IKBKAP 
                 NP_003631 
               
               
                   
                 1482 
                 IPO7 
                 NP_006382 
               
               
                   
                 1483 
                 IQCB1 
                 NP_001018864 
               
               
                   
                 1484 
                 IQSEC1 
                 NP_055684 
               
               
                   
                 1485 
                 KCMF1 
                 NP_064507 
               
               
                   
                 1486 
                 KIAA0391 
                 NP_055487 
               
               
                   
                 1487 
                 KLHL20 
                 NP_055273 
               
               
                   
                 1488 
                 KLHL24 
                 NP_060114 
               
               
                   
                 1489 
                 KRIT1 
                 NP_004903 
               
               
                   
                 1490 
                 LANCL1 
                 NP_006046 
               
               
                   
                 1491 
                 LARP1 
                 NP_056130 
               
               
                   
                 1492 
                 LARP4 
                 NP_443111 
               
               
                   
                 1493 
                 LRRC8D 
                 NP_060573 
               
               
                   
                 1494 
                 MACF1 
                 NP_036222 
               
               
                   
                 1495 
                 MANEA 
                 NP_078917 
               
               
                   
                 1496 
                 MDH1 
                 NP_005908 
               
               
                   
                 1497 
                 METTL5 
                 NP_054887 
               
               
                   
                 1498 
                 MLLT10 
                 NP_004632 
               
               
                   
                 1499 
                 MRPS10 
                 NP_060611 
               
               
                   
                 1500 
                 MTO1 
                 NP_036255 
               
               
                   
                 1501 
                 MTRR 
                 NP_002445 
               
               
                   
                 1502 
                 MXD1 
                 NP_002348 
               
               
                   
                 1503 
                 MYH9 
                 NP_002464 
               
               
                   
                 1504 
                 MYO9A 
                 NP_008832 
               
               
                   
                 1505 
                 NCBP1 
                 NP_002477 
               
               
                   
                 1506 
                 NEK1 
                 NP_036356 
               
               
                   
                 1507 
                 NFX1 
                 NP_002495 
               
               
                   
                 1508 
                 NGDN 
                 NP_056329 
               
               
                   
                 1509 
                 NIP7 
                 NP_057185 
               
               
                   
                 1510 
                 NOL10 
                 NP_079170 
               
               
                   
                 1511 
                 NOL8 
                 NP_060418 
               
               
                   
                 1512 
                 NOTCH2 
                 NP_077719 
               
               
                   
                 1513 
                 NR2C1 
                 NP_003288 
               
               
                   
                 1514 
                 PELI1 
                 NP_065702 
               
               
                   
                 1515 
                 PEX1 
                 NP_000457 
               
               
                   
                 1516 
                 PHC3 
                 NP_079223 
               
               
                   
                 1517 
                 PLCL2 
                 NP_055999 
               
               
                   
                 1518 
                 POLR2A 
                 NP_000928 
               
               
                   
                 1519 
                 PRKAB2 
                 NP_005390 
               
               
                   
                 1520 
                 PRPF39 
                 NP_060392 
               
               
                   
                 1521 
                 PRUNE 
                 NP_067045 
               
               
                   
                 1522 
                 PSMD5 
                 NP_005038 
               
               
                   
                 1523 
                 PTGS1 
                 NP_000953 
               
               
                   
                 1524 
                 PWP1 
                 NP_008993 
               
               
                   
                 1525 
                 RAB11FIP2 
                 NP_055719 
               
               
                   
                 1526 
                 RABGAP1L 
                 NP_055672 
               
               
                   
                 1527 
                 RAD50 
                 NP_005723 
               
               
                   
                 1528 
                 RBM26 
                 NP_071401 
               
               
                   
                 1529 
                 RCBTB2 
                 NP_001259 
               
               
                   
                 1530 
                 RDX 
                 NP_002897 
               
               
                   
                 1531 
                 REPS1 
                 NP_114128 
               
               
                   
                 1532 
                 RFC1 
                 NP_002904 
               
               
                   
                 1533 
                 RGS2 
                 NP_002914 
               
               
                   
                 1534 
                 RIOK2 
                 NP_060813 
               
               
                   
                 1535 
                 RMND1 
                 NP_060379 
               
               
                   
                 1536 
                 RNF170 
                 NP_112216 
               
               
                   
                 1537 
                 RNMT 
                 NP_003790 
               
               
                   
                 1538 
                 RRAGC 
                 NP_071440 
               
               
                   
                 1539 
                 S100PBP 
                 NP_073590 
               
               
                   
                 1540 
                 SIDT2 
                 NP_001035545 
               
               
                   
                 1541 
                 SLC35A3 
                 NP_036375 
               
               
                   
                 1542 
                 SLC35D1 
                 NP_055954 
               
               
                   
                 1543 
                 SLCO3A1 
                 NP_037404 
               
               
                   
                 1544 
                 SMC3 
                 NP_005436 
               
               
                   
                 1545 
                 SMC6 
                 NP_078900 
               
               
                   
                 1546 
                 STK17B 
                 NP_004217 
               
               
                   
                 1547 
                 SUPT7L 
                 NP_055675 
               
               
                   
                 1548 
                 SYNE2 
                 NP_055995 
               
               
                   
                 1549 
                 SYT11 
                 NP_689493 
               
               
                   
                 1550 
                 TBCE 
                 NP_003184 
               
               
                   
                 1551 
                 TCF12 
                 NP_003196 
               
               
                   
                 1552 
                 TCF7L2 
                 NP_110383 
               
               
                   
                 1553 
                 TFIP11 
                 NP_036275 
               
               
                   
                 1554 
                 TGS1 
                 NP_079107 
               
               
                   
                 1555 
                 THOC2 
                 NP_001075019 
               
               
                   
                 1556 
                 TIA1 
                 NP_071320 
               
               
                   
                 1557 
                 TLK1 
                 NP_036422 
               
               
                   
                 1558 
                 TMEM87A 
                 NP_056312 
               
               
                   
                 1559 
                 TNFSF8 
                 NP_001235 
               
               
                   
                 1560 
                 TRAPPC2 
                 NP_055378 
               
               
                   
                 1561 
                 TRIP11 
                 NP_004230 
               
               
                   
                 1562 
                 TTC17 
                 NP_060729 
               
               
                   
                 1563 
                 TTC27 
                 NP_060205 
               
               
                   
                 1564 
                 VEZT 
                 NP_060069 
               
               
                   
                 1565 
                 VNN3 
                 NP_001278631 
               
               
                   
                 1566 
                 VPS13A 
                 NP_056001 
               
               
                   
                 1567 
                 VPS13B 
                 NP_056058 
               
               
                   
                 1568 
                 VPS13C 
                 NP_060154 
               
               
                   
                 1569 
                 WDR70 
                 NP_060504 
               
               
                   
                 1570 
                 XPO4 
                 NP_071904 
               
               
                   
                 1571 
                 YEATS4 
                 NP_006521 
               
               
                   
                 1572 
                 YTHDC2 
                 NP_073739 
               
               
                   
                 1573 
                 ZMYND11 
                 NP_006615 
               
               
                   
                 1574 
                 ZNF507 
                 NP_055725 
               
               
                   
                 1575 
                 ZNF562 
                 NP_060126 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 EXEMPLARY  ESCHERICHIA COLI  DNA SEQUENCE 
               
               
                 INCLUDING SINGLE NUCLEOTIDE POLYMORPHISMS 
               
               
                 (SNPS) AT POSITIONS 396 AND 398 (BOLDED) 
               
            
           
           
               
               
               
               
            
               
                   
                 SEQ ID # DNA 
                 Organism 
                 GenBank Accession 
               
               
                   
                   
               
               
                   
                 1576 
                 
                   Escherichia coli 
                 
                 NR_074891 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 DESCRIPTION OF DATASETS AND NUMBER OF 
               
               
                 SAMPLES USED AS PART OF DISCOVERY OF 
               
               
                 DERIVED BIOMARKERS FOR BASIRS 
               
               
                 The total number of genes that were able to be used across all of these 
               
               
                 datasets was 3698. All useable samples in these datasets were randomly 
               
               
                 divided into BaSIRS discovery and validation (see Table 13) sets. 
               
            
           
           
               
               
               
               
               
            
               
                 Dataset Identifier 
                 Source 
                 # Samples 
                 Control 
                 Case 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 FEVER 
                 In-house 
                 30 
                 8 
                 22 
               
               
                 FEVER (Bact vs Viral) 
                 In-house 
                 34 
                 7 
                 27 
               
               
                 GAPPSS 
                 In-house 
                 32 
                 15 
                 17 
               
               
                 MARS (Healthy) 
                 In-house 
                 40 
                 20 
                 20 
               
               
                 MARS (Healthy vs All) 
                 In-house 
                 459 
                 21 
                 438 
               
               
                 MARS (SIRS) 
                 In-house 
                 73 
                 57 
                 16 
               
               
                 GSE16129 
                 GEO 
                 19 
                 6 
                 13 
               
               
                 GSE30119 
                 GEO 
                 40 
                 13 
                 27 
               
               
                 GSE40396 
                 GEO 
                 16 
                 10 
                 6 
               
               
                 GSE6269 
                 GEO 
                 16 
                 6 
                 10 
               
               
                 GSE63990 
                 GEO 
                 79 
                 44 
                 35 
               
               
                 GSE63990 (Bact vs Viral) 
                 GEO 
                 93 
                 58 
                 35 
               
               
                 GSE74224 
                 GEO 
                 53 
                 16 
                 37 
               
            
           
           
               
               
               
               
            
               
                   
                 984 
                 281 
                 703 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 DESCRIPTION OF DATASETS AND NUMBER 
               
               
                 OF SAMPLES USED AS PART OF VALIDATION 
               
               
                 OF DERIVED BIOMARKERS FOR BASIRS 
               
            
           
           
               
               
               
               
               
            
               
                 Dataset Identifier 
                 Source 
                 # Samples 
                 Control 
                 Case 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 FEVER 
                 In-house 
                 30 
                 8 
                 22 
               
               
                 FEVER (Bact vs Viral) 
                 In-house 
                 34 
                 7 
                 27 
               
               
                 GAPPSS 
                 In-house 
                 31 
                 14 
                 17 
               
               
                 MARS (Healthy) 
                 In-house 
                 40 
                 20 
                 20 
               
               
                 MARS (Healthy vs All) 
                 In-house 
                 459 
                 21 
                 438 
               
               
                 MARS (SIRS) 
                 In-house 
                 71 
                 56 
                 15 
               
               
                 GSE16129 
                 GEO 
                 39 
                 10 
                 29 
               
               
                 GSE30119 
                 GEO 
                 73 
                 31 
                 42 
               
               
                 GSE40396 
                 GEO 
                 20 
                 12 
                 8 
               
               
                 GSE6269 
                 GEO 
                 25 
                 6 
                 19 
               
               
                 GSE63990 
                 GEO 
                 79 
                 44 
                 35 
               
               
                 GSE63990 (Bact vs Viral) 
                 GEO 
                 92 
                 57 
                 35 
               
               
                 GSE74224 
                 GEO 
                 52 
                 15 
                 37 
               
            
           
           
               
               
               
               
            
               
                   
                 1045 
                 301 
                 744 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 DESCRIPTION OF CONTROL DATASETS AND 
               
               
                 NUMBER OF SAMPLES USED FOR SUBTRACTION 
               
               
                 FROM THE DERIVED BIOMARKERS FOR BASIRS 
               
               
                 The subtraction process ensured that the 
               
               
                 BaSIRS derived biomarkers were specific. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Dataset 
                 Numbers 
                 Comments 
                 Case 
                 Control 
                 Total 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GSE11908 
                 58 sterile inflammation; 
                 General inflammation: 
                 6 
                 58 
                 64 
               
               
                   
                 6  Staph  or  E. coli  infection 
                 inSIRS = SLE, Diabetes, 
               
               
                   
                   
                 Melanoma 
               
               
                 GSE52428 
                 39 healthy; 41 Influenza A 
                 Influenza virus 
                 41 
                 39 
                 80 
               
               
                 GSE19301 
                 394 healthy; 166 Asthma 
                 Asthma 
                 166 
                 394 
                 560 
               
               
                 GSE38485 
                 96 healthy; 106 schizophrenia 
                 Schizophrenia 
                 106 
                 96 
                 202 
               
               
                 GSE29532 
                 6 Healthy; 25 acute coronary 
                 Coronary artery disease 
                 25 
                 6 
                 31 
               
               
                   
                 syndrome 
               
               
                 GSE46743 
                 160 baseline; 160 stress 
                 Depression/stress 
                 160 
                 160 
                 320 
               
               
                 GSE64813 
                 141 Pre-deployment; 47 post- 
                 PTSD 
                 47 
                 141 
                 188 
               
               
                   
                 deployment Post- Traumatic 
               
               
                   
                 Stress Disorder 
               
               
                 GSE51808 
                 9 healthy; 28 infected 
                 Dengue Virus 
                 28 
                 9 
                 37 
               
               
                 GSE41752 
                 11 controls; 19 cases 
                 Lassa Virus 
                 19 
                 11 
                 30 
               
               
                 GSE42834 
                 198 healthy; 46 controls 
                 Patients with tuberculosis, 
                 198 
                 35 
                 233 
               
               
                   
                   
                 sarcoidosis, and lung 
               
               
                   
                   
                 cancer (pneumonia patients 
               
               
                   
                   
                 removed) 
                   
                   
                   
               
               
                   
                   
                   
                 796 
                 949 
                 1745 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 PERFORMANCE (AS MEASURED BY AUC) OF THE 
               
               
                 FINAL BASIRS SIGNATURE IN EACH OF THE DISCOVERY, 
               
               
                 VALIDATION AND CONTROL DATASETS 
               
            
           
           
               
               
               
               
            
               
                   
                 Dataset 
                 AUC 
                 Analysis 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 FEVER 
                 0.858 
                 Discovery 
               
               
                   
                 FEVER (Bact vs Viral) 
                 0.910 
                 Discovery 
               
               
                   
                 GAPPSS 
                 0.925 
                 Discovery 
               
               
                   
                 GSE16129 
                 1.000 
                 Discovery 
               
               
                   
                 GSE30119 
                 0.892 
                 Discovery 
               
               
                   
                 GSE36809 
                 0.899 
                 Discovery 
               
               
                   
                 GSE40012 (Healthy) 
                 0.834 
                 Discovery 
               
               
                   
                 GSE40012 (SIRS) 
                 0.834 
                 Discovery 
               
               
                   
                 GSE40396 
                 1.000 
                 Discovery 
               
               
                   
                 GSE6269 
                 1.000 
                 Discovery 
               
               
                   
                 GSE63990 
                 0.890 
                 Discovery 
               
               
                   
                 GSE63990 (Bact vs Viral) 
                 0.940 
                 Discovery 
               
               
                   
                 GSE74224 
                 0.856 
                 Discovery 
               
               
                   
                 MARS (Healthy) 
                 1.000 
                 Discovery 
               
               
                   
                 MARS (Healthy vs All) 
                 0.987 
                 Discovery 
               
               
                   
                 MARS (SIRS) 
                 0.935 
                 Discovery 
               
               
                   
                 FEVER 
                 0.926 
                 Validation 
               
               
                   
                 FEVER (Bact vs Viral) 
                 0.799 
                 Validation 
               
               
                   
                 GAPPSS 
                 0.916 
                 Validation 
               
               
                   
                 GSE16129 
                 0.928 
                 Validation 
               
               
                   
                 GSE30119 
                 0.856 
                 Validation 
               
               
                   
                 GSE36809 
                 0.729 
                 Validation 
               
               
                   
                 GSE40012 (Healthy) 
                 0.910 
                 Validation 
               
               
                   
                 GSE40012 (SIRS) 
                 0.551 
                 Validation 
               
               
                   
                 GSE40396 
                 0.979 
                 Validation 
               
               
                   
                 GSE6269 
                 0.965 
                 Validation 
               
               
                   
                 GSE63990 
                 0.795 
                 Validation 
               
               
                   
                 GSE63990 (Bact vs Viral) 
                 0.873 
                 Validation 
               
               
                   
                 GSE74224 
                 0.942 
                 Validation 
               
               
                   
                 MARS (Healthy) 
                 1.000 
                 Validation 
               
               
                   
                 MARS (Healthy vs All) 
                 0.986 
                 Validation 
               
               
                   
                 MARS_SIRS 
                 0.927 
                 Validation 
               
               
                   
                 GSE19301 
                 0.573 
                 Non-BaSIRS 
               
               
                   
                 GSE29532 
                 0.807 
                 Non-BaSIRS 
               
               
                   
                 GSE38485 
                 0.569 
                 Non-BaSIRS 
               
               
                   
                 GSE64813 
                 0.674 
                 Non-BaSIRS 
               
               
                   
                 GSE46743 
                 0.517 
                 Non-BaSIRS 
               
               
                   
                 GSE11908 
                 0.546 
                 Non-BaSIRS 
               
               
                   
                 GSE42834 
                 0.647 
                 Non-BaSIRS 
               
               
                   
                 GSE52428 
                 0.633 
                 Non-BaSIRS 
               
               
                   
                 GSE41752 
                 0.694 
                 Non-BaSIRS 
               
               
                   
                 GSE51808 
                 0.484 
                 Non-BaSIRS 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 PERFORMANCE (AS MEASURED BY AUC) OF THE TOP 102 BASIRS DERIVED  
               
               
                 BIOMARKERS IN EACH OF THE BASIRS VALIDATION DATASETS. 
               
               
                 Only those derived biomarkers with a mean AUC &gt;0.85 were used in a greedy  
               
               
                 search to identify the best combination of derived biomarkers 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 FEVER 
                 GSE63990 
                   
               
               
                   
                   
                   
                   
                   
                 MARS 
                 (Bact vs 
                 (Bact vs 
                   
               
               
                 Derived Biomarker 
                 FEVER 
                 GAPPSS 
                 GSE63990 
                 GSE74224 
                 (SIRS) 
                 Viral) 
                 Viral) 
                 Mean 
               
               
                   
               
               
                 PDGFC_KLRF1 
                 0.972 
                 0.882 
                 0.823 
                 0.923 
                 0.933 
                 0.947 
                 0.899 
                 0.911 
               
               
                 TMEM165_PARP8 
                 0.960 
                 0.950 
                 0.863 
                 0.796 
                 0.865 
                 0.931 
                 0.954 
                 0.903 
               
               
                 ITGA7_KLRF1 
                 0.966 
                 0.916 
                 0.767 
                 0.888 
                 0.955 
                 0.963 
                 0.828 
                 0.897 
               
               
                 CR1_GAB2 
                 0.983 
                 0.878 
                 0.891 
                 0.829 
                 0.854 
                 0.937 
                 0.903 
                 0.896 
               
               
                 PCOLCE2_KLRF1 
                 0.966 
                 0.891 
                 0.826 
                 0.897 
                 0.894 
                 0.947 
                 0.850 
                 0.896 
               
               
                 ITGA7_INPP5D 
                 0.938 
                 0.903 
                 0.792 
                 0.850 
                 0.971 
                 0.915 
                 0.894 
                 0.895 
               
               
                 GALNT2_CCNK 
                 0.920 
                 0.916 
                 0.847 
                 0.872 
                 0.889 
                 0.963 
                 0.842 
                 0.893 
               
               
                 PDGFC_KLRD1 
                 0.920 
                 0.882 
                 0.830 
                 0.877 
                 0.889 
                 0.937 
                 0.911 
                 0.892 
               
               
                 PDGFC_CCNK 
                 0.949 
                 0.916 
                 0.821 
                 0.899 
                 0.860 
                 0.910 
                 0.886 
                 0.891 
               
               
                 CR1_ADAM19 
                 0.983 
                 0.954 
                 0.825 
                 0.802 
                 0.842 
                 0.947 
                 0.882 
                 0.891 
               
               
                 ITGA7_CCNK 
                 0.949 
                 0.941 
                 0.859 
                 0.816 
                 0.869 
                 0.905 
                 0.889 
                 0.890 
               
               
                 PCOLCE2_PRSS23 
                 0.920 
                 0.916 
                 0.827 
                 0.886 
                 0.876 
                 0.915 
                 0.877 
                 0.888 
               
               
                 TMEM165_PRPF38B 
                 0.977 
                 0.933 
                 0.852 
                 0.840 
                 0.743 
                 0.937 
                 0.935 
                 0.888 
               
               
                 PDGFC_PHF3 
                 0.926 
                 0.924 
                 0.814 
                 0.825 
                 0.918 
                 0.889 
                 0.911 
                 0.887 
               
               
                 GAS7_NLRP1 
                 0.909 
                 0.958 
                 0.857 
                 0.766 
                 0.965 
                 0.831 
                 0.912 
                 0.885 
               
               
                 PCOLCE2_KLRD1 
                 0.903 
                 0.908 
                 0.860 
                 0.867 
                 0.846 
                 0.921 
                 0.891 
                 0.885 
               
               
                 GALNT2_KLRD1 
                 0.926 
                 0.853 
                 0.841 
                 0.852 
                 0.899 
                 0.947 
                 0.871 
                 0.884 
               
               
                 KIAA0101_IL2RB 
                 0.949 
                 0.845 
                 0.853 
                 0.829 
                 0.855 
                 0.958 
                 0.897 
                 0.884 
               
               
                 CR1_HAL 
                 1.000 
                 0.815 
                 0.869 
                 0.791 
                 0.950 
                 0.926 
                 0.834 
                 0.884 
               
               
                 PDGFC_RFC1 
                 0.989 
                 0.723 
                 0.825 
                 0.892 
                 0.893 
                 0.947 
                 0.911 
                 0.883 
               
               
                 ENTPD7_KLRF1 
                 0.977 
                 0.874 
                 0.792 
                 0.854 
                 0.931 
                 0.952 
                 0.795 
                 0.882 
               
               
                 PDGFC_GRK5 
                 0.864 
                 0.958 
                 0.827 
                 0.877 
                 0.890 
                 0.857 
                 0.901 
                 0.882 
               
               
                 PCOLCE2_PYHIN1 
                 0.920 
                 0.866 
                 0.844 
                 0.798 
                 0.902 
                 0.931 
                 0.910 
                 0.882 
               
               
                 GAS7_PRKDC 
                 0.903 
                 0.950 
                 0.807 
                 0.654 
                 0.974 
                 0.963 
                 0.914 
                 0.881 
               
               
                 GAS7_CAMK1D 
                 0.892 
                 0.899 
                 0.867 
                 0.755 
                 0.908 
                 0.931 
                 0.910 
                 0.880 
               
               
                 MGAM_MME 
                 0.977 
                 0.920 
                 0.836 
                 0.744 
                 0.957 
                 0.841 
                 0.884 
                 0.880 
               
               
                 GAS7_GAB2 
                 0.841 
                 0.975 
                 0.824 
                 0.773 
                 0.933 
                 0.889 
                 0.911 
                 0.878 
               
               
                 PDGFC_INPP5D 
                 0.884 
                 0.903 
                 0.793 
                 0.894 
                 0.858 
                 0.921 
                 0.883 
                 0.876 
               
               
                 ST3GAL2_PRKD2 
                 0.795 
                 0.958 
                 0.846 
                 0.921 
                 0.771 
                 0.952 
                 0.889 
                 0.876 
               
               
                 HK3_INPP5D 
                 0.966 
                 0.815 
                 0.761 
                 0.874 
                 0.917 
                 0.942 
                 0.856 
                 0.876 
               
               
                 ENTPD7_KLRD1 
                 0.926 
                 0.830 
                 0.840 
                 0.823 
                 0.895 
                 0.947 
                 0.865 
                 0.875 
               
               
                 PDGFC_SIDT1 
                 1.000 
                 0.794 
                 0.805 
                 0.773 
                 0.856 
                 0.963 
                 0.936 
                 0.875 
               
               
                 PDGFC_SPIN1 
                 0.955 
                 0.737 
                 0.805 
                 0.845 
                 0.914 
                 0.974 
                 0.893 
                 0.875 
               
               
                 PCOLCE2_YPEL1 
                 0.966 
                 0.916 
                 0.866 
                 0.849 
                 0.787 
                 0.862 
                 0.869 
                 0.873 
               
               
                 PDGFC_SYTL2 
                 0.972 
                 0.807 
                 0.808 
                 0.852 
                 0.860 
                 0.921 
                 0.894 
                 0.873 
               
               
                 PDGFC_TGFBR3 
                 0.938 
                 0.790 
                 0.817 
                 0.802 
                 0.889 
                 0.963 
                 0.914 
                 0.873 
               
               
                 IGFBP7_KLRF1 
                 0.841 
                 1.000 
                 0.832 
                 0.890 
                 0.813 
                 0.889 
                 0.846 
                 0.873 
               
               
                 PCOLCE2_RUNX2 
                 0.909 
                 0.916 
                 0.806 
                 0.917 
                 0.962 
                 0.770 
                 0.832 
                 0.873 
               
               
                 SMPDL3A_KLRD1 
                 0.881 
                 0.777 
                 0.798 
                 0.877 
                 0.932 
                 0.958 
                 0.888 
                 0.873 
               
               
                 GALNT2_KLRF1 
                 0.943 
                 0.786 
                 0.812 
                 0.872 
                 0.927 
                 0.942 
                 0.826 
                 0.873 
               
               
                 PDGFC_YPEL1 
                 0.977 
                 0.819 
                 0.818 
                 0.863 
                 0.835 
                 0.910 
                 0.886 
                 0.873 
               
               
                 HK3_DENND3 
                 0.920 
                 0.824 
                 0.778 
                 0.960 
                 0.967 
                 0.820 
                 0.836 
                 0.872 
               
               
                 PDGFC_CBLL1 
                 0.989 
                 0.815 
                 0.782 
                 0.825 
                 0.911 
                 0.873 
                 0.910 
                 0.872 
               
               
                 OPLAH_KLRD1 
                 0.943 
                 0.723 
                 0.830 
                 0.838 
                 0.924 
                 0.952 
                 0.892 
                 0.872 
               
               
                 OPLAH_ZHX2 
                 0.972 
                 0.777 
                 0.812 
                 0.849 
                 0.914 
                 0.915 
                 0.860 
                 0.871 
               
               
                 PDGFC_RYK 
                 0.994 
                 0.723 
                 0.799 
                 0.845 
                 0.913 
                 0.923 
                 0.900 
                 0.871 
               
               
                 PDGFC_IKZF5 
                 0.932 
                 0.765 
                 0.809 
                 0.933 
                 0.915 
                 0.825 
                 0.913 
                 0.870 
               
               
                 GALNT2_INPP5D 
                 0.926 
                 0.912 
                 0.819 
                 0.771 
                 0.874 
                 0.931 
                 0.858 
                 0.870 
               
               
                 PDGFC_GCC2 
                 0.915 
                 0.782 
                 0.805 
                 0.872 
                 0.898 
                 0.915 
                 0.905 
                 0.870 
               
               
                 PDGFC_MBIP 
                 0.977 
                 0.693 
                 0.835 
                 0.915 
                 0.870 
                 0.899 
                 0.891 
                 0.869 
               
               
                 COX15_UTRN 
                 0.943 
                 0.899 
                 0.858 
                 0.796 
                 0.814 
                 0.926 
                 0.837 
                 0.868 
               
               
                 SMPDL3A_QRICH1 
                 0.966 
                 0.777 
                 0.792 
                 0.825 
                 0.890 
                 0.947 
                 0.874 
                 0.867 
               
               
                 PDGFC_LPIN2 
                 0.841 
                 0.861 
                 0.836 
                 0.849 
                 0.808 
                 0.974 
                 0.901 
                 0.867 
               
               
                 TSPO_NLRP1 
                 0.903 
                 0.676 
                 0.832 
                 0.899 
                 0.975 
                 0.915 
                 0.867 
                 0.867 
               
               
                 PCOLCE2_NMUR1 
                 0.920 
                 0.895 
                 0.826 
                 0.926 
                 0.836 
                 0.804 
                 0.860 
                 0.867 
               
               
                 FAM129A_GAB2 
                 0.943 
                 0.832 
                 0.771 
                 0.845 
                 0.925 
                 0.952 
                 0.794 
                 0.866 
               
               
                 ALPL_NLRP1 
                 0.920 
                 0.803 
                 0.778 
                 0.872 
                 0.973 
                 0.894 
                 0.821 
                 0.866 
               
               
                 TSPO_ZFP36L2 
                 0.966 
                 0.651 
                 0.820 
                 0.856 
                 0.919 
                 0.958 
                 0.891 
                 0.866 
               
               
                 ALPL_ZFP36L2 
                 0.943 
                 0.773 
                 0.790 
                 0.818 
                 0.980 
                 0.915 
                 0.841 
                 0.866 
               
               
                 PCOLCE2_FOXJ3 
                 0.972 
                 0.903 
                 0.818 
                 0.822 
                 0.870 
                 0.825 
                 0.849 
                 0.866 
               
               
                 PDGFC_KIAA0355 
                 0.864 
                 0.845 
                 0.839 
                 0.899 
                 0.885 
                 0.810 
                 0.917 
                 0.865 
               
               
                 PDGFC_KIAA0907 
                 0.966 
                 0.723 
                 0.800 
                 0.856 
                 0.895 
                 0.905 
                 0.906 
                 0.864 
               
               
                 GAS7_DOCK5 
                 0.886 
                 0.945 
                 0.834 
                 0.654 
                 0.902 
                 0.905 
                 0.922 
                 0.864 
               
               
                 CD82_CNNM3 
                 0.960 
                 0.714 
                 0.882 
                 0.859 
                 0.871 
                 0.889 
                 0.872 
                 0.864 
               
               
                 GAS7_EXTL3 
                 0.949 
                 0.941 
                 0.856 
                 0.598 
                 0.871 
                 0.937 
                 0.895 
                 0.864 
               
               
                 TSPO_RNASE6 
                 0.938 
                 0.685 
                 0.806 
                 0.829 
                 0.974 
                 0.937 
                 0.874 
                 0.863 
               
               
                 ALPL_MME 
                 0.920 
                 0.857 
                 0.779 
                 0.814 
                 0.979 
                 0.878 
                 0.807 
                 0.862 
               
               
                 HK3_TLE3 
                 0.892 
                 0.853 
                 0.724 
                 0.957 
                 0.954 
                 0.831 
                 0.822 
                 0.862 
               
               
                 MCTP1_PARP8 
                 0.830 
                 0.866 
                 0.833 
                 0.923 
                 0.880 
                 0.847 
                 0.854 
                 0.862 
               
               
                 TSPO_HCLS1 
                 0.920 
                 0.912 
                 0.783 
                 0.894 
                 0.860 
                 0.788 
                 0.872 
                 0.861 
               
               
                 TSPO_CASS4 
                 0.909 
                 0.647 
                 0.851 
                 0.876 
                 0.938 
                 0.942 
                 0.863 
                 0.861 
               
               
                 GAS7_RBM23 
                 0.903 
                 0.983 
                 0.740 
                 0.650 
                 0.902 
                 0.931 
                 0.910 
                 0.860 
               
               
                 GAS7_EPHB4 
                 0.929 
                 0.941 
                 0.842 
                 0.591 
                 0.871 
                 0.952 
                 0.893 
                 0.860 
               
               
                 PDGFC_RBM15 
                 0.955 
                 0.756 
                 0.769 
                 0.858 
                 0.921 
                 0.942 
                 0.810 
                 0.859 
               
               
                 ADM_CLEC7A 
                 0.955 
                 0.798 
                 0.810 
                 0.881 
                 0.917 
                 0.831 
                 0.818 
                 0.858 
               
               
                 PDGFC_LEPROTL1 
                 0.943 
                 0.815 
                 0.733 
                 0.811 
                 0.898 
                 0.963 
                 0.842 
                 0.858 
               
               
                 PDGFC_NPAT 
                 1.000 
                 0.807 
                 0.801 
                 0.764 
                 0.844 
                 0.884 
                 0.905 
                 0.858 
               
               
                 TSPO_PLA2G7 
                 0.909 
                 0.643 
                 0.822 
                 0.872 
                 0.930 
                 0.947 
                 0.877 
                 0.857 
               
               
                 GALNT2_IK 
                 0.955 
                 0.782 
                 0.812 
                 0.823 
                 0.908 
                 0.873 
                 0.842 
                 0.856 
               
               
                 CD82_JARID2 
                 0.972 
                 0.744 
                 0.810 
                 0.836 
                 0.942 
                 0.878 
                 0.812 
                 0.856 
               
               
                 PDGFC_ICK 
                 0.938 
                 0.660 
                 0.823 
                 0.883 
                 0.899 
                 0.897 
                 0.892 
                 0.856 
               
               
                 GALNT2_SAP130 
                 0.920 
                 0.714 
                 0.836 
                 0.856 
                 0.920 
                 0.926 
                 0.816 
                 0.856 
               
               
                 PDGFC_FBXO28 
                 0.895 
                 0.769 
                 0.780 
                 0.868 
                 0.930 
                 0.865 
                 0.881 
                 0.855 
               
               
                 TSPO_GAB2 
                 0.898 
                 0.668 
                 0.792 
                 0.930 
                 0.924 
                 0.937 
                 0.838 
                 0.855 
               
               
                 COX15_INPP5D 
                 0.881 
                 0.899 
                 0.801 
                 0.877 
                 0.826 
                 0.884 
                 0.817 
                 0.855 
               
               
                 ITGA7_LAG3 
                 0.943 
                 0.769 
                 0.759 
                 0.796 
                 0.888 
                 0.921 
                 0.908 
                 0.855 
               
               
                 TSPO_CAMK1D 
                 0.909 
                 0.639 
                 0.840 
                 0.865 
                 0.931 
                 0.942 
                 0.859 
                 0.855 
               
               
                 OPLAH_POGZ 
                 0.955 
                 0.761 
                 0.758 
                 0.865 
                 0.877 
                 0.905 
                 0.864 
                 0.855 
               
               
                 ALPL_RNASE6 
                 0.920 
                 0.794 
                 0.753 
                 0.852 
                 0.962 
                 0.894 
                 0.804 
                 0.854 
               
               
                 RAB32_NLRP1 
                 0.926 
                 0.866 
                 0.779 
                 0.897 
                 0.939 
                 0.746 
                 0.826 
                 0.854 
               
               
                 TLR5_SEMA4D 
                 0.886 
                 0.845 
                 0.812 
                 0.741 
                 0.902 
                 0.915 
                 0.876 
                 0.854 
               
               
                 IMPDH1_NLRP1 
                 0.875 
                 0.697 
                 0.810 
                 0.901 
                 0.943 
                 0.921 
                 0.830 
                 0.854 
               
               
                 ALPL_CAMK1D 
                 0.915 
                 0.756 
                 0.779 
                 0.879 
                 0.938 
                 0.905 
                 0.800 
                 0.853 
               
               
                 TSPO_NFIC 
                 0.915 
                 0.639 
                 0.815 
                 0.892 
                 0.910 
                 0.947 
                 0.854 
                 0.853 
               
               
                 GAS7_HAL 
                 0.869 
                 0.924 
                 0.778 
                 0.757 
                 0.977 
                 0.836 
                 0.829 
                 0.853 
               
               
                 PDGFC_NCOA6 
                 0.821 
                 0.769 
                 0.841 
                 0.928 
                 0.907 
                 0.825 
                 0.877 
                 0.853 
               
               
                 PDGFC_PIK3C2A 
                 0.886 
                 0.824 
                 0.756 
                 0.793 
                 0.926 
                 0.921 
                 0.861 
                 0.852 
               
               
                 TSPO_ADAM19 
                 0.881 
                 0.685 
                 0.758 
                 0.941 
                 0.915 
                 0.942 
                 0.844 
                 0.852 
               
               
                 CD82_NOV 
                 0.943 
                 0.718 
                 0.813 
                 0.903 
                 0.937 
                 0.878 
                 0.768 
                 0.851 
               
               
                 PDGFC_PDS5B 
                 0.892 
                 0.744 
                 0.799 
                 0.861 
                 0.918 
                 0.868 
                 0.872 
                 0.850 
               
               
                 FIG4_INPP5D 
                 0.869 
                 0.908 
                 0.724 
                 0.818 
                 0.981 
                 0.878 
                 0.773 
                 0.850 
               
               
                 TSPO_NOV 
                 0.909 
                 0.643 
                 0.804 
                 0.883 
                 0.915 
                 0.947 
                 0.850 
                 0.850 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 DETAILS OF GENE EXPRESSION OMNIBUS 
               
               
                 (GEO) DATASETS USED FOR DISCOVERY 
               
               
                 OF VIRAL DERIVED BIOMARKERS 
               
            
           
           
               
               
               
            
               
                   
                 Dataset 
                 Description and Comparison Made 
               
               
                   
                   
               
               
                   
                 GSE40336 
                 Cytomegalovirus in humans (natural infection) 
               
               
                   
                   
                 Comparison of nonagenarians with a titer of 0 
               
               
                   
                   
                 (n = 6) vs &gt;20,000 (n = 67) Herpesviridae; 
               
               
                   
                   
                 Baltimore Group I 
               
               
                   
                 GSE41752 
                 Lassa virus in macaques (time course, challenge) 
               
               
                   
                   
                 Comparison of samples collected pre-challenge 
               
               
                   
                   
                 (n = 11) to those collected on Days 2, 3, and 
               
               
                   
                   
                 6, post-challenge (n = 9) Arenaviridae; 
               
               
                   
                   
                 Baltimore Group V 
               
               
                   
                 GSE51808 
                 Dengue virus in humans (natural infection) 
               
               
                   
                   
                 Comparison of healthy controls (n = 9) vs 
               
               
                   
                   
                 samples collected at acute infection (n = 28) 
               
               
                   
                   
                 Flaviviridae; Baltimore Group IV 
               
               
                   
                 GSE52428 
                 Influenza virus (H1N1 &amp; H3N2) (time course, 
               
               
                   
                   
                 challenge) Comparison of samples collected 
               
               
                   
                   
                 pre-challenge (n = 20) vs samples collected 
               
               
                   
                   
                 in the early stages of symptom development 
               
               
                   
                   
                 (before peak) (n = 62) Orthomyxoviridae; 
               
               
                   
                   
                 Baltimore Group V 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 DETAILS OF GENE EXPRESSION OMNIBUS 
               
               
                 (GEO) DATASETS USED FOR VALIDATION 
               
               
                 OF VIRAL DERIVED BIOMARKERS 
               
            
           
           
               
               
            
               
                 Dataset 
                 Description and Comparison Made 
               
               
                   
               
               
                 GSE6269 
                 Influenza infection in humans (naturally acquired) 
               
               
                   
                 Comparison of influenza A/B (n = 30/6) vs healthy 
               
               
                   
                 (n = 6) Orthomyxoviridae; Baltimore Group V 
               
               
                 GSE40396 
                 Adenovirus, Human Herpes Virus 6, Enterovirus and 
               
               
                   
                 Rhinovirus in humans (pediatric, naturally 
               
               
                   
                 acquired) Comparison of virus-infected (n = 35) vs 
               
               
                   
                 virus-negative afebrile controls (n = 19) Adenoviridae; 
               
               
                   
                 Baltimore Group I 
               
               
                 GSE40012 
                 Influenza A infection in humans (naturally acquired) 
               
               
                   
                 Comparison of influenza A infected (n = 39, up to five 
               
               
                   
                 time points, 9 subjects) vs healthy controls (n = 36, 
               
               
                   
                 two time points, 18 subjects) Orthomyxoviridae; 
               
               
                   
                 Baltimore Group V 
               
               
                 GSE18090 
                 Dengue fever in humans (naturally acquired) 
               
               
                   
                 Comparison of febrile dengue fever (n = 18) vs 
               
               
                   
                 febrile patients without dengue fever (n = 8) 
               
               
                   
                 Flaviviridae; Baltimore Group IV 
               
               
                 GSE30550 
                 Influenza A (H3N2) infection in humans (challenged) 
               
               
                   
                 Comparison of all samples where symptoms reported 
               
               
                   
                 (17 subjects) vs samples where no symptoms were 
               
               
                   
                 reported Orthomyxoviridae; Baltimore Group V 
               
               
                 GSE40224 
                 Hepatitis C virus infection in humans (naturally 
               
               
                   
                 acquired) Comparison of infected (n = 10) vs 
               
               
                   
                 healthy (n = 8) Flaviviridae; Baltimore Group IV 
               
               
                 GSE5790 
                 Lymphocytic choriomeningitis virus infection in 
               
               
                   
                 macaques (challenged) Comparison of samples taken 
               
               
                   
                 pre-infection (n = 11) vs samples taken pre- and 
               
               
                   
                 post-viremia with lethal dose (n = 8) 
               
               
                   
                 Arenaviridae; Baltimore Group V 
               
               
                 GSE34205 
                 Influenza A and Respiratory Syncytial Virus 
               
               
                   
                 in humans (pediatric, naturally acquired) 
               
               
                   
                 Comparison of infected (Influenza, n = 28; 
               
               
                   
                 RSV, n = 51) vs healthy controls (n = 22) 
               
               
                   
                 Orthomyxoviridae; Baltimore Group V 
               
               
                   
                 Paramyxoviridae; Baltimore Group V 
               
               
                 GSE5808 
                 Measles virus in humans (naturally acquired) 
               
               
                   
                 Comparison of infected at hospital entry 
               
               
                   
                 (n = 5) and healthy controls (n = 3) 
               
               
                   
                 Paramyxoviridae; Baltimore Group V 
               
               
                 GSE2729 
                 Rotavirus infection in humans (naturally 
               
               
                   
                 acquired) Comparison of acute infection 
               
               
                   
                 (n = 10) vs healthy controls (n = 8) 
               
               
                   
                 Reoviridae; Baltimore Group III 
               
               
                 GSE29429 
                 Human immunodeficiency virus infection 
               
               
                   
                 in humans (naturally acquired) 
               
               
                   
                 Comparison of acute infection at enrolment 
               
               
                   
                 (African cohort, n = 17) vs matched 
               
               
                   
                 uninfected controls (n = 30) 
               
               
                   
                 Retroviridae; Baltimore Group VI 
               
               
                 GSE14790 
                 Porcine circovirus in pigs (challenged) 
               
               
                   
                 Comparison of pre-challenge (Day 0, n = 4) 
               
               
                   
                 to post-challenge on Days 7, 14, 21 
               
               
                   
                 and 28 (n = 15) For performance 
               
               
                   
                 calculations in this dataset N4BP1 was 
               
               
                   
                 substituted for OASL since it is known 
               
               
                   
                 that OASL does not exist in pigs Circoviridae; 
               
               
                   
                 Baltimore Group II 
               
               
                 GSE22160 
                 Hepatitis C and E in chimpanzees (challenged, 
               
               
                   
                 liver biopsies) Comparison of pre-challenge 
               
               
                   
                 samples (HCV, n = 3) (HEV, n = 4) to post- 
               
               
                   
                 challenge samples over time. HCV: 
               
               
                   
                 Flaviviridae, Baltimore Group IV HEV: 
               
               
                   
                 Hepeviridae, Baltimore Group IV 
               
               
                 GSE69606 
                 Respiratory Syncytial Virus in children 
               
               
                   
                 Comparison of mild (n = 9), moderate (n = 9) and 
               
               
                   
                 severe (n = 8) cases at presentation to 
               
               
                   
                 recovery samples 4-6 weeks later (in 
               
               
                   
                 moderate and severe cases). 
               
               
                   
                 Paramyxoviridae, Baltimore Group V 
               
               
                 GSE67059 
                 Rhinovirus in children 
               
               
                   
                 Comparison of HRV− (n = 37) versus HRV+ 
               
               
                   
                 asymptomatic (n = 14), HRV+ outpatients 
               
               
                   
                 (n = 30), HRV+ inpatients (n = 70). 
               
               
                   
                 Picornaviridae, Baltimore Group IV 
               
               
                 GSE58287 
                 Marburg virus in Macaques 
               
               
                   
                 Comparison of pre-inoculation samples (n = 3) 
               
               
                   
                 to samples taken over five time 
               
               
                   
                 points. Total samples = 15. 
               
               
                   
                 Filoviridae, Baltimore Group V 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 DESCRIPTION OF CONTROL DATASETS 
               
               
                 USED FOR SUBTRACTION FROM THE 
               
               
                 DERIVED BIOMARKERS FOR VASIRS 
               
               
                 The subtraction process ensured that the 
               
               
                 VaSIRS derived biomarkers were specific. 
               
            
           
           
               
               
            
               
                 Dataset 
                 Description and Comparison Made 
               
               
                   
               
               
                 GSE33341 
                 Bacterial sepsis in humans (natural infection) 
               
               
                   
                 Comparison of healthy (n = 43) vs bacteremia ( Staphylococcus aureus  (n = 34), 
               
               
                   
                   Escherichia coli  (n = 15)) 
               
               
                 GSE40366 
                 Age in humans (CMV titer = 0) 
               
               
                   
                 Comparison of nonagenerians (n = 6) vs young (n = 11) (&lt;28 years old) 
               
               
                 GSE42834 
                 Multiple conditions in humans (naturally acquired) 
               
               
                   
                 Comparison of controls (healthy, n = 147) vs tuberculosis (n = 66); sarcoidosis 
               
               
                   
                 (active, n = 68; non-active n = 22); lung cancer (n = 16); bacterial pneumonia 
               
               
                   
                 (treated and untreated with antibiotics) (n = 16) 
               
               
                 GSE25504 
                 Bacterial sepsis in humans (neonates, naturally acquired). 
               
               
                   
                 Comparison of controls (healthy and blood taken for other clinical reasons, 
               
               
                   
                 n = 35) vs sepsis (n = 28) 
               
               
                 GSE30119 
                 Bacterial sepsis in humans (naturally acquired) 
               
               
                   
                 Comparison of controls (healthy, n = 44) vs sepsis ( Staphylococcus aureus   
               
               
                   
                 infection including bacteremia, n = 99) 
               
               
                 GSE17755 
                 Autoimmune disease in humans 
               
               
                   
                 Comparison of healthy (n = 53) vs autoimmune disease (rheumatoid arthritis, 
               
               
                   
                 n = 112; Systemic Lupus Erythematosis, n = 22; Poly juvenile idiopathic arthritis, 
               
               
                   
                 n = 6; Systemic juvenile idiopathic arthritis, n = 51) 
               
               
                 GSE19301 
                 Asthma in humans (n = 117) 
               
               
                   
                 Comparison of “quiet” (n = 292) vs “exacerbation” (n = 117) 
               
               
                 GSE47655 
                 Anaphylaxis in humans (naturally acquired) 
               
               
                   
                 Comparison of healthy (6 subjects, three time points, n = 18) vs anaphylaxis (6 
               
               
                   
                 patients, three time points, n = 18) 
               
               
                 GSE38485 
                 Schizophrenia in humans 
               
               
                   
                 Comparison of healthy (n = 22) vs schizophrenia (n = 15) 
               
               
                 GSE36809 
                 Blunt trauma in humans 
               
               
                   
                 Comparison of healthy (n = 37) vs trauma within 12 hours (n = 167) 
               
               
                 GSE29532 
                 Coronary artery disease in humans, multiple time points. 
               
               
                   
                 Comparison of controls (n = 6) vs CAD upon admission to ER (n = 49) 
               
               
                 GSE46743 
                 Dexamethasone in human subjects (oral dose, induced) 
               
               
                   
                 Comparison of pre-dose (n = 160) vs 3 hours post-dose (n = 160) 
               
               
                 GSE61672 
                 Generalised anxiety disorder in humans 
               
               
                   
                 Comparison of controls (n = 179) vs Patients on first visit (n = 157) 
               
               
                 GSE64813 
                 Post-traumatic stress disorder in humans 
               
               
                   
                 Comparison of 94 pre-deployment with 47 post-deployment with PTSD 
               
               
                 GSE11908 
                 Multiple conditions in humans (naturally acquired) 
               
               
                   
                 Comparison of healthy controls (n = 10) vs systemic juvenile idiopathic arthritis 
               
               
                   
                 (n = 47); systemic lupus erythematosus (n = 40); type I diabetes (n = 20); 
               
               
                   
                 metastatic melanoma (n = 39);  Escherichia coli  (n = 22);  Staphylococcus aureus   
               
               
                   
                 (n = 18); Liver-transplant recipients undergoing immunosuppressive therapy 
               
               
                   
                 (n = 37) 
               
               
                 GSE16129 
                   Staphylococcus aureus  infection in humans (naturally acquired) 
               
               
                   
                 Comparison of healthy control (n = 29) vs  Staphylococcus aureus : (n = 97) 
               
               
                 GSE40012 
                 SIRS in humans (naturally acquired) 
               
               
                   
                 Comparison of healthy controls (n = 36, two time points, 18 subjects) vs SIRS 
               
               
                   
                 (n = 40, multiple time points, 13 subjects) 
               
               
                 GSE40396 
                 Bacterial infection in human (pediatric) (naturally acquired) 
               
               
                   
                 Comparison of virus-negative afebrile controls (n = 19) vs culture positive 
               
               
                   
                   Escherichia coli  (n = 2) and  Staphylococcus aureus  (n = 4) 
               
               
                 GSE6269 
                 Bacterial infection in human (pediatric) (naturally acquired) 
               
               
                   
                 Comparison of healthy control (n = 6) vs  Staphylococcus aureus  (n = 50); 
               
               
                   
                   Escherichia coli  (n = 29);  Streptococcus pneumoniae  (n = 22) 
               
               
                 GSE35846 
                 Race, gender and obesity in human subjects (mean age 51) 
               
               
                   
                 Comparison of men (n = 69) vs women (n = 124) 
               
               
                   
                 Comparison across race (Caucasian, n = 140; African American, n = 37; Asian, 
               
               
                   
                 n = 11; American Indian, n = 1) 
               
               
                   
                 Comparison across percentage body fat (9-53%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 LIST OF DERIVED VASIRS BIOMARKERS 
               
               
                 WITH AN OF AUC &gt;0.8 IN AT LEAST 
               
               
                 11 OF 14 VIRAL DATASETS. 
               
            
           
           
               
               
               
            
               
                   
                 Derived  
                 Mean  
               
               
                   
                 Biomarker 
                 AUC 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 IFI6:IL16 
                 0.916 
               
               
                   
                 OASL:NR3C1 
                 0.915 
               
               
                   
                 OASL:EMR2 
                 0.914 
               
               
                   
                 OASL:SORL1 
                 0.908 
               
               
                   
                 OASL:SERTAD2 
                 0.907 
               
               
                   
                 OASL:LPAR2 
                 0.904 
               
               
                   
                 OASL:ITGAX 
                 0.902 
               
               
                   
                 OASL:TGFBR2 
                 0.901 
               
               
                   
                 OASL:KIAA0247 
                 0.9 
               
               
                   
                 OASL:ARHGAP26 
                 0.899 
               
               
                   
                 OASL:LYN 
                 0.899 
               
               
                   
                 OASL:PCBP2 
                 0.898 
               
               
                   
                 OASL:TOPORS 
                 0.898 
               
               
                   
                 EIF2AK2:IL16 
                 0.896 
               
               
                   
                 OASL:NCOA1 
                 0.896 
               
               
                   
                 OASL:PTGER4 
                 0.896 
               
               
                   
                 OASL:TLR2 
                 0.895 
               
               
                   
                 OASL:PACSIN2 
                 0.894 
               
               
                   
                 OASL:LILRA2 
                 0.893 
               
               
                   
                 OASL:PTPRE 
                 0.893 
               
               
                   
                 OASL:RPS6KA1 
                 0.893 
               
               
                   
                 OASL:CASC3 
                 0.892 
               
               
                   
                 OASL:VEZF1 
                 0.892 
               
               
                   
                 OASL:CRLF3 
                 0.891 
               
               
                   
                 OASL:NDEL1 
                 0.891 
               
               
                   
                 OASL:RASSF2 
                 0.891 
               
               
                   
                 OASL:TLE4 
                 0.891 
               
               
                   
                 OASL:ADGRE5 
                 0.89 
               
               
                   
                 OASL:CEP68 
                 0.89 
               
               
                   
                 OASL:RXRA 
                 0.89 
               
               
                   
                 OASL:SP3 
                 0.89 
               
               
                   
                 OASL:ABLIM1 
                 0.889 
               
               
                   
                 OASL:AOAH 
                 0.889 
               
               
                   
                 OASL:MBP 
                 0.889 
               
               
                   
                 OASL:NLRP1 
                 0.889 
               
               
                   
                 OASL:PBX3 
                 0.889 
               
               
                   
                 OASL:PTPN6 
                 0.889 
               
               
                   
                 OASL:RYBP 
                 0.889 
               
               
                   
                 OASL:IL13RA1 
                 0.888 
               
               
                   
                 OASL:LCP2 
                 0.888 
               
               
                   
                 OASL:LRP10 
                 0.888 
               
               
                   
                 OASL:SYPL1 
                 0.888 
               
               
                   
                 OASL:VAMP3 
                 0.888 
               
               
                   
                 IFI44:LTB 
                 0.887 
               
               
                   
                 OASL:ARHGEF2 
                 0.887 
               
               
                   
                 OASL:CTDSP2 
                 0.887 
               
               
                   
                 OASL:LST1 
                 0.887 
               
               
                   
                 OASL:MAPK1 
                 0.887 
               
               
                   
                 OASL:N4BP1 
                 0.887 
               
               
                   
                 OASL:STAT5B 
                 0.887 
               
               
                   
                 IFI44:ABLIM1 
                 0.886 
               
               
                   
                 IFI44:IL6ST 
                 0.886 
               
               
                   
                 OASL:BACH1 
                 0.886 
               
               
                   
                 OASL:KLF7 
                 0.886 
               
               
                   
                 OASL:PRMT2 
                 0.886 
               
               
                   
                 OASL:HCK 
                 0.885 
               
               
                   
                 OASL:ITPKB 
                 0.885 
               
               
                   
                 OASL:MAP4K4 
                 0.885 
               
               
                   
                 OASL:PPM1F 
                 0.885 
               
               
                   
                 OASL:RAB14 
                 0.885 
               
               
                   
                 IFI6:ABLIM1 
                 0.884 
               
               
                   
                 OAS2:FAIM3 
                 0.884 
               
               
                   
                 OASL:ARHGAP25 
                 0.884 
               
               
                   
                 OASL:GNA12 
                 0.884 
               
               
                   
                 OASL:NUMB 
                 0.884 
               
               
                   
                 OASL:CREBBP 
                 0.883 
               
               
                   
                 OASL:PINK1 
                 0.883 
               
               
                   
                 OASL:PITPNA 
                 0.883 
               
               
                   
                 OASL:SEMA4D 
                 0.883 
               
               
                   
                 OASL:TGFBI 
                 0.883 
               
               
                   
                 OASL:APLP2 
                 0.882 
               
               
                   
                 OASL:CCNG2 
                 0.882 
               
               
                   
                 OASL:MKRN1 
                 0.882 
               
               
                   
                 OASL:RGS14 
                 0.882 
               
               
                   
                 OASL:LYST 
                 0.881 
               
               
                   
                 OASL:TNRC6B 
                 0.881 
               
               
                   
                 OASL:TYROBP 
                 0.881 
               
               
                   
                 OASL:WDR37 
                 0.881 
               
               
                   
                 OASL:WDR47 
                 0.881 
               
               
                   
                 UBE2L6:IL16 
                 0.881 
               
               
                   
                 OASL:BTG1 
                 0.88 
               
               
                   
                 OASL:CD93 
                 0.88 
               
               
                   
                 OASL:DCP2 
                 0.88 
               
               
                   
                 OASL:FYB 
                 0.88 
               
               
                   
                 OASL:MAML1 
                 0.88 
               
               
                   
                 OASL:SNRK 
                 0.88 
               
               
                   
                 OASL:USP4 
                 0.88 
               
               
                   
                 OASL:YTHDF3 
                 0.88 
               
               
                   
                 OASL:CEP170 
                 0.879 
               
               
                   
                 OASL:PLEKHO2 
                 0.879 
               
               
                   
                 OASL:SMAD4 
                 0.879 
               
               
                   
                 OASL:ST3GAL1 
                 0.879 
               
               
                   
                 OASL:ZNF292 
                 0.879 
               
               
                   
                 IFI44:IL4R 
                 0.878 
               
               
                   
                 OASL:HPCAL1 
                 0.878 
               
               
                   
                 OASL:IGSF6 
                 0.878 
               
               
                   
                 OASL:MTMR3 
                 0.878 
               
               
                   
                 OASL:PHF20 
                 0.878 
               
               
                   
                 OASL:PPARD 
                 0.878 
               
               
                   
                 OASL:PPP4R1 
                 0.878 
               
               
                   
                 OASL:RBMS1 
                 0.878 
               
               
                   
                 OASL:RHOG 
                 0.878 
               
               
                   
                 OASL:TIAM1 
                 0.878 
               
               
                   
                 USP18:IL16 
                 0.878 
               
               
                   
                 OASL:CBX7 
                 0.877 
               
               
                   
                 OASL:RAF1 
                 0.877 
               
               
                   
                 OASL:SERINC5 
                 0.877 
               
               
                   
                 OASL:UBQLN2 
                 0.877 
               
               
                   
                 OASL:XPO6 
                 0.877 
               
               
                   
                 OASL:ATP6V1B2 
                 0.876 
               
               
                   
                 OASL:CSF2RB 
                 0.876 
               
               
                   
                 OASL:GYPC 
                 0.876 
               
               
                   
                 OASL:IL4R 
                 0.876 
               
               
                   
                 OASL:MMP25 
                 0.876 
               
               
                   
                 OASL:PSEN1 
                 0.876 
               
               
                   
                 OASL:SH2B3 
                 0.876 
               
               
                   
                 OASL:STAT5A 
                 0.876 
               
               
                   
                 ISG15:IL16 
                 0.875 
               
               
                   
                 MX1:LEF1 
                 0.875 
               
               
                   
                 OASL:CAMK2G 
                 0.875 
               
               
                   
                 OASL:ETS2 
                 0.875 
               
               
                   
                 OASL:POLB 
                 0.875 
               
               
                   
                 OASL:STK38L 
                 0.875 
               
               
                   
                 OASL:TFE3 
                 0.875 
               
               
                   
                 OASL:ICAM3 
                 0.874 
               
               
                   
                 OASL:ITGB2 
                 0.874 
               
               
                   
                 OASL:PISD 
                 0.874 
               
               
                   
                 OASL:PLXNC1 
                 0.874 
               
               
                   
                 OASL:SNX27 
                 0.874 
               
               
                   
                 OASL:TNIP1 
                 0.874 
               
               
                   
                 OASL:ZMIZ1 
                 0.874 
               
               
                   
                 OASL:FOXO3 
                 0.873 
               
               
                   
                 OASL:IL10RB 
                 0.873 
               
               
                   
                 OASL:MAP3K5 
                 0.873 
               
               
                   
                 OASL:POLD4 
                 0.873 
               
               
                   
                 OASL:ARAP1 
                 0.872 
               
               
                   
                 OASL:CTBP2 
                 0.872 
               
               
                   
                 OASL:DGKA 
                 0.872 
               
               
                   
                 OASL:NFYA 
                 0.872 
               
               
                   
                 OASL:PCNX 
                 0.872 
               
               
                   
                 OASL:PFDN5 
                 0.872 
               
               
                   
                 OASL:R3HDM2 
                 0.872 
               
               
                   
                 OASL:STX6 
                 0.872 
               
               
                   
                 EIF2AK2:SYPL1 
                 0.871 
               
               
                   
                 ISG15:ABLIM1 
                 0.871 
               
               
                   
                 OASL:FOXJ2 
                 0.871 
               
               
                   
                 OASL:IQSEC1 
                 0.871 
               
               
                   
                 OASL:LRMP 
                 0.871 
               
               
                   
                 OASL:NAB1 
                 0.871 
               
               
                   
                 OASL:RAB31 
                 0.871 
               
               
                   
                 OASL:WASF2 
                 0.871 
               
               
                   
                 OASL:ZNF274 
                 0.871 
               
               
                   
                 OAS2:LEF1 
                 0.87 
               
               
                   
                 OASL:BRD1 
                 0.87 
               
               
                   
                 OASL:GNAQ 
                 0.87 
               
               
                   
                 OASL:GSK3B 
                 0.87 
               
               
                   
                 OASL:IL6R 
                 0.87 
               
               
                   
                 OASL:MAPK14 
                 0.87 
               
               
                   
                 USP18:TGFBR2 
                 0.87 
               
               
                   
                 ISG15:LTB 
                 0.869 
               
               
                   
                 OASL:INPP5D 
                 0.869 
               
               
                   
                 OASL:MED13 
                 0.869 
               
               
                   
                 OASL:MORC3 
                 0.869 
               
               
                   
                 OASL:PTAFR 
                 0.869 
               
               
                   
                 OASL:RBM23 
                 0.869 
               
               
                   
                 OASL:SNN 
                 0.869 
               
               
                   
                 OASL:ST13 
                 0.869 
               
               
                   
                 OASL:TFEB 
                 0.869 
               
               
                   
                 OASL:ZFYVE16 
                 0.869 
               
               
                   
                 EIF2AK2:SATB1 
                 0.868 
               
               
                   
                 OASL:ABAT 
                 0.868 
               
               
                   
                 OASL:ABI1 
                 0.868 
               
               
                   
                 OASL:ACVR1B 
                 0.868 
               
               
                   
                 OASL:GPSM3 
                 0.868 
               
               
                   
                 OASL:MPPE1 
                 0.868 
               
               
                   
                 OASL:PTEN 
                 0.868 
               
               
                   
                 OASL:SEC62 
                 0.868 
               
               
                   
                 IFI6:MYC 
                 0.867 
               
               
                   
                 IFI6:PCF11 
                 0.867 
               
               
                   
                 OASL:AIF1 
                 0.867 
               
               
                   
                 OASL:CSNK1D 
                 0.867 
               
               
                   
                 OASL:GABARAP 
                 0.867 
               
               
                   
                 OASL:HAL 
                 0.867 
               
               
                   
                 OASL:LAPTM5 
                 0.867 
               
               
                   
                 OASL:XPC 
                 0.867 
               
               
                   
                 USP18:NFKB1 
                 0.867 
               
               
                   
                 OASL:ACAP2 
                 0.866 
               
               
                   
                 OASL:CLEC4A 
                 0.866 
               
               
                   
                 OASL:HIP1 
                 0.866 
               
               
                   
                 OASL:PIAS1 
                 0.866 
               
               
                   
                 OASL:PPP3R1 
                 0.866 
               
               
                   
                 OASL:RALB 
                 0.866 
               
               
                   
                 OASL:RGS19 
                 0.866 
               
               
                   
                 OASL:TRIOBP 
                 0.866 
               
               
                   
                 EIF2AK2:PDE3B 
                 0.865 
               
               
                   
                 OASL:NCOA4 
                 0.865 
               
               
                   
                 OASL:RARA 
                 0.865 
               
               
                   
                 OASL:RPS6KA3 
                 0.865 
               
               
                   
                 OASL:SIRPA 
                 0.865 
               
               
                   
                 OASL:TLE3 
                 0.865 
               
               
                   
                 OASL:TNFRSF1A 
                 0.865 
               
               
                   
                 DDX60:TGFBR2 
                 0.864 
               
               
                   
                 OASL:FLOT2 
                 0.864 
               
               
                   
                 OASL:FNBP1 
                 0.864 
               
               
                   
                 OASL:MAP3K3 
                 0.864 
               
               
                   
                 OASL:STX10 
                 0.864 
               
               
                   
                 OASL:ZDHHC18 
                 0.864 
               
               
                   
                 OASL:ZNF143 
                 0.864 
               
               
                   
                 TAP1:TGFBR2 
                 0.864 
               
               
                   
                 OAS2:ABLIM1 
                 0.863 
               
               
                   
                 OASL:ARRB2 
                 0.863 
               
               
                   
                 OASL:IKBKB 
                 0.863 
               
               
                   
                 OASL:KBTBD2 
                 0.863 
               
               
                   
                 OASL:PHC2 
                 0.863 
               
               
                   
                 OASL:PUM2 
                 0.863 
               
               
                   
                 OASL:SSFA2 
                 0.863 
               
               
                   
                 IFI44:MYC 
                 0.862 
               
               
                   
                 OASL:ABHD2 
                 0.862 
               
               
                   
                 OASL:CYLD 
                 0.862 
               
               
                   
                 OASL:MAST3 
                 0.862 
               
               
                   
                 OASL:UBN1 
                 0.862 
               
               
                   
                 IFI6:IL6ST 
                 0.861 
               
               
                   
                 IFIH1:TGFBR2 
                 0.861 
               
               
                   
                 OASL:CNPY3 
                 0.861 
               
               
                   
                 OASL:KIAA0232 
                 0.861 
               
               
                   
                 USP18:CHMP7 
                 0.861 
               
               
                   
                 USP18:NECAP2 
                 0.861 
               
               
                   
                 OASL:CAP1 
                 0.86 
               
               
                   
                 OASL:HPS1 
                 0.86 
               
               
                   
                 OASL:IL1RAP 
                 0.86 
               
               
                   
                 OASL:MEF2A 
                 0.86 
               
               
                   
                 OASL:RNF19B 
                 0.86 
               
               
                   
                 OASL:TMEM127 
                 0.86 
               
               
                   
                 USP18:IL27RA 
                 0.86 
               
               
                   
                 OASL:CDIPT 
                 0.859 
               
               
                   
                 OASL:CREB1 
                 0.859 
               
               
                   
                 OASL:GPS2 
                 0.859 
               
               
                   
                 OASL:NDE1 
                 0.859 
               
               
                   
                 OASL:RAB11FIP1 
                 0.859 
               
               
                   
                 USP18:ABLIM1 
                 0.859 
               
               
                   
                 EIF2AK2:TNRC6B 
                 0.858 
               
               
                   
                 OASL:FAM134A 
                 0.858 
               
               
                   
                 OASL:FCGRT 
                 0.858 
               
               
                   
                 OASL:LPIN2 
                 0.858 
               
               
                   
                 OASL:PECAM1 
                 0.858 
               
               
                   
                 OASL:WBP2 
                 0.858 
               
               
                   
                 OASL:ZNF148 
                 0.858 
               
               
                   
                 OASL:RTN3 
                 0.857 
               
               
                   
                 OASL:TYK2 
                 0.857 
               
               
                   
                 USP18:LTB 
                 0.857 
               
               
                   
                 DHX58:IL16 
                 0.856 
               
               
                   
                 ISG15:IL4R 
                 0.856 
               
               
                   
                 OASL:BRD4 
                 0.856 
               
               
                   
                 OASL:CCNT2 
                 0.856 
               
               
                   
                 OASL:FGR 
                 0.856 
               
               
                   
                 OASL:ITSN2 
                 0.856 
               
               
                   
                 OASL:LYL1 
                 0.856 
               
               
                   
                 OASL:PHF3 
                 0.856 
               
               
                   
                 OASL:PSAP 
                 0.856 
               
               
                   
                 OASL:STX3 
                 0.856 
               
               
                   
                 OASL:TNK2 
                 0.856 
               
               
                   
                 EIF2AK2:ZNF274 
                 0.855 
               
               
                   
                 OASL:ACAA1 
                 0.855 
               
               
                   
                 OASL:CHD3 
                 0.855 
               
               
                   
                 OASL:FRY 
                 0.855 
               
               
                   
                 OASL:GRB2 
                 0.855 
               
               
                   
                 OASL:MAP3K11 
                 0.855 
               
               
                   
                 OASL:NEK7 
                 0.855 
               
               
                   
                 OASL:PPP2R5A 
                 0.855 
               
               
                   
                 USP18:ST13 
                 0.855 
               
               
                   
                 XAF1:LEF1 
                 0.855 
               
               
                   
                 OASL:CASP8 
                 0.854 
               
               
                   
                 OASL:PCF11 
                 0.854 
               
               
                   
                 OASL:PRKCD 
                 0.854 
               
               
                   
                 OASL:PSTPIP1 
                 0.854 
               
               
                   
                 OASL:SLCO3A1 
                 0.854 
               
               
                   
                 OASL:ZDHHC17 
                 0.854 
               
               
                   
                 USP18:FOXO1 
                 0.854 
               
               
                   
                 OASL:ASAP1 
                 0.853 
               
               
                   
                 OASL:BAZ2B 
                 0.853 
               
               
                   
                 OASL:FAM65B 
                 0.853 
               
               
                   
                 OASL:HHEX 
                 0.853 
               
               
                   
                 OASL:MAX 
                 0.853 
               
               
                   
                 OASL:PHF2 
                 0.853 
               
               
                   
                 OASL:RNF130 
                 0.853 
               
               
                   
                 OASL:SOS2 
                 0.853 
               
               
                   
                 OASL:STAM2 
                 0.853 
               
               
                   
                 OASL:ZFC3H1 
                 0.853 
               
               
                   
                 IFI44:CYLD 
                 0.852 
               
               
                   
                 IFIH1:CRLF3 
                 0.852 
               
               
                   
                 OASL:BANP 
                 0.852 
               
               
                   
                 OASL:CCND3 
                 0.852 
               
               
                   
                 OASL:DGCR2 
                 0.852 
               
               
                   
                 OASL:USP15 
                 0.852 
               
               
                   
                 USP18:EIF3H 
                 0.852 
               
               
                   
                 OASL:LAT2 
                 0.851 
               
               
                   
                 OASL:ZYX 
                 0.851 
               
               
                   
                 USP18:CAMK1D 
                 0.851 
               
               
                   
                 ZBP1:NDE1 
                 0.851 
               
               
                   
                 EIF2AK2:IL4R 
                 0.85 
               
               
                   
                 IFI44:SESN1 
                 0.85 
               
               
                   
                 OASL:CD37 
                 0.85 
               
               
                   
                 OASL:CST3 
                 0.85 
               
               
                   
                 OASL:DPEP2 
                 0.85 
               
               
                   
                 OASL:MYC 
                 0.85 
               
               
                   
                 OASL:RERE 
                 0.85 
               
               
                   
                 OASL:USP10 
                 0.85 
               
               
                   
                 USP18:LEF1 
                 0.85 
               
               
                   
                 OASL:MXI1 
                 0.849 
               
               
                   
                 OASL:PRUNE 
                 0.849 
               
               
                   
                 OASL:VPS8 
                 0.849 
               
               
                   
                 OASL:CYTH4 
                 0.848 
               
               
                   
                 OASL:FBXO11 
                 0.848 
               
               
                   
                 OASL:PRKAA1 
                 0.848 
               
               
                   
                 OASL:SERINC3 
                 0.848 
               
               
                   
                 OASL:UBXN2B 
                 0.848 
               
               
                   
                 USP18:DPF2 
                 0.848 
               
               
                   
                 USP18:NACA 
                 0.848 
               
               
                   
                 USP18:SYPL1 
                 0.848 
               
               
                   
                 ISG15:DGKA 
                 0.847 
               
               
                   
                 OASL:MARK3 
                 0.847 
               
               
                   
                 USP18:DIDO1 
                 0.846 
               
               
                   
                 CUL1:IL16 
                 0.845 
               
               
                   
                 OASL:DOCK9 
                 0.845 
               
               
                   
                 USP18:PIK3IP1 
                 0.845 
               
               
                   
                 OASL:FBXO9 
                 0.844 
               
               
                   
                 OASL:MKLN1 
                 0.844 
               
               
                   
                 OASL:PPP1R11 
                 0.844 
               
               
                   
                 USP18:DGKA 
                 0.844 
               
               
                   
                 USP18:ZNF274 
                 0.844 
               
               
                   
                 OASL:POLR1D 
                 0.843 
               
               
                   
                 OASL:SETD2 
                 0.843 
               
               
                   
                 DDX60:ABLIM1 
                 0.842 
               
               
                   
                 OASL:ARHGAP15 
                 0.842 
               
               
                   
                 OASL:BCL2 
                 0.842 
               
               
                   
                 OASL:GOLGA7 
                 0.842 
               
               
                   
                 OASL:KIAA0513 
                 0.842 
               
               
                   
                 OASL:MARCH7 
                 0.842 
               
               
                   
                 USP18:LDLRAP1 
                 0.842 
               
               
                   
                 C19orf66:IL16 
                 0.841 
               
               
                   
                 OASL:ARRB1 
                 0.841 
               
               
                   
                 OASL:BMP2K 
                 0.841 
               
               
                   
                 OASL:LIMK2 
                 0.841 
               
               
                   
                 OASL:RNASET2 
                 0.841 
               
               
                   
                 USP18:ATM 
                 0.841 
               
               
                   
                 USP18:CYLD 
                 0.841 
               
               
                   
                 USP18:NOSIP 
                 0.841 
               
               
                   
                 OASL:TNFSF13 
                 0.84 
               
               
                   
                 OASL:TRIM8 
                 0.84 
               
               
                   
                 XAF1:IL4R 
                 0.84 
               
               
                   
                 DHX58:ABLIM1 
                 0.839 
               
               
                   
                 OASL:MANSC1 
                 0.839 
               
               
                   
                 OASL:MAP1LC3B 
                 0.839 
               
               
                   
                 OASL:OSBPL2 
                 0.839 
               
               
                   
                 OASL:RAB7A 
                 0.839 
               
               
                   
                 EIF2AK2:ZFC3H1 
                 0.838 
               
               
                   
                 IFIH1:LTB 
                 0.838 
               
               
                   
                 OASL:FES 
                 0.838 
               
               
                   
                 OASL:HGSNAT 
                 0.838 
               
               
                   
                 OASL:KLF6 
                 0.838 
               
               
                   
                 OASL:TM2D3 
                 0.838 
               
               
                   
                 OASL:KLHL2 
                 0.837 
               
               
                   
                 OASL:MAPRE2 
                 0.837 
               
               
                   
                 OASL:RNF146 
                 0.837 
               
               
                   
                 USP18:RPL22 
                 0.837 
               
               
                   
                 DHX58:LTB 
                 0.836 
               
               
                   
                 OASL:GMIP 
                 0.836 
               
               
                   
                 DDX60:SYPL1 
                 0.835 
               
               
                   
                 EIF2AK2:IL6ST 
                 0.835 
               
               
                   
                 EIF2AK2:PCF11 
                 0.835 
               
               
                   
                 ISG15:NOSIP 
                 0.835 
               
               
                   
                 OASL:NRBF2 
                 0.835 
               
               
                   
                 OASL:RNF141 
                 0.835 
               
               
                   
                 OASL:VAV3 
                 0.835 
               
               
                   
                 OASL:ZFAND5 
                 0.835 
               
               
                   
                 USP18:NDFIP1 
                 0.835 
               
               
                   
                 USP18:TMEM204 
                 0.835 
               
               
                   
                 USP18:UBE2D2 
                 0.835 
               
               
                   
                 OASL:CAMK1D 
                 0.834 
               
               
                   
                 OASL:CLK4 
                 0.834 
               
               
                   
                 OASL:MCTP2 
                 0.834 
               
               
                   
                 OASL:MOSPD2 
                 0.834 
               
               
                   
                 OASL:TSC22D3 
                 0.834 
               
               
                   
                 USP18:CRLF3 
                 0.834 
               
               
                   
                 USP18:SESN1 
                 0.834 
               
               
                   
                 USP18:ZC3HAV1 
                 0.834 
               
               
                   
                 OASL:MSL1 
                 0.833 
               
               
                   
                 OASL:TREM1 
                 0.833 
               
               
                   
                 OASL:YPEL5 
                 0.833 
               
               
                   
                 USP18:CIAPIN1 
                 0.833 
               
               
                   
                 USP18:PDCD6IP 
                 0.833 
               
               
                   
                 HERC5:ABLIM1 
                 0.832 
               
               
                   
                 OASL:OSBPL11 
                 0.832 
               
               
                   
                 OASL:PLEKHO1 
                 0.832 
               
               
                   
                 USP18:CRTC3 
                 0.832 
               
               
                   
                 HERC6:ATM 
                 0.831 
               
               
                   
                 ISG15:SESN1 
                 0.831 
               
               
                   
                 OAS2:MYC 
                 0.831 
               
               
                   
                 OASL:OGFRL1 
                 0.831 
               
               
                   
                 OASL:ZXDC 
                 0.831 
               
               
                   
                 USP18:CCR7 
                 0.831 
               
               
                   
                 OASL:APBB1IP 
                 0.83 
               
               
                   
                 OASL:CHST11 
                 0.83 
               
               
                   
                 OASL:GPBP1L1 
                 0.83 
               
               
                   
                 USP18:SSBP2 
                 0.83 
               
               
                   
                 OASL:RC3H2 
                 0.829 
               
               
                   
                 USP18:UTP14A 
                 0.829 
               
               
                   
                 OASL:GCC2 
                 0.828 
               
               
                   
                 USP18:LRMP 
                 0.828 
               
               
                   
                 USP18:TRIB2 
                 0.828 
               
               
                   
                 OASL:GPR97 
                 0.827 
               
               
                   
                 EIF2AK2:BTG1 
                 0.826 
               
               
                   
                 EIF2AK2:CYLD 
                 0.826 
               
               
                   
                 OASL:PAFAH1B1 
                 0.826 
               
               
                   
                 USP18:BTG1 
                 0.826 
               
               
                   
                 USP18:NCBP2 
                 0.826 
               
               
                   
                 USP18:PPP1R2 
                 0.826 
               
               
                   
                 LAP3:MAP4K4 
                 0.825 
               
               
                   
                 OASL:ERBB2IP 
                 0.825 
               
               
                   
                 OASL:NOD2 
                 0.825 
               
               
                   
                 OASL:RIN3 
                 0.825 
               
               
                   
                 OASL:TMBIM1 
                 0.825 
               
               
                   
                 ZBP1:XPO6 
                 0.825 
               
               
                   
                 ISG15:LDLRAP1 
                 0.824 
               
               
                   
                 OASL:CHMP1B 
                 0.824 
               
               
                   
                 OASL:LILRB3 
                 0.824 
               
               
                   
                 OASL:PHF20L1 
                 0.823 
               
               
                   
                 USP18:PCF11 
                 0.823 
               
               
                   
                 OASL:ANKRD49 
                 0.822 
               
               
                   
                 OASL:DOK3 
                 0.822 
               
               
                   
                 OASL:PRKAG2 
                 0.822 
               
               
                   
                 OASL:SOAT1 
                 0.822 
               
               
                   
                 USP18:IL6ST 
                 0.822 
               
               
                   
                 USP18:RPL10A 
                 0.822 
               
               
                   
                 LAP3:SYPL1 
                 0.82 
               
               
                   
                 OASL:MARCH8 
                 0.819 
               
               
                   
                 TAP1:TNRC6B 
                 0.819 
               
               
                   
                 OASL:KLF3 
                 0.818 
               
               
                   
                 PHF11:ZNF274 
                 0.818 
               
               
                   
                 OASL:PGS1 
                 0.817 
               
               
                   
                 OASL:ZNF238 
                 0.817 
               
               
                   
                 STAT1:PCBP2 
                 0.817 
               
               
                   
                 OASL:SH2D3C 
                 0.816 
               
               
                   
                 USP18:SAFB2 
                 0.816 
               
               
                   
                 EIF2AK2:CAMK1D 
                 0.815 
               
               
                   
                 LAP3:CNPY3 
                 0.815 
               
               
                   
                 LAP3:NDFIP1 
                 0.815 
               
               
                   
                 LAP3:TRAK1 
                 0.815 
               
               
                   
                 OASL:NPL 
                 0.815 
               
               
                   
                 OASL:NSUN3 
                 0.815 
               
               
                   
                 OASL:ATAD2B 
                 0.814 
               
               
                   
                 ZBP1:KLF7 
                 0.813 
               
               
                   
                 ZBP1:PCF11 
                 0.813 
               
               
                   
                 LAP3:ABLIM1 
                 0.812 
               
               
                   
                 OASL:CSAD 
                 0.812 
               
               
                   
                 PHF11:IL16 
                 0.812 
               
               
                   
                 USP18:BEX4 
                 0.812 
               
               
                   
                 USP18:METTL3 
                 0.812 
               
               
                   
                 RTP4:ABLIM1 
                 0.811 
               
               
                   
                 HERC6:MYC 
                 0.81 
               
               
                   
                 USP18:ALDH3A2 
                 0.81 
               
               
                   
                 OASL:RAB4B 
                 0.809 
               
               
                   
                 USP18:ATF7IP2 
                 0.809 
               
               
                   
                 TAP1:TGOLN2 
                 0.807 
               
               
                   
                 PARP12:ABLIM1 
                 0.806 
               
               
                   
                 RSAD2:CAMK1D 
                 0.806 
               
               
                   
                 ZBP1:CYLD 
                 0.806 
               
               
                   
                 STAT1:FBXO11 
                 0.805 
               
               
                   
                 ZBP1:ZFC3H1 
                 0.805 
               
               
                   
                 OASL:SIRPB1 
                 0.804 
               
               
                   
                 OASL:C2orf68 
                 0.802 
               
               
                   
                 RTP4:SYPL1 
                 0.802 
               
               
                   
                 LAP3:JAK1 
                 0.801 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 DETAILS OF GENE EXPRESSION OMNIBUS 
               
               
                 (GEO) DATASETS USED FOR DISCOVERY 
               
               
                 OF PROTOZOAL DERIVED BIOMARKER 
               
            
           
           
               
               
               
               
               
               
            
               
                 Dataset 
                 Group 
                 Case 
                 Controls 
                 Total # 
                 Genes 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GSE34404 
                 Malaria 
                 42 
                 61 
                 103 
                 21511 
               
               
                 GSE64610 
                 
                   Leishmania 
                 
                 10 
                 5 
                 15 
                 6805 
               
               
                 GSE15221 
                 Malaria 
                 14 
                 14 
                 28 
                 36292 
               
               
                 GSE5418 
                 Malaria 
                 15 
                 22 
                 37 
                 12439 
               
               
                 Merged Data 
                 All 
                 86 
                 107 
                 193 
                 4421 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 DESCRIPTION OF THE GEO DATASETS USED FOR VALIDATION 
               
               
                 OF THE PROTOZOAL DERIVED BIOMARKERS 
               
            
           
           
               
               
               
               
            
               
                 GEO 
                   
                   
                   
               
               
                 Dataset 
                 Organism 
                 Tissue 
                 Study Description 
               
               
                   
               
               
                 GSE43661 
                 
                   Leishmania 
                 
                 Macrophages, 
                 3 donors, cultured cells either infected with 
               
               
                   
                 
                   major 
                 
                 in vitro 
                   Leishmania  or not. Samples taken at 0, 3, 
               
               
                   
                   
                   
                 6, 12 and 24 hours 
               
               
                 GSE23750 
                 
                   Entamoeba 
                 
                 Intestinal 
                 8 donors, samples taken on Day 1 and 60, 
               
               
                   
                 
                   histolytica 
                 
                 biopsies 
                 pre- and post-treatment 
               
               
                 GSE7047 
                 
                   Trypanosoma 
                 
                 HeLa cells, 
                 3 replicates of cells either infected or not 
               
               
                   
                 
                   cruzi 
                 
                 in vitro 
               
               
                 GSE50957 
                 
                   Plasmodium 
                 
                 Peripheral 
                 Pilot study: 5 donors, samples taken pre- 
               
               
                   
                 
                   falciparum 
                 
                 blood 
                 and post- being bitten by infected mosquitos. 
               
               
                   
                   
                   
                 All donors were on chloroquin treatment 
               
               
                 GSE52166 
                 
                   Plasmodium 
                 
                 Peripheral 
                 Large study, as per GSE50957 
               
               
                   
                 
                   falciparum 
                 
                 blood 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 DESCRIPTION OF CONTROL DATASETS 
               
               
                 USED FOR SUBTRACTION FROM THE 
               
               
                 DERIVED BIOMARKERS FOR PASIRS 
               
               
                 The subtraction process ensured that the 
               
               
                 PaSIRS derived biomarkers were specific. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Dataset 
                 Case 
                 Controls 
                 Total # 
                 Genes 
                 Response 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GSE40366 
                 69 
                 17 
                 86 
                 20293 
                 Viral 
               
               
                 GSE38485 
                 106 
                 96 
                 202 
                 19206 
                 SIRS 
               
               
                 GSE46743 
                 160 
                 160 
                 320 
                 9595 
                 SIRS 
               
               
                 GSE64813 
                 47 
                 141 
                 188 
                 10146 
                 SIRS 
               
               
                 GSE17755 
                 191 
                 53 
                 244 
                 6620 
                 SIRS 
               
               
                 GSE41752 
                 19 
                 11 
                 30 
                 18515 
                 Viral 
               
               
                 GSE29532 
                 25 
                 6 
                 31 
                 14332 
                 SIRS 
               
               
                 GSE51808 
                 28 
                 9 
                 37 
                 18353 
                 Viral 
               
               
                 GSE19301 
                 166 
                 394 
                 560 
                 12631 
                 SIRS 
               
               
                 GSE52428 
                 41 
                 39 
                 80 
                 12631 
                 Viral 
               
               
                 GSE11908 
                 40 
                 196 
                 236 
                 12631 
                 Bacterial 
               
               
                 GSE47655 
                 1 
                 35 
                 36 
                 5196 
                 SIRS 
               
               
                 GSE25504 
                 26 
                 37 
                 63 
                 13510 
                 Bacterial 
               
               
                 GSE61672 
                 157 
                 179 
                 336 
                 9291 
                 SIRS 
               
               
                 GSE35846 
                 124 
                 65 
                 189 
                 10330 
                 Gender 
               
               
                 GSE33341 
                 51 
                 43 
                 94 
                 12631 
                 Bacterial 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 DESCRIPTION OF DATASETS USED FOR 
               
               
                 DISCOVERY, VALIDATION AND SUBTRACTION 
               
               
                 FROM THE DERIVED BIOMARKERS FOR INSIRS. 
               
               
                 The subtraction process ensured that the 
               
               
                 InSIRS derived biomarkers were specific. 
               
            
           
           
               
               
               
            
               
                 Dataset 
                 Description 
                 How Used 
               
               
                   
               
               
                 GAPPSS 
                 In-house clinical trial. Pediatric patients 
                 Discovery/Validation 
               
               
                   
                 in ICU. Post-surgical vs confirmed sepsis 
               
               
                 GSE17755 
                 Autoimmune disease vs infected 
                 Discovery/Validation 
               
               
                 GSE36809 
                 Trauma (non-infected early stage vs 
                 Discovery/Validation 
               
               
                   
                 infected) 
               
               
                 GSE47655 
                 Anaphylaxis (presentation vs resolved) 
                 Discovery/Validation 
               
               
                 GSE63990 
                 Acute respiratory inflammation 
                 Discovery/Validation 
               
               
                   
                 (infected vs non-infected) 
               
               
                 GSE74224 
                 Sepsis vs SIRS (in-house data) 
                 Discovery/Validation 
               
               
                 GSE11908 
                 Autoimmune disease, cancer, liver 
                 Control/Subtraction 
               
               
                   
                 cirrhosis vs infected 
               
               
                 GSE19301 
                 Asthma (exacerbation vs quiescent) 
                 Control/Subtraction 
               
               
                 GSE38485 
                 Schizophrenia vs healthy control 
                 Control/Subtraction 
               
               
                 GSE41752 
                 Lassa virus infection vs healthy 
                 Control/Subtraction 
               
               
                 GSE42834 
                 Tuberculosis vs sarcoidosis 
                 Control/Subtraction 
               
               
                 GSE51808 
                 Dengue virus vs healthy control 
                 Control/Subtraction 
               
               
                 GSE52428 
                 Influenza virus vs healthy control 
                 Control/Subtraction 
               
               
                 GSE61672 
                 Anxiety vs healthy control 
                 Control/Subtraction 
               
               
                 GSE64813 
                 Post-traumatic stress disorder vs 
                 Control/Subtraction 
               
               
                   
                 pre-stress 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 DERIVED BIOMARKERS GROUPED (A, B, C, D) BASED ON  
               
               
                 CORRELATION TO EACH OF THE BIOMARKERS IN THE  
               
               
                 FINAL BASIRS SIGNATURE (OPLAH, ZHX2, TSPO, HCLS1) 
               
            
           
           
               
               
               
               
            
               
                 Group A 
                 Group B 
                 Group C 
                 Group D 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Corre- 
                   
                   
                 Corre- 
                   
                   
                 Corre- 
                   
                   
                 Corre- 
                   
                   
               
               
                 lation 
                 HUGO  
                 DNA  
                 lation 
                 HUGO  
                 DNA  
                 lation 
                 HUGO 
                 DNA  
                 lation 
                 HUGO  
                 DNA  
               
               
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ  
                 to  
                 Gene 
                 SEQ  
                 to  
                 Gene 
                 SEQ  
               
               
                 OPLAH 
                 Symbol 
                 ID 
                 ZHX2 
                 Symbol 
                 ID 
                 TSPO 
                 Symbol 
                 ID 
                 HCLS1 
                 Symbol 
                 ID 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 0.703 
                 ENTPD7 
                 15 
                 0.474 
                 SAP130 
                 79 
                 0.789 
                 HK3 
                 29 
                 0.490 
                 SEMA4D 
                 80 
               
               
                 0.678 
                 PCOLCE2 
                 59 
                 0.468 
                 NLRP1 
                 53 
                 0.770 
                 RAB32 
                 72 
                 0.488 
                 INPP5D 
                 36 
               
               
                 0.656 
                 ITGA7 
                 37 
                 0.440 
                 CNNM3 
                 10 
                 0.763 
                 IMPDH1 
                 35 
                 0.381 
                 ZFP36L2 
                 93 
               
               
                 0.611 
                 PDGFC 
                 60 
                 0.427 
                 POGZ 
                 65 
                 0.703 
                 FAM129A 
                 18 
                 0.337 
                 CLEC7A 
                 9 
               
               
                 0.590 
                 SMPDL3A 
                 82 
                 0.387 
                 GRK5 
                 26 
                 0.661 
                 GAS7 
                 24 
                 0.321 
                 RNASE6 
                 76 
               
               
                 0.531 
                 GALNT2 
                 23 
                 0.375 
                 IL2RB 
                 34 
                 0.622 
                 CD82 
                 8 
                 0.292 
                 MME 
                 50 
               
               
                 0.465 
                 CR1 
                 12 
                 0.357 
                 NPAT 
                 56 
                 0.599 
                 ADM 
                 2 
                 0.291 
                 PARP8 
                 58 
               
               
                 0.458 
                 IGFBP7 
                 31 
                 0.352 
                 PRKD2 
                 66 
                 0.563 
                 IK 
                 32 
                 0.242 
                 NCOA6 
                 51 
               
               
                 0.441 
                 FIG4 
                 20 
                 0.350 
                 FOXJ3 
                 21 
                 0.525 
                 ALPL 
                 3 
                 0.127 
                 LPIN2 
                 46 
               
               
                 0.404 
                 COX15 
                 11 
                 0.335 
                 JARID2 
                 38 
                 0.519 
                 TLR5 
                 88 
                   
                   
                   
               
               
                 0.386 
                 NMUR1 
                 54 
                 0.323 
                 RBM23 
                 74 
                 0.484 
                 DENND3 
                 13 
                   
                   
                   
               
               
                 0.364 
                 MCTP1 
                 48 
                 0.318 
                 PRKDC 
                 67 
                 0.470 
                 MGAM 
                 49 
                   
                   
                   
               
               
                 0.348 
                 EPHB4 
                 16 
                 0.310 
                 TGFBR3 
                 86 
                 0.435 
                 TMEM165 
                 89 
                   
                   
                   
               
               
                 0.302 
                 ICK 
                 30 
                 0.308 
                 SIDT1 
                 81 
                 0.409 
                 PRPF38B 
                 68 
                   
                   
                   
               
               
                 0.218 
                 MBIP 
                 47 
                 0.305 
                 TLE3 
                 87 
                 0.402 
                 EXTL3 
                 17 
                   
                   
                   
               
               
                 0.155 
                 PDS5B 
                 61 
                 0.296 
                 QRICH1 
                 71 
                 0.352 
                 ADAM19 
                 1 
                   
                   
                   
               
               
                 0.082 
                 IKZF5 
                 33 
                 0.286 
                 KLRD1 
                 42 
                 0.335 
                 ST3GAL2 
                 84 
                   
                   
                   
               
               
                 0.046 
                 KIAA0101 
                 39 
                 0.267 
                 NFIC 
                 52 
                 0.330 
                 CAMK1D 
                 4 
                   
                   
                   
               
               
                   
                   
                   
                 0.265 
                 HAL 
                 27 
                 0.310 
                 DOCK5 
                 14 
                   
                   
                   
               
               
                   
                   
                   
                 0.260 
                 RBM15 
                 73 
                 0.290 
                 GAB2 
                 22 
                   
                   
                   
               
               
                   
                   
                   
                 0.258 
                 KIAA0355 
                 40 
                 0.283 
                 CCNK 
                 7 
                   
                   
                   
               
               
                   
                   
                   
                 0.255 
                 CBLL1 
                 6 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.251 
                 PYHIN1 
                 70 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.249 
                 KIAA0907 
                 41 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.217 
                 RFC1 
                 75 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.210 
                 KLRF1 
                 43 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.205 
                 SPIN1 
                 83 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.198 
                 PHF3 
                 62 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.196 
                 UTRN 
                 91 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.190 
                 RUNX2 
                 77 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.184 
                 PRSS23 
                 69 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.178 
                 NOV 
                 55 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.177 
                 RYK 
                 78 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.176 
                 LEPROTL1 
                 45 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.174 
                 CASS4 
                 5 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.164 
                 GCC2 
                 25 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.146 
                 PLA2G7 
                 64 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.141 
                 FBXO28 
                 19 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.140 
                 YPEL1 
                 92 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.134 
                 PIK3C2A 
                 63 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.133 
                 LAG3 
                 44 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 0.120 
                 SYTL2 
                 85 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 DERIVED BIOMARKERS GROUPED (A, B, C, D) BASED ON CORRELATION TO EACH OF THE 
               
               
                 BIOMARKErS IN THE FINAL VASIRS SIGNATURE (ISG15, IL16, OASL ADGRE5) 
               
            
           
           
               
               
               
               
            
               
                 Group A 
                 Group B 
                 Group C 
                 Group D 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Corre- 
                   
                   
                 Corre- 
                   
                   
                 Corre- 
                   
                   
                 Corre- 
                   
                   
               
               
                 lation  
                 HUGO 
                   
                 lation  
                 HUGO 
                   
                 lation  
                 HUGO  
                   
                 lation  
                 HUGO  
                   
               
               
                 to 
                 Gene 
                 SEQ  
                 to 
                 Gene 
                 SEQ  
                 to 
                 Gene 
                   
                 to 
                 Gene 
                   
               
               
                 ISG15 
                 Name 
                 ID 
                 IL16 
                 Name 
                 ID 
                 OASL 
                 Name 
                 SEQID 
                 ADGRE5 
                 Name 
                 SEQID 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1.000 
                 ISG15 
                 330 
                 1.000 
                 IL16 
                 322 
                 1.000 
                 OASL 
                 415 
                 1.000 
                 ADGRE5 
                 237 
               
               
                 0.915 
                 IFI44 
                 315 
                 0.661 
                 ITPKB 
                 333 
                 0.529 
                 N4BP1 
                 393 
                 0.634 
                 CYTH4 
                 261 
               
               
                 0.915 
                 RSAD2 
                 496 
                 0.600 
                 CAMK2G 
                 226 
                 0.460 
                 NOD2 
                 407 
                 0.599 
                 HCK 
                 306 
               
               
                 0.913 
                 HERC5 
                 307 
                 0.567 
                 CTDSP2 
                 258 
                 0.455 
                 RNF19B 
                 491 
                 0.582 
                 ARHGAP26 
                 205 
               
               
                 0.906 
                 MX1 
                 390 
                 0.555 
                 DPEP2 
                 270 
                 0.437 
                 PRKAG2 
                 456 
                 0.555 
                 RARA 
                 477 
               
               
                 0.895 
                 HERC6 
                 308 
                 0.551 
                 LTB 
                 358 
                 0.413 
                 IGSF6 
                 318 
                 0.547 
                 XPO6 
                 584 
               
               
                 0.894 
                 OA52 
                 414 
                 0.549 
                 CBX7 
                 230 
                 0.352 
                 MEF2A 
                 380 
                 0.534 
                 TNFRSF1A 
                 550 
               
               
                 0.894 
                 XAF1 
                 582 
                 0.535 
                 FNBP1 
                 286 
                 0.343 
                 LPIN2 
                 354 
                 0.527 
                 SLCO3A1 
                 514 
               
               
                 0.892 
                 IFI6 
                 316 
                 0.534 
                 FOXO1 
                 288 
                 0.341 
                 PPP1R11 
                 450 
                 0.526 
                 ICAM3 
                 314 
               
               
                 0.873 
                 PARP12 
                 421 
                 0.531 
                 MAST3 
                 375 
                 0.316 
                 USP15 
                 570 
                 0.521 
                 PTPN6 
                 466 
               
               
                 0.872 
                 EIF2AK2 
                 272 
                 0.529 
                 LDLRAP1 
                 348 
                 0.308 
                 BACH1 
                 214 
                 0.519 
                 PRKCD 
                 457 
               
               
                 0.849 
                 DHX58 
                 266 
                 0.529 
                 TMEM204 
                 549 
                 0.307 
                 SSFA2 
                 524 
                 0.518 
                 RAB11FIP1 
                 470 
               
               
                 0.844 
                 UBE2L6 
                 565 
                 0.526 
                 FAIM3 
                 277 
                 0.299 
                 MKLN1 
                 382 
                 0.514 
                 CSF2RB 
                 254 
               
               
                 0.838 
                 DDX60 
                 263 
                 0.516 
                 RGS14 
                 483 
                 0.270 
                 FYB 
                 291 
                 0.512 
                 LCP2 
                 347 
               
               
                 0.819 
                 USP18 
                 571 
                 0.516 
                 IKBKB 
                 319 
                 0.250 
                 NSUN3 
                 412 
                 0.509 
                 TYROBP 
                 563 
               
               
                 0.817 
                 RTP4 
                 498 
                 0.516 
                 ZXDC 
                 600 
                 0.232 
                 MAX 
                 376 
                 0.499 
                 PHC2 
                 431 
               
               
                 0.815 
                 PHF11 
                 432 
                 0.508 
                 PHF20 
                 434 
                 0.218 
                 STAM2 
                 527 
                 0.496 
                 RHOG 
                 485 
               
               
                 0.812 
                 IFIH1 
                 317 
                 0.507 
                 DGKA 
                 265 
                 0.209 
                 HHEX 
                 310 
                 0.496 
                 PSAP 
                 460 
               
               
                 0.792 
                 ZBP1 
                 587 
                 0.501 
                 XPC 
                 583 
                 0.207 
                 CLEC4A 
                 246 
                 0.496 
                 LYN 
                 360 
               
               
                 0.766 
                 STAT1 
                 528 
                 0.499 
                 PPARD 
                 448 
                 0.197 
                 ZFAND5 
                 592 
                 0.494 
                 TMEM127 
                 548 
               
               
                 0.765 
                 LAP3 
                 344 
                 0.499 
                 C2orf68 
                 224 
                 0.188 
                 ABI1 
                 191 
                 0.492 
                 LILRA2 
                 350 
               
               
                 0.755 
                 TAP1 
                 536 
                 0.494 
                 NLRP1 
                 406 
                 0.144 
                 MORC3 
                 385 
                 0.485 
                 AOAH 
                 199 
               
               
                 0.741 
                 C19orf66 
                 223 
                 0.488 
                 IL27RA 
                 324 
                 0.142 
                 RC3H2 
                 481 
                 0.476 
                 FGR 
                 284 
               
               
                 0.617 
                 CUL1 
                 259 
                 0.480 
                 ABLIM1 
                 192 
                 0.137 
                 MAP1LC3B 
                 364 
                 0.470 
                 PLEKHO2 
                 443 
               
               
                 0.453 
                 POLB 
                 445 
                 0.477 
                 JAK1 
                 335 
                 0.120 
                 TM2D3 
                 546 
                 0.470 
                 ARAP1 
                 202 
               
               
                 0.395 
                 ZC3HAV1 
                 589 
                 0.475 
                 METTL3 
                 381 
                 0.100 
                 CHST11 
                 244 
                 0.468 
                 RBM23 
                 479 
               
               
                   
                   
                   
                 0.474 
                 SAFB2 
                 501 
                 0.097 
                 NAB1 
                 394 
                 0.462 
                 PTPRE 
                 467 
               
               
                   
                   
                   
                 0.474 
                 PPM1F 
                 449 
                 0.014 
                 KLF3 
                 340 
                 0.459 
                 KLF6 
                 341 
               
               
                   
                   
                   
                 0.473 
                 TYK2 
                 562 
                 −0.030 
                 YPEL5 
                 585 
                 0.458 
                 LIMK2 
                 352 
               
               
                   
                   
                   
                 0.471 
                 BANP 
                 215 
                 −0.063 
                 MXI1 
                 391 
                 0.456 
                 LILRB3 
                 351 
               
               
                   
                   
                   
                 0.470 
                 CRTC3 
                 252 
                   
                   
                   
                 0.454 
                 TLR2 
                 545 
               
               
                   
                   
                   
                 0.468 
                 ATM 
                 212 
                   
                   
                   
                 0.451 
                 GPR97 
                 299 
               
               
                   
                   
                   
                 0.453 
                 PAFAH1B1 
                 420 
                   
                   
                   
                 0.451 
                 GMIP 
                 294 
               
               
                   
                   
                   
                 0.447 
                 PIK3IP1 
                 438 
                   
                   
                   
                 0.446 
                 SIRPA 
                 512 
               
               
                   
                   
                   
                 0.445 
                 WDR37 
                 580 
                   
                   
                   
                 0.444 
                 LRP10 
                 356 
               
               
                   
                   
                   
                 0.444 
                 TGFBR2 
                 540 
                   
                   
                   
                 0.444 
                 LPAR2 
                 353 
               
               
                   
                   
                   
                 0.442 
                 ZNF274 
                 598 
                   
                   
                   
                 0.442 
                 TREM1 
                 557 
               
               
                   
                   
                   
                 0.429 
                 STAT5B 
                 530 
                   
                   
                   
                 0.441 
                 IL13RA1 
                 321 
               
               
                   
                   
                   
                 0.427 
                 MAML1 
                 362 
                   
                   
                   
                 0.439 
                 ITGAX 
                 331 
               
               
                   
                   
                   
                 0.420 
                 SATB1 
                 502 
                   
                   
                   
                 0.435 
                 ARHGAP25 
                 204 
               
               
                   
                   
                   
                 0.419 
                 DOCK9 
                 268 
                   
                   
                   
                 0.433 
                 SIRPB1 
                 513 
               
               
                   
                   
                   
                 0.417 
                 CHMP7 
                 243 
                   
                   
                   
                 0.433 
                 ZDHHC18 
                 591 
               
               
                   
                   
                   
                 0.413 
                 BRD1 
                 220 
                   
                   
                   
                 0.433 
                 TLE3 
                 543 
               
               
                   
                   
                   
                 0.410 
                 BTG1 
                 222 
                   
                   
                   
                 0.432 
                 ITGB2 
                 332 
               
               
                   
                   
                   
                 0.408 
                 ATF7IP2 
                 211 
                   
                   
                   
                 0.432 
                 SNX27 
                 518 
               
               
                   
                   
                   
                 0.408 
                 DIDO1 
                 267 
                   
                   
                   
                 0.431 
                 PGS1 
                 430 
               
               
                   
                   
                   
                 0.407 
                 LEF1 
                 349 
                   
                   
                   
                 0.429 
                 ATP6V1B2 
                 213 
               
               
                   
                   
                   
                 0.407 
                 TNRC6B 
                 554 
                   
                   
                   
                 0.428 
                 RAB31 
                 472 
               
               
                   
                   
                   
                 0.405 
                 SERTAD2 
                 507 
                   
                   
                   
                 0.427 
                 MAP3K11 
                 365 
               
               
                   
                   
                   
                 0.405 
                 CEP68 
                 240 
                   
                   
                   
                 0.427 
                 PACSIN2 
                 419 
               
               
                   
                   
                   
                 0.398 
                 BCL2 
                 217 
                   
                   
                   
                 0.427 
                 KIAA0513 
                 339 
               
               
                   
                   
                   
                 0.397 
                 VPS8 
                 577 
                   
                   
                   
                 0.426 
                 EMR2 
                 274 
               
               
                   
                   
                   
                 0.396 
                 CHD3 
                 241 
                   
                   
                   
                 0.426 
                 RERE 
                 482 
               
               
                   
                   
                   
                 0.393 
                 PUM2 
                 468 
                   
                   
                   
                 0.426 
                 NUMB 
                 413 
               
               
                   
                   
                   
                 0.390 
                 TGOLN2 
                 541 
                   
                   
                   
                 0.425 
                 RALB 
                 476 
               
               
                   
                   
                   
                 0.383 
                 NDE1 
                 399 
                   
                   
                   
                 0.425 
                 ETS2 
                 276 
               
               
                   
                   
                   
                 0.382 
                 CCR7 
                 234 
                   
                   
                   
                 0.422 
                 STAT5A 
                 529 
               
               
                   
                   
                   
                 0.381 
                 PSTPIP1 
                 462 
                   
                   
                   
                 0.421 
                 LST1 
                 357 
               
               
                   
                   
                   
                 0.379 
                 TIAM1 
                 542 
                   
                   
                   
                 0.417 
                 RIN3 
                 486 
               
               
                   
                   
                   
                 0.376 
                 PECAM1 
                 428 
                   
                   
                   
                 0.417 
                 TNK2 
                 553 
               
               
                   
                   
                   
                 0.374 
                 PDE3B 
                 427 
                   
                   
                   
                 0.416 
                 IQSEC1 
                 329 
               
               
                   
                   
                   
                 0.374 
                 MYC 
                 392 
                   
                   
                   
                 0.413 
                 PISD 
                 440 
               
               
                   
                   
                   
                 0.371 
                 FOXJ2 
                 287 
                   
                   
                   
                 0.412 
                 SORL1 
                 520 
               
               
                   
                   
                   
                 0.370 
                 PRMT2 
                 458 
                   
                   
                   
                 0.412 
                 FES 
                 283 
               
               
                   
                   
                   
                 0.370 
                 CSNK1D 
                 255 
                   
                   
                   
                 0.411 
                 K1AA0247 
                 338 
               
               
                   
                   
                   
                 0.357 
                 RPL10A 
                 492 
                   
                   
                   
                 0.404 
                 IL6R 
                 326 
               
               
                   
                   
                   
                 0.356 
                 SERINC5 
                 506 
                   
                   
                   
                 0.404 
                 LAPTM5 
                 345 
               
               
                   
                   
                   
                 0.354 
                 ARHGEF2 
                 206 
                   
                   
                   
                 0.402 
                 VAMP3 
                 574 
               
               
                   
                   
                   
                 0.352 
                 HGSNAT 
                 309 
                   
                   
                   
                 0.400 
                 FAM65B 
                 279 
               
               
                   
                   
                   
                 0.350 
                 TRAK1 
                 556 
                   
                   
                   
                 0.398 
                 MAP3K5 
                 367 
               
               
                   
                   
                   
                 0.350 
                 PHF2 
                 433 
                   
                   
                   
                 0.396 
                 TRIM8 
                 559 
               
               
                   
                   
                   
                 0.349 
                 PBX3 
                 422 
                   
                   
                   
                 0.396 
                 ZYX 
                 601 
               
               
                   
                   
                   
                 0.349 
                 SESN1 
                 508 
                   
                   
                   
                 0.388 
                 MAPK14 
                 370 
               
               
                   
                   
                   
                 0.341 
                 DPF2 
                 271 
                   
                   
                   
                 0.387 
                 PLEKHO1 
                 442 
               
               
                   
                   
                   
                 0.338 
                 IL4R 
                 325 
                   
                   
                   
                 0.387 
                 NCOA1 
                 397 
               
               
                   
                   
                   
                 0.334 
                 NOSIP 
                 408 
                   
                   
                   
                 0.384 
                 RNASET2 
                 487 
               
               
                   
                   
                   
                 0.331 
                 MPPE1 
                 387 
                   
                   
                   
                 0.383 
                 APBB1IP 
                 200 
               
               
                   
                   
                   
                 0.321 
                 NR3C1 
                 410 
                   
                   
                   
                 0.381 
                 RXRA 
                 499 
               
               
                   
                   
                   
                 0.320 
                 ABAT 
                 189 
                   
                   
                   
                 0.375 
                 PTAFR 
                 463 
               
               
                   
                   
                   
                 0.320 
                 GCC2 
                 293 
                   
                   
                   
                 0.373 
                 CNPY3 
                 248 
               
               
                   
                   
                   
                 0.316 
                 ZFC3H1 
                 593 
                   
                   
                   
                 0.373 
                 TNFSF13 
                 551 
               
               
                   
                   
                   
                 0.311 
                 SETD2 
                 509 
                   
                   
                   
                 0.368 
                 RPS6KA1 
                 494 
               
               
                   
                   
                   
                 0.308 
                 ITSN2 
                 334 
                   
                   
                   
                 0.367 
                 OSBPL2 
                 418 
               
               
                   
                   
                   
                 0.306 
                 R3HDM2 
                 469 
                   
                   
                   
                 0.367 
                 MTMR3 
                 389 
               
               
                   
                   
                   
                 0.302 
                 ARHGAP15 
                 203 
                   
                   
                   
                 0.362 
                 TMBIM1 
                 547 
               
               
                   
                   
                   
                 0.301 
                 PCF11 
                 424 
                   
                   
                   
                 0.359 
                 TFEB 
                 538 
               
               
                   
                   
                   
                 0.301 
                 MAPRE2 
                 371 
                   
                   
                   
                 0.359 
                 TFE3 
                 537 
               
               
                   
                   
                   
                 0.299 
                 ST3GAL1 
                 526 
                   
                   
                   
                 0.358 
                 RAF1 
                 475 
               
               
                   
                   
                   
                 0.299 
                 NACA 
                 395 
                   
                   
                   
                 0.357 
                 STX3 
                 533 
               
               
                   
                   
                   
                 0.299 
                 WDR47 
                 581 
                   
                   
                   
                 0.357 
                 LAT2 
                 346 
               
               
                   
                   
                   
                 0.298 
                 SSBP2 
                 523 
                   
                   
                   
                 0.356 
                 GRB2 
                 302 
               
               
                   
                   
                   
                 0.293 
                 CLK4 
                 247 
                   
                   
                   
                 0.355 
                 NDEL1 
                 400 
               
               
                   
                   
                   
                 0.289 
                 EIF3H 
                 273 
                   
                   
                   
                 0.355 
                 SEMA4D 
                 504 
               
               
                   
                   
                   
                 0.287 
                 FRY 
                 290 
                   
                   
                   
                 0.353 
                 FCGRT 
                 282 
               
               
                   
                   
                   
                 0.286 
                 ZNF238 
                 597 
                   
                   
                   
                 0.353 
                 DOK3 
                 269 
               
               
                   
                   
                   
                 0.286 
                 PTGER4 
                 465 
                   
                   
                   
                 0.353 
                 HIP1 
                 311 
               
               
                   
                   
                   
                 0.285 
                 PCNX 
                 425 
                   
                   
                   
                 0.353 
                 UBN1 
                 566 
               
               
                   
                   
                   
                 0.283 
                 NECAP2 
                 402 
                   
                   
                   
                 0.352 
                 PLXNC1 
                 444 
               
               
                   
                   
                   
                 0.279 
                 CASC3 
                 228 
                   
                   
                   
                 0.351 
                 NRBF2 
                 411 
               
               
                   
                   
                   
                 0.279 
                 MSL1 
                 388 
                   
                   
                   
                 0.348 
                 INPP5D 
                 328 
               
               
                   
                   
                   
                 0.278 
                 VEZF1 
                 576 
                   
                   
                   
                 0.347 
                 SH2D3C 
                 511 
               
               
                   
                   
                   
                 0.275 
                 K1AA0232 
                 337 
                   
                   
                   
                 0.347 
                 MMP25 
                 384 
               
               
                   
                   
                   
                 0.274 
                 RASSF2 
                 478 
                   
                   
                   
                 0.342 
                 IL10RB 
                 320 
               
               
                   
                   
                   
                 0.268 
                 RPL22 
                 493 
                   
                   
                   
                 0.340 
                 FLOT2 
                 285 
               
               
                   
                   
                   
                 0.265 
                 ACAA1 
                 193 
                   
                   
                   
                 0.339 
                 PIAS1 
                 437 
               
               
                   
                   
                   
                 0.263 
                 MAP4K4 
                 368 
                   
                   
                   
                 0.338 
                 PITPNA 
                 441 
               
               
                   
                   
                   
                 0.263 
                 BEX4 
                 218 
                   
                   
                   
                 0.334 
                 APLP2 
                 201 
               
               
                   
                   
                   
                 0.263 
                 NCBP2 
                 396 
                   
                   
                   
                 0.333 
                 CTBP2 
                 257 
               
               
                   
                   
                   
                 0.262 
                 LRMP 
                 355 
                   
                   
                   
                 0.332 
                 GPSM3 
                 301 
               
               
                   
                   
                   
                 0.259 
                 CAMK1D 
                 225 
                   
                   
                   
                 0.331 
                 RNF130 
                 488 
               
               
                   
                   
                   
                 0.257 
                 UTP14A 
                 573 
                   
                   
                   
                 0.326 
                 DGCR2 
                 264 
               
               
                   
                   
                   
                 0.253 
                 STX6 
                 534 
                   
                   
                   
                 0.326 
                 ZMIZ1 
                 595 
               
               
                   
                   
                   
                 0.253 
                 RPS6KA3 
                 495 
                   
                   
                   
                 0.320 
                 CAP1 
                 227 
               
               
                   
                   
                   
                 0.249 
                 PRKAA1 
                 455 
                   
                   
                   
                 0.319 
                 GSK3B 
                 303 
               
               
                   
                   
                   
                 0.240 
                 GOLGA7 
                 297 
                   
                   
                   
                 0.318 
                 RGS19 
                 484 
               
               
                   
                   
                   
                 0.239 
                 ZNF143 
                 596 
                   
                   
                   
                 0.317 
                 RAB7A 
                 474 
               
               
                   
                   
                   
                 0.237 
                 SNRK 
                 517 
                   
                   
                   
                 0.316 
                 CREBBP 
                 250 
               
               
                   
                   
                   
                 0.233 
                 SYPL1 
                 535 
                   
                   
                   
                 0.313 
                 RBMS1 
                 480 
               
               
                   
                   
                   
                 0.229 
                 CYLD 
                 260 
                   
                   
                   
                 0.310 
                 IL1RAP 
                 323 
               
               
                   
                   
                   
                 0.228 
                 PRUNE 
                 459 
                   
                   
                   
                 0.308 
                 RTN3 
                 497 
               
               
                   
                   
                   
                 0.224 
                 CRLF3 
                 251 
                   
                   
                   
                 0.308 
                 PPP4R1 
                 454 
               
               
                   
                   
                   
                 0.223 
                 CD93 
                 236 
                   
                   
                   
                 0.307 
                 TRIOBP 
                 560 
               
               
                   
                   
                   
                 0.223 
                 GPS2 
                 300 
                   
                   
                   
                 0.306 
                 GABARAP 
                 292 
               
               
                   
                   
                   
                 0.221 
                 FBXO11 
                 280 
                   
                   
                   
                 0.305 
                 MCTP2 
                 378 
               
               
                   
                   
                   
                 0.217 
                 UBE2D2 
                 564 
                   
                   
                   
                 0.304 
                 NFKB1 
                 404 
               
               
                   
                   
                   
                 0.217 
                 USP10 
                 569 
                   
                   
                   
                 0.303 
                 CST3 
                 256 
               
               
                   
                   
                   
                 0.216 
                 CCNG2 
                 232 
                   
                   
                   
                 0.292 
                 ABHD2 
                 190 
               
               
                   
                   
                   
                 0.212 
                 S0S2 
                 521 
                   
                   
                   
                 0.285 
                 SH2B3 
                 510 
               
               
                   
                   
                   
                 0.211 
                 ARRB1 
                 207 
                   
                   
                   
                 0.284 
                 STX10 
                 532 
               
               
                   
                   
                   
                 0.207 
                 CEP170 
                 239 
                   
                   
                   
                 0.282 
                 TSC22D3 
                 561 
               
               
                   
                   
                   
                 0.206 
                 SMAD4 
                 515 
                   
                   
                   
                 0.280 
                 TLE4 
                 544 
               
               
                   
                   
                   
                 0.205 
                 CIAPIN1 
                 245 
                   
                   
                   
                 0.277 
                 HAL 
                 305 
               
               
                   
                   
                   
                 0.204 
                 KLF7 
                 342 
                   
                   
                   
                 0.277 
                 ARRB2 
                 208 
               
               
                   
                   
                   
                 0.198 
                 PHF20L1 
                 435 
                   
                   
                   
                 0.276 
                 MAP3K3 
                 366 
               
               
                   
                   
                   
                 0.194 
                 ALDH3A2 
                 197 
                   
                   
                   
                 0.274 
                 NPL 
                 409 
               
               
                   
                   
                   
                 0.193 
                 PDCD6IP 
                 426 
                   
                   
                   
                 0.265 
                 CCND3 
                 231 
               
               
                   
                   
                   
                 0.185 
                 WASF2 
                 578 
                   
                   
                   
                 0.265 
                 SERINC3 
                 505 
               
               
                   
                   
                   
                 0.184 
                 TGFBI 
                 539 
                   
                   
                   
                 0.263 
                 GNAQ 
                 296 
               
               
                   
                   
                   
                 0.175 
                 GPBP1L1 
                 298 
                   
                   
                   
                 0.262 
                 USP4 
                 572 
               
               
                   
                   
                   
                 0.174 
                 PCBP2 
                 423 
                   
                   
                   
                 0.261 
                 PSEN1 
                 461 
               
               
                   
                   
                   
                 0.166 
                 DCP2 
                 262 
                   
                   
                   
                 0.256 
                 KBTBD2 
                 336 
               
               
                   
                   
                   
                 0.165 
                 LYST 
                 361 
                   
                   
                   
                 0.254 
                 LYL1 
                 359 
               
               
                   
                   
                   
                 0.154 
                 ERBB2IP 
                 275 
                   
                   
                   
                 0.241 
                 AIF1 
                 196 
               
               
                   
                   
                   
                 0.146 
                 ANKRD49 
                 198 
                   
                   
                   
                 0.239 
                 MBP 
                 377 
               
               
                   
                   
                   
                 0.145 
                 NDFIP1 
                 401 
                   
                   
                   
                 0.238 
                 ACVR1B 
                 195 
               
               
                   
                   
                   
                 0.141 
                 ATAD2B 
                 210 
                   
                   
                   
                 0.238 
                 RAB4B 
                 473 
               
               
                   
                   
                   
                 0.138 
                 ZNF292 
                 599 
                   
                   
                   
                 0.232 
                 PTEN 
                 464 
               
               
                   
                   
                   
                 0.137 
                 CCNT2 
                 233 
                   
                   
                   
                 0.231 
                 ASAP1 
                 209 
               
               
                   
                   
                   
                 0.134 
                 MARCH7 
                 372 
                   
                   
                   
                 0.231 
                 MANSC1 
                 363 
               
               
                   
                   
                   
                 0.133 
                 ACAP2 
                 194 
                   
                   
                   
                 0.228 
                 RYBP 
                 500 
               
               
                   
                   
                   
                 0.132 
                 MED13 
                 379 
                   
                   
                   
                 0.225 
                 CSAD 
                 253 
               
               
                   
                   
                   
                 0.131 
                 IL6ST 
                 327 
                   
                   
                   
                 0.223 
                 UBXN2B 
                 568 
               
               
                   
                   
                   
                 0.131 
                 PHF3 
                 436 
                   
                   
                   
                 0.223 
                 TNIP1 
                 552 
               
               
                   
                   
                   
                 0.129 
                 SP3 
                 522 
                   
                   
                   
                 0.222 
                 WBP2 
                 579 
               
               
                   
                   
                   
                 0.110 
                 SEC62 
                 503 
                   
                   
                   
                 0.211 
                 OGFRL1 
                 416 
               
               
                   
                   
                   
                 0.098 
                 ZFYVE16 
                 594 
                   
                   
                   
                 0.209 
                 SNN 
                 516 
               
               
                   
                   
                   
                 0.095 
                 NEK7 
                 403 
                   
                   
                   
                 0.205 
                 HPCAL1 
                 312 
               
               
                   
                   
                   
                 0.094 
                 POLD4 
                 446 
                   
                   
                   
                 0.196 
                 CD37 
                 235 
               
               
                   
                   
                   
                 0.091 
                 GNA12 
                 295 
                   
                   
                   
                 0.194 
                 RNF146 
                 490 
               
               
                   
                   
                   
                 0.087 
                 TRIB2 
                 558 
                   
                   
                   
                 0.184 
                 RAB14 
                 471 
               
               
                   
                   
                   
                 0.086 
                 YTHDF3 
                 586 
                   
                   
                   
                 0.177 
                 TOPORS 
                 555 
               
               
                   
                   
                   
                 0.082 
                 PPP2R5A 
                 452 
                   
                   
                   
                 0.176 
                 NFYA 
                 405 
               
               
                   
                   
                   
                 0.081 
                 PPP1R2 
                 451 
                   
                   
                   
                 0.172 
                 FOXO3 
                 289 
               
               
                   
                   
                   
                 0.076 
                 ZDHHC17 
                 590 
                   
                   
                   
                 0.171 
                 CREB1 
                 249 
               
               
                   
                   
                   
                 0.060 
                 STK38L 
                 531 
                   
                   
                   
                 0.170 
                 MAPK1 
                 369 
               
               
                   
                   
                   
                 0.057 
                 ST13 
                 525 
                   
                   
                   
                 0.170 
                 SOAT1 
                 519 
               
               
                   
                   
                   
                 0.046 
                 FAM134A 
                 278 
                   
                   
                   
                 0.168 
                 UBQLN2 
                 567 
               
               
                   
                   
                   
                 0.022 
                 PFDN5 
                 429 
                   
                   
                   
                 0.166 
                 OSBPL11 
                 417 
               
               
                   
                   
                   
                 0.015 
                 MARCH8 
                 373 
                   
                   
                   
                 0.165 
                 KLHL2 
                 343 
               
               
                   
                   
                   
                 −0.041 
                 POLR1D 
                 447 
                   
                   
                   
                 0.153 
                 VAV3 
                 575 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.135 
                 BRD4 
                 221 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.130 
                 MARK3 
                 374 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.114 
                 BAZ2B 
                 216 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.112 
                 ZNF148 
                 597 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.110 
                 CASP8 
                 229 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.108 
                 CHMP1B 
                 242 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.105 
                 HPS1 
                 313 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.099 
                 RNF141 
                 489 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.096 
                 MOSPD2 
                 386 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.081 
                 PINK1 
                 439 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.080 
                 CDIPT 
                 238 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.060 
                 NCOA4 
                 398 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.059 
                 PPP3R1 
                 453 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.014 
                 MKRN1 
                 383 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.005 
                 GYPC 
                 304 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 −0.021 
                 BMP2K 
                 219 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 −0.058 
                 FBXO9 
                 281 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 DERIVED BIOMARKERS GROUPED (A, B, C, D) BASED ON CORRELATION TO EACH OF THE BIOMARKERS IN THE FINAL PASIRS SIGNATURE (TTC17, G6PD, HERC6, LAP3, NUP160, TPP1) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Group A 
                 Group B 
                 Group C 
                 Group D 
                 Group E 
                 Group F 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
               
               
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
               
               
                 TTC17 
                 Symbol 
                 ID 
                 G6PD 
                 Symbol 
                 ID 
                 HERC6 
                 Symbol 
                 ID 
                 LAP3 
                 Symbol 
                 ID 
                 NUP160 
                 Symbol 
                 ID 
                 TPP1 
                 Symbol 
                 ID 
               
               
                   
               
               
                 1    
                 TTC17 
                 1132 
                 1    
                 G6PD 
                 1057 
                 1    
                 HERC6 
                 1063 
                 1    
                 LAP3 
                 1071 
                 1    
                 NUP160 
                 1082 
                 1    
                 TPP1 
                 1125 
               
               
                 0.647 
                 ZMYND11 
                 1142 
                 0.723 
                 SP11 
                 1112 
                 0.408 
                 SETX 
                 1107 
                 0.889 
                 WARS 
                 1139 
                 0.736 
                 TOP2B 
                 1124 
                 0.634 
                 WAS 
                 1140 
               
               
                 0.574 
                 ASXL2 
                 1022 
                 0.692 
                 PGD 
                 1086 
                 0.241 
                 HLA- 
                 1064 
                 0.845 
                 UBE2L6 
                 1134 
                 0.686 
                 METAP1 
                 1074 
                 0.630 
                 RTN4 
                 1102 
               
               
                   
                   
                   
                   
                   
                   
                   
                 DPA1 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 0.570 
                 ARID1A 
                 1020 
                 0.682 
                 GRINA 
                 1061 
                   
                   
                   
                 0.801 
                 TAP1 
                 1117 
                 0.653 
                 ZBED5 
                 1141 
                 0.562 
                 ATP6V1B2 
                 1025 
               
               
                 0.560 
                 CEP192 
                 1037 
                 0.679 
                 CD63 
                 1035 
                   
                   
                   
                 0.797 
                 SQRDL 
                 1113 
                 0.626 
                 FNTA 
                 1056 
                 0.528 
                 TIMP2 
                 1120 
               
               
                 0.551 
                 PCID2 
                 1084 
                 0.663 
                 FGR 
                 1053 
                   
                   
                   
                 0.782 
                 POMP 
                 1089 
                 0.624 
                 TRIT1 
                 1128 
                 0.482 
                 FLII 
                 1054 
               
               
                 0.534 
                 BCL11A 
                 1026 
                 0.657 
                 TCIRG1 
                 1119 
                   
                   
                   
                 0.781 
                 PLSCR1 
                 1088 
                 0.611 
                 ZNF266 
                 1143 
                 0.481 
                 RAB7A 
                 1093 
               
               
                 0.534 
                 ARIH2 
                 1021 
                 0.642 
                 NUMB 
                 1081 
                   
                   
                   
                 0.706 
                 MYD88 
                 1077 
                 0.604 
                 EXOSC10 
                 1047 
                   
                   
                   
               
               
                 0.524 
                 ARHGAP17 
                 1019 
                 0.618 
                 PRKCD 
                 1091 
                   
                   
                   
                 0.701 
                 ATOX1 
                 1023 
                 0.598 
                 APEX1 
                 1018 
                   
                   
                   
               
               
                 0.504 
                 EXOSC2 
                 1048 
                 0.607 
                 TSPO 
                 1131 
                   
                   
                   
                 0.694 
                 SH3GLB1 
                 1108 
                 0.595 
                 SERBP1 
                 1104 
                   
                   
                   
               
               
                 0.465 
                 TCF4 
                 1118 
                 0.570 
                 BCL3 
                 1027 
                   
                   
                   
                 0.678 
                 CEBPB 
                 1036 
                 0.555 
                 TRAF3IP3 
                 1126 
                   
                   
                   
               
               
                 0.460 
                 RPL15 
                 1097 
                 0.569 
                 JUNB 
                 1069 
                   
                   
                   
                 0.675 
                 SERPINB1 
                 1105 
                 0.552 
                 MLLT10 
                 1076 
                   
                   
                   
               
               
                 0.459 
                 GLG1 
                 1058 
                 0.553 
                 BCL6 
                 1028 
                   
                   
                   
                 0.674 
                 FCER1G 
                 1052 
                 0.537 
                 IMP3 
                 1066 
                   
                   
                   
               
               
                 0.452 
                 CSNK1G2 
                 1041 
                 0.551 
                 TNIP1 
                 1123 
                   
                   
                   
                 0.671 
                 RALB 
                 1094 
                 0.533 
                 ADSL 
                 1016 
                   
                   
                   
               
               
                 0.445 
                 SUCLG2 
                 1115 
                 0.550 
                 ENO1 
                 1044 
                   
                   
                   
                 0.661 
                 IRF1 
                 1067 
                 0.533 
                 MGEA5 
                 1075 
                   
                   
                   
               
               
                 0.444 
                 LY9 
                 1073 
                 0.536 
                 FLOT1 
                 1055 
                   
                   
                   
                 0.658 
                 GNG5 
                 1059 
                 0.525 
                 NOSIP 
                 1080 
                   
                   
                   
               
               
                 0.442 
                 USP34 
                 1137 
                 0.514 
                 PLAUR 
                 1087 
                   
                   
                   
                 0.655 
                 TANK 
                 1116 
                 0.522 
                 SEH1L 
                 1103 
                   
                   
                   
               
               
                 0.416 
                 ADK 
                 1015 
                 0.491 
                 PCBP1 
                 1083 
                   
                   
                   
                 0.651 
                 VAMP3 
                 1138 
                 0.521 
                 PREPL 
                 1090 
                   
                   
                   
               
               
                 0.411 
                 CNOT7 
                 1040 
                 0.476 
                 GPI 
                 1060 
                   
                   
                   
                 0.626 
                 LDHA 
                 1072 
                 0.478 
                 FBXO11 
                 1051 
                   
                   
                   
               
               
                 0.410 
                 UFM1 
                 1135 
                 0.424 
                 NFKBIA 
                 1079 
                   
                   
                   
                 0.617 
                 UPP1 
                 1136 
                 0.477 
                 CAMK2G 
                 1030 
                   
                   
                   
               
               
                 0.403 
                 AHCTF1 
                 1017 
                 0.422 
                 CCND3 
                 1031 
                   
                   
                   
                 0.612 
                 HCK 
                 1062 
                 0.476 
                 TMEM50B 
                 1122 
                   
                   
                   
               
               
                 0.372 
                 TROVE2 
                 1129 
                   
                   
                   
                   
                   
                   
                 0.607 
                 NFIL3 
                 1078 
                 0.470 
                 RPS4X 
                 1101 
                   
                   
                   
               
               
                 0.364 
                 CLIP4 
                 1039 
                   
                   
                   
                   
                   
                   
                 0.605 
                 SLAMF7 
                 1109 
                 0.466 
                 RPL9 
                 1099 
                   
                   
                   
               
               
                 0.350 
                 CD52 
                 1033 
                   
                   
                   
                   
                   
                   
                 0.593 
                 ACSL4 
                 1014 
                 0.463 
                 RPL22 
                 1098 
                   
                   
                   
               
               
                 0.326 
                 SERTAD2 
                 1106 
                   
                   
                   
                   
                   
                   
                 0.592 
                 ERLIN1 
                 1045 
                 0.457 
                 FBL 
                 1050 
                   
                   
                   
               
               
                 0.323 
                 IRF8 
                 1068 
                   
                   
                   
                   
                   
                   
                 0.584 
                 RBMS1 
                 1095 
                 0.438 
                 CCR7 
                 1032 
                   
                   
                   
               
               
                 0.234 
                 CHN2 
                 1038 
                   
                   
                   
                   
                   
                   
                 0.581 
                 STAT3 
                 1114 
                 0.412 
                 IL10RA 
                 1065 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.572 
                 TRIB1 
                 1127 
                 0.403 
                 DNAJC10 
                 1043 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.570 
                 C3AR1 
                 1029 
                 0.384 
                 RPS14 
                 1100 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.560 
                 ATP2A2 
                 1024 
                 0.371 
                 EXOSC9 
                 1049 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.546 
                 SOCS3 
                 1110 
                 0.367 
                 TMEM106B 
                 1121 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.545 
                 RIT1 
                 1096 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.538 
                 SORT1 
                 1111 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.538 
                 RAB27A 
                 1092 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.536 
                 ETV6 
                 1046 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.529 
                 TUBA1B 
                 1133 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.499 
                 PCMT1 
                 1085 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.486 
                 CD55 
                 1034 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.476 
                 CSTB 
                 1042 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.424 
                 TRPC4AP 
                 1130 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.389 
                 KIF1B 
                 1070 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 DERIVED BIOMARKERS GROUPED (A, B, C, D) BASED ON CORRELATION TO EACH OF THE BIOMARKERS  
               
               
                 IN THE FINAL INSIRS SIGNATURE (ARL6IP5, ENTPD1, HEATR1, TNFSF8 
               
            
           
           
               
               
               
               
            
               
                 Group A 
                 Group B 
                 Group C 
                 Group D 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
                 Correlation  
                 HUGO 
                 DNA 
               
               
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
                 to  
                 Gene 
                 SEQ 
               
               
                 ARL6IP5 
                 Name 
                 ID 
                 ENTPD1 
                 Name 
                 ID 
                 HEATR1 
                 Name 
                 ID 
                 TNFSF8 
                 Name 
                 ID 
               
               
                   
               
               
                 0.902 
                 MACF1 
                 1343 
                 0.957 
                 KCMF1 
                 1334 
                 0.974 
                 BCKDHB 
                 1286 
                 0.867 
                 KLHL24 
                 1337 
               
               
                 0.884 
                 EFHD2 
                 1306 
                 0.949 
                 IQSEC1 
                 1333 
                 0.974 
                 CLOCK 
                 1299 
                 0.858 
                 RBM26 
                 1377 
               
               
                 0.850 
                 TIA1 
                 1405 
                 0.943 
                 SLCO3A1 
                 1392 
                 0.972 
                 MY09A 
                 1353 
                 0.832 
                 SUPT7L 
                 1396 
               
               
                 0.847 
                 FCF1 
                 1316 
                 0.930 
                 GAB2 
                 1319 
                 0.971 
                 XPO4 
                 1419 
                 0.829 
                 SYNE2 
                 1397 
               
               
                 0.831 
                 THOC2 
                 1404 
                 0.925 
                 STK17B 
                 1395 
                 0.965 
                 HLTF 
                 1326 
                 0.826 
                 RABGAP1L 
                 1375 
               
               
                 0.814 
                 MDH1 
                 1345 
                 0.919 
                 HEBP2 
                 1324 
                 0.964 
                 SLC35D1 
                 1391 
                 0.825 
                 PLCL2 
                 1366 
               
               
                 0.775 
                 ADSL 
                 1276 
                 0.916 
                 BTN2A1 
                 1288 
                 0.961 
                 CDK6 
                 1295 
                 0.822 
                 ATXN3 
                 1285 
               
               
                 0.704 
                 SIDT2 
                 1389 
                 0.916 
                 CDKN1B 
                 1296 
                 0.961 
                 VPS13A 
                 1415 
                 0.807 
                 KIAA0391 
                 1335 
               
               
                   
                   
                   
                 0.910 
                 EXOC7 
                 1313 
                 0.960 
                 ANK3 
                 1279 
                 0.783 
                 NGDN 
                 1357 
               
               
                   
                   
                   
                 0.904 
                 MXD1 
                 1351 
                 0.960 
                 PRKAB2 
                 1368 
                 0.764 
                 TRAPPC2 
                 1409 
               
               
                   
                   
                   
                 0.891 
                 IGF2R 
                 1329 
                 0.957 
                 LANCL1 
                 1339 
                 0.763 
                 FUT8 
                 1317 
               
               
                   
                   
                   
                 0.888 
                 ADAM19 
                 1274 
                 0.956 
                 IDE 
                 1328 
                 0.761 
                 G3BP1 
                 1318 
               
               
                   
                   
                   
                 0.887 
                 VNN3 
                 1414 
                 0.955 
                 LARP4 
                 1341 
                 0.757 
                 VPS13C 
                 1417 
               
               
                   
                   
                   
                 0.882 
                 TFIP11 
                 1402 
                 0.955 
                 NEK1 
                 1355 
                 0.754 
                 TMEM87A 
                 1407 
               
               
                   
                   
                   
                 0.880 
                 POLR2A 
                 1367 
                 0.953 
                 SLC35A3 
                 1390 
                 0.740 
                 PWP1 
                 1373 
               
               
                   
                   
                   
                 0.876 
                 HAL 
                 1322 
                 0.951 
                 RAB11FIP2 
                 1374 
                 0.732 
                 CD28 
                 1291 
               
               
                   
                   
                   
                 0.869 
                 MYH9 
                 1352 
                 0.951 
                 DIAPH2 
                 1305 
                   
                   
                   
               
               
                   
                   
                   
                 0.850 
                 PELI1 
                 1363 
                 0.945 
                 KLHL20 
                 1336 
                   
                   
                   
               
               
                   
                   
                   
                 0.839 
                 ARHGEF6 
                 1281 
                 0.944 
                 TBCE 
                 1399 
                   
                   
                   
               
               
                   
                   
                   
                 0.827 
                 CLEC4E 
                 1298 
                 0.944 
                 TGS1 
                 1403 
                   
                   
                   
               
               
                   
                   
                   
                 0.822 
                 TTC17 
                 1411 
                 0.942 
                 ADRBK2 
                 1275 
                   
                   
                   
               
               
                   
                   
                   
                 0.819 
                 RGS2 
                 1382 
                 0.942 
                 TTC27 
                 1412 
                   
                   
                   
               
               
                   
                   
                   
                 0.811 
                 EXTL3 
                 1314 
                 0.942 
                 AGPAT5 
                 1278 
                   
                   
                   
               
               
                   
                   
                   
                 0.809 
                 CDA 
                 1294 
                 0.941 
                 TCF12 
                 1400 
                   
                   
                   
               
               
                   
                   
                   
                 0.805 
                 NOTCH2 
                 1361 
                 0.939 
                 BRCC3 
                 1287 
                   
                   
                   
               
               
                   
                   
                   
                 0.804 
                 RCBTB2 
                 1378 
                 0.935 
                 YTHDC2 
                 1421 
                   
                   
                   
               
               
                   
                   
                   
                 0.799 
                 CYP4F3 
                 1303 
                 0.934 
                 ZMYND11 
                 1422 
                   
                   
                   
               
               
                   
                   
                   
                 0.786 
                 RRAGC 
                 1387 
                 0.934 
                 NOL10 
                 1359 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.932 
                 C14orf1 
                 1290 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.932 
                 EFTUD1 
                 1307 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.932 
                 ZNF507 
                 1423 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.932 
                 TRIP11 
                 1410 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.931 
                 ASCC3 
                 1283 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.931 
                 ERCC4 
                 1311 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.930 
                 CD84 
                 1293 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.930 
                 RAD50 
                 1376 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.927 
                 CLUAP1 
                 1300 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.927 
                 FASTKD2 
                 1315 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.923 
                 TCF7L2 
                 1401 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.922 
                 CKAP2 
                 1297 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.921 
                 ESF1 
                 1312 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.921 
                 VPS13B 
                 1416 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.919 
                 RMND1 
                 1384 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.916 
                 PHC3 
                 1365 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.916 
                 ARHGAP5 
                 1280 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.913 
                 MLLT10 
                 1347 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.913 
                 CPA3 
                 1301 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.911 
                 NCBP1 
                 1354 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.911 
                 MANEA 
                 1344 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.908 
                 RDX 
                 1379 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.906 
                 RIOK2 
                 1383 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.900 
                 IP07 
                 1331 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.900 
                 SYT11 
                 1398 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.898 
                 RNF170 
                 1385 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.896 
                 SMC6 
                 1394 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.893 
                 PEX1 
                 1364 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.891 
                 ATP8A1 
                 1284 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.888 
                 HIBCH 
                 1325 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.887 
                 GOLPH3L 
                 1321 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.882 
                 ZNF562 
                 1424 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.874 
                 HRH4 
                 1327 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.864 
                 KRIT1 
                 1338 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.860 
                 IKBKAP 
                 1330 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.857 
                 YEATS4 
                 1420 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.854 
                 CREB1 
                 1302 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.854 
                 VEZT 
                 1413 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.851 
                 PSMD5 
                 1371 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.849 
                 LRRC8D 
                 1342 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.848 
                 PRPF39 
                 1369 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.839 
                 NR2C1 
                 1362 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.838 
                 CD40LG 
                 1292 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.835 
                 ENOSF1 
                 1309 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.831 
                 TLK1 
                 1406 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.825 
                 RFC1 
                 1381 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.823 
                 NIP7 
                 1358 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.822 
                 MTRR 
                 1350 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.819 
                 MTO1 
                 1349 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.819 
                 METTL5 
                 1346 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.814 
                 RNMT 
                 1386 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.813 
                 MRPS10 
                 1348 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.812 
                 WDR70 
                 1418 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.809 
                 IQCB1 
                 1332 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.809 
                 REPS1 
                 1380 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.806 
                 PRUNE 
                 1370 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.806 
                 NFX1 
                 1356 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.801 
                 AGA 
                 1277 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.796 
                 EIF5B 
                 1308 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.791 
                 NOL8 
                 1360 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.789 
                 SMC3 
                 1393 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.786 
                 S100PBP 
                 1388 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.779 
                 BZW2 
                 1289 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.761 
                 CYSLTR1 
                 1304 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.748 
                 LARP1 
                 1340 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.734 
                 GGPS1 
                 1320 
                   
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 0.599 
                 PTGS1 
                 1372 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 TOP PERFORMING (BASED ON AUC) BASIRS DERIVED 
               
               
                 BIOMARKERS FOLLOWING A GREEDY SEARCH ON A 
               
               
                 COMBINED DATASET 
               
               
                 The top derived biomarker was TSPO:HCLS1 with an AUC of 0.838. 
               
               
                 Incremental AUC increases can be made with the addition of further 
               
               
                 derived biomarkers as indicated. 
               
            
           
           
               
               
               
               
            
               
                   
                 Greedy Addition 
                 AUC 
                 AUC SD   
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 TSPO_HCLS1 
                 0.838 
                 0.0083 
               
               
                   
                 OPLAH_ZHX2 
                 0.863 
                 0.0061 
               
               
                   
                 TSPO_RNASE6 
                 0.881 
                 0.0055 
               
               
                   
                 GAS7_CAMK1D 
                 0.891 
                 0.0044 
               
               
                   
                 ST3GAL2_PRKD2 
                 0.897 
                 0.0032 
               
               
                   
                 PCOLCE2_NMUR1 
                 0.901 
                 0.0031 
               
               
                   
                 CR1_HAL 
                 0.901 
                 0.0040 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 BASIRS NUMERATORS AND DENOMINATORS APPEARING MORE 
               
               
                 THAN ONCE IN DERIVED BIOMARKERS WITH A MEAN AUC &gt; 
               
               
                 0.85 IN THE VALIDATION DATASETS 
               
               
                 BaSIRS numerators and denominators appearing more than once in 
               
               
                 derived biomarkers with an AUC &gt; 0.85 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Numerator 
                 # 
                 Denominator 
                 # 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 PDGFC 
                 28 
                 INPP5D 
                 6 
               
               
                   
                 TSPO 
                 11 
                 KLRD1 
                 6 
               
               
                   
                 GAS7 
                 9 
                 KLRF1 
                 6 
               
               
                   
                 PCOLCE2 
                 8 
                 NLRP1 
                 5 
               
               
                   
                 GALNT2 
                 6 
                 GAB2 
                 4 
               
               
                   
                 ALPL 
                 5 
                 CAMK1D 
                 3 
               
               
                   
                 ITGA7 
                 4 
                 CCNK 
                 3 
               
               
                   
                 CD82 
                 3 
                 ADAM19 
                 2 
               
               
                   
                 CR1 
                 3 
                 HAL 
                 2 
               
               
                   
                 HK3 
                 3 
                 MME 
                 2 
               
               
                   
                 OPLAH 
                 3 
                 NOV 
                 2 
               
               
                   
                 COX15 
                 2 
                 PARP8 
                 2 
               
               
                   
                 ENTPD7 
                 2 
                 RNASE6 
                 2 
               
               
                   
                 SMPDL3A 
                 2 
                 YPEL1 
                 2 
               
               
                   
                 TMEM165 
                 2 
                 ZFP36L2 
                 2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 TOP PERFORMING (BASED ON AUC) VASIRS DERIVED 
               
               
                 BIOMARKERS FOLLOWING A GREEDY SEARCH ON A 
               
               
                 COMBINED DATASET 
               
               
                 The top derived biomarker was ISG15:IL16 with an AUC of 0.92. 
               
               
                 Incremental AUC increases can be made with the addition of further 
               
               
                 derived biomarkers as indicated. 
               
            
           
           
               
               
               
               
            
               
                   
                 Greedy Addition 
                 Individual AUC 
                 Combined AUC 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 ISG15:IL16 
                 0.92 
                 0.92 
               
               
                   
                 OASL:ADGRE5 
                 0.865 
                 0.936 
               
               
                   
                 TAP1:TGFBR2 
                 0.879 
                 0.945 
               
               
                   
                 IFIH1:CRLF3 
                 0.873 
                 0.946 
               
               
                   
                 IFI44:IL4R 
                 0.867 
                 0.947 
               
               
                   
                 EIF2AK2:SYPL1 
                 0.859 
                 0.947 
               
               
                   
                 OAS2:LEF1 
                 0.875 
                 0.946 
               
               
                   
                 STAT1:PCBP2 
                 0.844 
                 0.944 
               
               
                   
                 IFI6:IL6ST 
                 0.821 
                 0.942 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 32 
               
             
            
               
                   
               
               
                 VASIRS NUMERATORS AND DENOMINATORS APPEARING 
               
               
                 MORE THAN TWICE IN THE 473 DERIVED BIOMARKERS WITH A 
               
               
                 MEAN AUC &gt; 0.80 IN AT LEAST 11 OF 14 VIRAL DATASETS. 
               
               
                 VaSIRS numerators and denominators appearing more than once in 
               
               
                 derived biomarkers with an AUC &gt; 0.80 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Numerator 
                 # 
                 Denominator 
                 # 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 OASL 
                 344 
                 ABLIM1 
                 12 
               
               
                   
                 USP18 
                 50 
                 IL16 
                 9 
               
               
                   
                 EIF2AK2 
                 13 
                 SYPL1 
                 6 
               
               
                   
                 ISG15 
                 8 
                 CYLD 
                 5 
               
               
                   
                 IFI44 
                 7 
                 IL4R 
                 5 
               
               
                   
                 LAP3 
                 7 
                 LTB 
                 5 
               
               
                   
                 ZBP1 
                 6 
                 MYC 
                 5 
               
               
                   
                 IFI6 
                 5 
                 PCF11 
                 5 
               
               
                   
                 OAS2 
                 4 
                 TGFBR2 
                 5 
               
               
                   
                 DDX60 
                 3 
                 CAMK1D 
                 4 
               
               
                   
                 DHX58 
                 3 
                 IL6ST 
                 4 
               
               
                   
                 IFIH1 
                 3 
                 LEF1 
                 4 
               
               
                   
                 TAP1 
                 3 
                 ZNF274 
                 4 
               
               
                   
                   
                   
                 BTG1 
                 3 
               
               
                   
                   
                   
                 CRLF3 
                 3 
               
               
                   
                   
                   
                 DGKA 
                 3 
               
               
                   
                   
                   
                 SESN1 
                 3 
               
               
                   
                   
                   
                 TNRC6B 
                 3 
               
               
                   
                   
                   
                 ZFC3H1 
                 3 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 TOP PERFORMING (BASED ON AUC) PASIRS DERIVED 
               
               
                 BIOMARKERS FOLLOWING A GREEDY SEARCH ON A 
               
               
                 COMBINED DATASET 
               
               
                 The top derived biomarker was TTC17:G6PD with an AUC of 0.96. 
               
               
                 Incremental AUC increases can be made with the addition of further 
               
               
                 derived biomarkers as indicated. 
               
            
           
           
               
               
               
               
            
               
                   
                 Greedy Addition 
                 Individual AUC 
                 Combined AUC 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 TTC17_G6PD 
                 0.96 
                 0.96 
               
               
                   
                 HERC6_LAP3 
                 0.84 
                 0.99 
               
               
                   
                 NUP160_TPP1 
                 0.847 
                 0.99 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 34 
               
             
            
               
                   
               
               
                 PASIRS NUMERATORS AND DENOMINATORS APPEARING MORE 
               
               
                 THAN TWICE IN THE 523 DERIVED BIOMARKERS WITH A MEAN 
               
               
                 AUC &gt; 0.75 IN THE VALIDATION DATASETS. 
               
               
                 PaSIRS numerators and denominators appearing more than once in 
               
               
                 derived biomarkers with an AUC &gt; 0.75 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Numerator 
                 # 
                 Denominator 
                 # 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 ARID1A 
                 62 
                 SQRDL 
                 45 
               
               
                   
                 CEP192 
                 35 
                 CEBPB 
                 40 
               
               
                   
                 EXOSC10 
                 33 
                 WARS 
                 39 
               
               
                   
                 IMP3 
                 33 
                 CD63 
                 38 
               
               
                   
                 RPL9 
                 24 
                 SH3GLB1 
                 31 
               
               
                   
                 TTC17 
                 24 
                 POMP 
                 23 
               
               
                   
                 BCL11A 
                 22 
                 PGD 
                 21 
               
               
                   
                 TCF4 
                 21 
                 FCER1G 
                 17 
               
               
                   
                 ASXL2 
                 18 
                 MYD88 
                 15 
               
               
                   
                 RPS4X 
                 15 
                 UPP1 
                 15 
               
               
                   
                 ZMYND11 
                 13 
                 G6PD 
                 13 
               
               
                   
                 AHCTF1 
                 12 
                 GNG5 
                 13 
               
               
                   
                 LY9 
                 12 
                 LAP3 
                 12 
               
               
                   
                 FBXO11 
                 11 
                 TCIRG1 
                 12 
               
               
                   
                 FNTA 
                 11 
                 SERPINB1 
                 11 
               
               
                   
                 ARIH2 
                 10 
                 ATOX1 
                 10 
               
               
                   
                 EXOSC2 
                 9 
                 TANK 
                 10 
               
               
                   
                 NUP160 
                 8 
                 TSPO 
                 10 
               
               
                   
                 ZBED5 
                 8 
                 TNIP1 
                 9 
               
               
                   
                 CAMK2G 
                 7 
                 CSTB 
                 8 
               
               
                   
                 CNOT7 
                 7 
                 ENO1 
                 8 
               
               
                   
                 TOP2B 
                 7 
                 RALB 
                 8 
               
               
                   
                 ARHGAP17 
                 6 
                 VAMP3 
                 7 
               
               
                   
                 HLA-DPA1 
                 6 
                 BCL6 
                 6 
               
               
                   
                 IRF8 
                 6 
                 LDHA 
                 6 
               
               
                   
                 PCID2 
                 6 
                 FGR 
                 5 
               
               
                   
                 RPL15 
                 6 
                 IRF1 
                 5 
               
               
                   
                 RPL22 
                 6 
                 ERLIN1 
                 4 
               
               
                   
                 ADSL 
                 5 
                 PCMT1 
                 4 
               
               
                   
                 IL10RA 
                 5 
                 PRKCD 
                 4 
               
               
                   
                 NOSIP 
                 5 
                 RTN4 
                 4 
               
               
                   
                 SETX 
                 5 
                 SPI1 
                 4 
               
               
                   
                 SUCLG2 
                 5 
                 TAP1 
                 4 
               
               
                   
                 CSNK1G2 
                 4 
                 UBE2L6 
                 4 
               
               
                   
                 PREPL 
                 4 
                 C3AR1 
                 3 
               
               
                   
                 RPS14 
                 4 
                 FLII 
                 3 
               
               
                   
                 TMEM50B 
                 4 
                 NFIL3 
                 3 
               
               
                   
                 TROVE2 
                 4 
                 PLAUR 
                 3 
               
               
                   
                 CHN2 
                 3 
                 SLAMF7 
                 3 
               
               
                   
                 METAP1 
                 3 
                 WAS 
                 3 
               
               
                   
                 MLLT10 
                 3 
                 ATP2A2 
                 2 
               
               
                   
                 SERBP1 
                 3 
                 ETV6 
                 2 
               
               
                   
                 SERTAD2 
                 3 
                 GPI 
                 2 
               
               
                   
                 CCR7 
                 2 
                 HCK 
                 2 
               
               
                   
                 CLIP4 
                 2 
                 PCBP1 
                 2 
               
               
                   
                 SEH1L 
                 2 
                 PLSCR1 
                 2 
               
               
                   
                 TRAF3IP3 
                 2 
                 RAB27A 
                 2 
               
               
                   
                 UFM1 
                 2 
                 STAT3 
                 2 
               
               
                   
                 USP34 
                 2 
                 TIMP2 
                 2 
               
               
                   
                 ZNF266 
                 2 
                 TPP1 
                 2 
               
               
                   
                   
                   
                 TUBA1B 
                 2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 35 
               
             
            
               
                   
               
               
                 TABLE OF INDIVIDUAL PERFORMANCE, IN DESCENDING AUC, OF THE 523 PASIRS DERIVED  
               
               
                 BIOMARKERS WITH AN AVERAGE AUC &gt;0.75 ACROSS EACH OF FIVE PROTOZOAL DATASETS. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Severe vs 
                   
                   
                   
               
               
                   
                   
                   
                 Mild 
                   
                   
                   
               
               
                   
                 Malaria 
                 Leishmania 
                 Malaria 
                 Malaria 
                 Malaria 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Derived Biomarker 
                 GSE34404 
                 G5E64610 
                 G5E33811 
                 G5E15221 
                 G5E5418 
                 Mean 
               
               
                 RPL9_WARS 
                 0.935 
                 0.920 
                 1.000 
                 0.852 
                 0.964 
                 0.934 
               
               
                 RPL9_CSTB 
                 0.895 
                 0.900 
                 1.000 
                 0.888 
                 0.982 
                 0.933 
               
               
                 NUP160_WARS 
                 0.915 
                 0.980 
                 0.920 
                 0.898 
                 0.948 
                 0.932 
               
               
                 IMP3_ATOX1 
                 0.950 
                 0.900 
                 0.880 
                 0.974 
                 0.955 
                 0.932 
               
               
                 RPS4X_WARS 
                 0.937 
                 1.000 
                 0.840 
                 0.944 
                 0.933 
                 0.931 
               
               
                 TCF4_CEBPB 
                 0.984 
                 0.960 
                 0.840 
                 0.959 
                 0.909 
                 0.930 
               
               
                 IMP3_LAP3 
                 0.937 
                 0.900 
                 0.920 
                 0.929 
                 0.952 
                 0.927 
               
               
                 EXOSC10_WARS 
                 0.960 
                 1.000 
                 0.840 
                 0.939 
                 0.891 
                 0.926 
               
               
                 TTC17_WARS 
                 0.954 
                 1.000 
                 0.800 
                 0.990 
                 0.885 
                 0.926 
               
               
                 TCF4_WARS 
                 0.955 
                 0.960 
                 0.960 
                 0.903 
                 0.848 
                 0.925 
               
               
                 METAP1_WARS 
                 0.912 
                 0.940 
                 0.880 
                 0.913 
                 0.979 
                 0.925 
               
               
                 FNTA_POMP 
                 0.966 
                 0.920 
                 0.840 
                 0.923 
                 0.970 
                 0.924 
               
               
                 TCF4_TANK 
                 0.975 
                 0.980 
                 0.960 
                 0.781 
                 0.921 
                 0.923 
               
               
                 TOP2B_CEBPB 
                 0.936 
                 1.000 
                 0.760 
                 0.934 
                 0.979 
                 0.922 
               
               
                 AHCTF1_CEBPB 
                 0.977 
                 0.820 
                 0.840 
                 0.980 
                 0.991 
                 0.921 
               
               
                 RPS4X_MYD88 
                 0.935 
                 0.980 
                 0.800 
                 0.929 
                 0.964 
                 0.921 
               
               
                 IMP3_CEBPB 
                 0.976 
                 0.880 
                 0.840 
                 0.923 
                 0.985 
                 0.921 
               
               
                 RPL9_CEBPB 
                 0.952 
                 1.000 
                 0.800 
                 0.852 
                 1.000 
                 0.921 
               
               
                 RPS4X_CEBPB 
                 0.949 
                 1.000 
                 0.720 
                 0.949 
                 0.985 
                 0.921 
               
               
                 TTC17_CEBPB 
                 0.980 
                 1.000 
                 0.640 
                 0.990 
                 0.991 
                 0.920 
               
               
                 PREPL_WARS 
                 0.911 
                 1.000 
                 0.920 
                 0.791 
                 0.979 
                 0.920 
               
               
                 TCF4_LAP3 
                 0.944 
                 0.980 
                 0.880 
                 0.918 
                 0.876 
                 0.920 
               
               
                 ZBED5_WARS 
                 0.940 
                 0.940 
                 0.880 
                 0.974 
                 0.864 
                 0.920 
               
               
                 TCF4_POMP 
                 0.952 
                 0.900 
                 0.880 
                 0.954 
                 0.909 
                 0.919 
               
               
                 NUP160_SQRDL 
                 0.899 
                 0.960 
                 0.800 
                 0.959 
                 0.973 
                 0.918 
               
               
                 TRIT1_WARS 
                 0.908 
                 1.000 
                 0.800 
                 0.903 
                 0.976 
                 0.917 
               
               
                 ZBED5_CEBPB 
                 0.965 
                 0.940 
                 0.720 
                 0.990 
                 0.964 
                 0.916 
               
               
                 IMP3_WARS 
                 0.964 
                 0.880 
                 0.920 
                 0.908 
                 0.906 
                 0.916 
               
               
                 RPS4X_SQRDL 
                 0.934 
                 1.000 
                 0.720 
                 0.980 
                 0.942 
                 0.915 
               
               
                 NUP160_POMP 
                 0.923 
                 0.880 
                 0.840 
                 0.954 
                 0.979 
                 0.915 
               
               
                 EXOSC10_LAP3 
                 0.946 
                 1.000 
                 0.760 
                 0.939 
                 0.927 
                 0.914 
               
               
                 RPS4X_GNG5 
                 0.965 
                 0.960 
                 0.760 
                 0.898 
                 0.988 
                 0.914 
               
               
                 TOP2B_WARS 
                 0.930 
                 1.000 
                 0.840 
                 0.923 
                 0.876 
                 0.914 
               
               
                 RPL9_POMP 
                 0.959 
                 0.840 
                 0.880 
                 0.918 
                 0.970 
                 0.913 
               
               
                 EXOSC10_ATOX1 
                 0.959 
                 1.000 
                 0.680 
                 1.000 
                 0.927 
                 0.913 
               
               
                 TTC17_TANK 
                 0.958 
                 1.000 
                 0.720 
                 0.923 
                 0.964 
                 0.913 
               
               
                 EXOSC10_CEBPB 
                 0.977 
                 1.000 
                 0.680 
                 0.929 
                 0.979 
                 0.913 
               
               
                 NOSIP_CEBPB 
                 0.963 
                 0.900 
                 0.840 
                 0.949 
                 0.912 
                 0.913 
               
               
                 RPL22_CEBPB 
                 0.950 
                 1.000 
                 0.720 
                 0.959 
                 0.933 
                 0.913 
               
               
                 TTC17_ATP2A2 
                 0.941 
                 0.940 
                 0.760 
                 0.939 
                 0.982 
                 0.912 
               
               
                 SEH1L_WARS 
                 0.955 
                 0.980 
                 0.840 
                 0.837 
                 0.945 
                 0.911 
               
               
                 EXOSC10_UBE2L6 
                 0.932 
                 1.000 
                 0.800 
                 0.969 
                 0.852 
                 0.911 
               
               
                 TTC17_LAP3 
                 0.919 
                 1.000 
                 0.680 
                 1.000 
                 0.948 
                 0.910 
               
               
                 SUCLG2_CEBPB 
                 0.976 
                 1.000 
                 0.800 
                 0.959 
                 0.812 
                 0.909 
               
               
                 EXOSC10_G6PD 
                 0.982 
                 1.000 
                 0.800 
                 0.898 
                 0.864 
                 0.909 
               
               
                 CEP192_WARS 
                 0.945 
                 0.840 
                 0.920 
                 0.934 
                 0.903 
                 0.908 
               
               
                 NUP160_CD63 
                 0.951 
                 0.940 
                 0.760 
                 0.923 
                 0.964 
                 0.908 
               
               
                 TMEM50B_WARS 
                 0.959 
                 0.980 
                 0.840 
                 0.964 
                 0.794 
                 0.908 
               
               
                 EXOSC10_LDHA 
                 0.980 
                 0.900 
                 0.760 
                 0.954 
                 0.942 
                 0.907 
               
               
                 ARID1A_CSTB 
                 0.944 
                 0.860 
                 0.880 
                 0.913 
                 0.939 
                 0.907 
               
               
                 SUCLG2_WARS 
                 0.963 
                 1.000 
                 0.920 
                 0.969 
                 0.682 
                 0.907 
               
               
                 ARID1A_CEBPB 
                 0.976 
                 0.940 
                 0.680 
                 0.954 
                 0.982 
                 0.906 
               
               
                 FBXO11_TANK 
                 0.908 
                 0.940 
                 0.760 
                 0.918 
                 1.000 
                 0.905 
               
               
                 SUCLG2_SH3GLB1 
                 0.976 
                 1.000 
                 0.800 
                 0.923 
                 0.827 
                 0.905 
               
               
                 TTC17_G6PD 
                 0.986 
                 0.880 
                 0.760 
                 1.000 
                 0.900 
                 0.905 
               
               
                 IMP3_PCMT1 
                 0.962 
                 0.900 
                 0.840 
                 0.974 
                 0.848 
                 0.905 
               
               
                 ARID1A_LAP3 
                 0.909 
                 0.980 
                 0.760 
                 0.939 
                 0.936 
                 0.905 
               
               
                 IMP3_SQRDL 
                 0.966 
                 0.820 
                 0.840 
                 0.959 
                 0.936 
                 0.904 
               
               
                 TCF4_ATOX1 
                 0.948 
                 0.980 
                 0.760 
                 0.923 
                 0.909 
                 0.904 
               
               
                 IMP3_SH3GLB1 
                 0.970 
                 0.780 
                 0.840 
                 0.934 
                 0.994 
                 0.904 
               
               
                 EXOSC10_MYD88 
                 0.957 
                 1.000 
                 0.680 
                 0.929 
                 0.952 
                 0.904 
               
               
                 LY9_WARS 
                 0.949 
                 0.820 
                 0.960 
                 0.964 
                 0.824 
                 0.903 
               
               
                 IMP3_CSTB 
                 0.985 
                 0.780 
                 0.920 
                 0.908 
                 0.921 
                 0.903 
               
               
                 RPL15_CEBPB 
                 0.968 
                 1.000 
                 0.800 
                 0.985 
                 0.761 
                 0.903 
               
               
                 ARHGAP17_ATOX1 
                 0.983 
                 0.980 
                 0.800 
                 0.872 
                 0.876 
                 0.902 
               
               
                 TTC17_MYD88 
                 0.968 
                 0.960 
                 0.680 
                 0.944 
                 0.958 
                 0.902 
               
               
                 EXOSC10_TCIRG1 
                 0.977 
                 1.000 
                 0.680 
                 0.934 
                 0.918 
                 0.902 
               
               
                 ZMYND11_CEBPB 
                 0.938 
                 1.000 
                 0.600 
                 0.980 
                 0.991 
                 0.902 
               
               
                 CEP192_TANK 
                 0.959 
                 0.860 
                 0.840 
                 0.872 
                 0.976 
                 0.901 
               
               
                 IMP3_UBE2L6 
                 0.918 
                 0.900 
                 0.840 
                 0.954 
                 0.894 
                 0.901 
               
               
                 RPS4X_CD63 
                 0.973 
                 1.000 
                 0.640 
                 0.974 
                 0.918 
                 0.901 
               
               
                 RPL9_CD63 
                 0.984 
                 0.920 
                 0.720 
                 0.908 
                 0.973 
                 0.901 
               
               
                 ARID1A_UBE2L6 
                 0.887 
                 0.960 
                 0.760 
                 0.959 
                 0.933 
                 0.900 
               
               
                 TCF4_UBE2L6 
                 0.923 
                 0.960 
                 0.920 
                 0.888 
                 0.806 
                 0.899 
               
               
                 ARID1A_WARS 
                 0.938 
                 0.920 
                 0.800 
                 0.918 
                 0.918 
                 0.899 
               
               
                 CAMK2G_G6PD 
                 0.925 
                 0.980 
                 0.720 
                 0.944 
                 0.924 
                 0.899 
               
               
                 RPS4X_SH3GLB1 
                 0.941 
                 0.940 
                 0.680 
                 0.954 
                 0.979 
                 0.899 
               
               
                 RPL9_TANK 
                 0.929 
                 0.960 
                 0.880 
                 0.730 
                 0.994 
                 0.898 
               
               
                 IMP3_TANK 
                 0.942 
                 0.840 
                 0.880 
                 0.842 
                 0.988 
                 0.898 
               
               
                 ZBED5_SH3GLB1 
                 0.959 
                 0.880 
                 0.720 
                 0.990 
                 0.942 
                 0.898 
               
               
                 TMEM50B_CEBPB 
                 0.963 
                 1.000 
                 0.680 
                 0.964 
                 0.882 
                 0.898 
               
               
                 RPS4X_POMP 
                 0.953 
                 0.940 
                 0.680 
                 0.969 
                 0.945 
                 0.898 
               
               
                 TOP2B_POMP 
                 0.948 
                 0.980 
                 0.640 
                 0.949 
                 0.970 
                 0.897 
               
               
                 METAP1_POMP 
                 0.921 
                 0.880 
                 0.760 
                 0.934 
                 0.991 
                 0.897 
               
               
                 EXOSC10_CSTB 
                 0.964 
                 0.940 
                 0.760 
                 0.918 
                 0.903 
                 0.897 
               
               
                 ZNF266_CEBPB 
                 0.948 
                 0.920 
                 0.720 
                 0.985 
                 0.912 
                 0.897 
               
               
                 TTC17_ATOX1 
                 0.914 
                 1.000 
                 0.600 
                 0.995 
                 0.976 
                 0.897 
               
               
                 CSNK1G2_G6PD 
                 0.978 
                 1.000 
                 0.680 
                 0.923 
                 0.900 
                 0.896 
               
               
                 SETX_CEBPB 
                 0.983 
                 0.960 
                 0.680 
                 0.893 
                 0.964 
                 0.896 
               
               
                 ARHGAP17_CEBPB 
                 0.986 
                 1.000 
                 0.800 
                 0.791 
                 0.900 
                 0.895 
               
               
                 ZMYND11_WARS 
                 0.919 
                 1.000 
                 0.680 
                 0.974 
                 0.903 
                 0.895 
               
               
                 IMP3_UPP1 
                 0.982 
                 0.880 
                 0.800 
                 0.934 
                 0.879 
                 0.895 
               
               
                 EXOSC10_IRF1 
                 0.961 
                 1.000 
                 0.760 
                 0.821 
                 0.930 
                 0.895 
               
               
                 UFM1_CEBPB 
                 0.948 
                 0.920 
                 0.640 
                 1.000 
                 0.964 
                 0.894 
               
               
                 ARID1A_LDHA 
                 0.956 
                 0.800 
                 0.800 
                 0.954 
                 0.961 
                 0.894 
               
               
                 RPL9_ATOX1 
                 0.906 
                 0.960 
                 0.680 
                 0.934 
                 0.991 
                 0.894 
               
               
                 TTC17_GNG5 
                 0.972 
                 0.840 
                 0.680 
                 0.990 
                 0.988 
                 0.894 
               
               
                 EXOSC10_POMP 
                 0.979 
                 0.980 
                 0.600 
                 0.959 
                 0.948 
                 0.893 
               
               
                 ARID1A_ATOX1 
                 0.904 
                 0.980 
                 0.600 
                 0.995 
                 0.988 
                 0.893 
               
               
                 RPL9_SH3GLB1 
                 0.951 
                 0.900 
                 0.680 
                 0.934 
                 1.000 
                 0.893 
               
               
                 LY9_CEBPB 
                 0.971 
                 0.760 
                 0.800 
                 0.969 
                 0.964 
                 0.893 
               
               
                 RP514_WARS 
                 0.942 
                 0.980 
                 0.840 
                 0.883 
                 0.818 
                 0.893 
               
               
                 FNTA_SQRDL 
                 0.960 
                 0.900 
                 0.720 
                 0.964 
                 0.918 
                 0.893 
               
               
                 APEX1_CD63 
                 0.965 
                 1.000 
                 0.720 
                 0.964 
                 0.812 
                 0.892 
               
               
                 SETX_WARS 
                 0.950 
                 0.940 
                 0.760 
                 0.939 
                 0.870 
                 0.892 
               
               
                 IMP3_TNIP1 
                 0.971 
                 0.860 
                 0.840 
                 0.872 
                 0.915 
                 0.892 
               
               
                 FNTA_CD63 
                 0.995 
                 0.900 
                 0.760 
                 0.923 
                 0.879 
                 0.891 
               
               
                 TTC17_TCIRG1 
                 0.988 
                 0.920 
                 0.680 
                 0.995 
                 0.873 
                 0.891 
               
               
                 EXOSC10_SH3GLB1 
                 0.981 
                 0.960 
                 0.600 
                 0.913 
                 1.000 
                 0.891 
               
               
                 RPS4X_FCER1G 
                 0.979 
                 0.880 
                 0.640 
                 0.969 
                 0.985 
                 0.891 
               
               
                 RPS4X_PGD 
                 0.970 
                 1.000 
                 0.680 
                 0.980 
                 0.824 
                 0.891 
               
               
                 CAMK2G_CEBPB 
                 0.926 
                 1.000 
                 0.600 
                 0.944 
                 0.982 
                 0.890 
               
               
                 ZMYND11_G6PD 
                 0.968 
                 0.880 
                 0.640 
                 1.000 
                 0.964 
                 0.890 
               
               
                 FNTA_CEBPB 
                 0.977 
                 1.000 
                 0.600 
                 0.898 
                 0.976 
                 0.890 
               
               
                 ZMYND11_CD63 
                 0.968 
                 0.980 
                 0.560 
                 1.000 
                 0.942 
                 0.890 
               
               
                 TCF4_RALB 
                 0.980 
                 0.980 
                 0.800 
                 0.929 
                 0.761 
                 0.890 
               
               
                 ARHGAP17_LAP3 
                 0.959 
                 0.980 
                 0.880 
                 0.776 
                 0.855 
                 0.890 
               
               
                 IMP3_CD63 
                 0.994 
                 0.720 
                 0.840 
                 0.964 
                 0.930 
                 0.890 
               
               
                 ZMYND11_C3AR1 
                 0.978 
                 0.840 
                 0.720 
                 0.964 
                 0.945 
                 0.890 
               
               
                 AHCTF1_WARS 
                 0.943 
                 0.800 
                 0.840 
                 0.929 
                 0.936 
                 0.890 
               
               
                 RPS4X_ENO1 
                 0.937 
                 0.920 
                 0.720 
                 0.995 
                 0.873 
                 0.889 
               
               
                 CEP192_PLSCR1 
                 0.950 
                 0.960 
                 0.760 
                 0.913 
                 0.861 
                 0.889 
               
               
                 EXOSC9_POMP 
                 0.977 
                 0.940 
                 0.760 
                 0.969 
                 0.797 
                 0.889 
               
               
                 FNTA_GNG5 
                 0.968 
                 0.960 
                 0.640 
                 0.898 
                 0.976 
                 0.888 
               
               
                 CEP192_IRF1 
                 0.945 
                 0.980 
                 0.800 
                 0.765 
                 0.952 
                 0.888 
               
               
                 CEP192_CEBPB 
                 0.989 
                 0.860 
                 0.680 
                 0.923 
                 0.988 
                 0.888 
               
               
                 ZMYND11_CSTB 
                 0.907 
                 0.960 
                 0.640 
                 0.980 
                 0.952 
                 0.888 
               
               
                 FNTA_SH3GLB1 
                 0.966 
                 0.880 
                 0.720 
                 0.893 
                 0.979 
                 0.888 
               
               
                 ARID1A_TAP1 
                 0.937 
                 0.980 
                 0.640 
                 0.944 
                 0.936 
                 0.887 
               
               
                 NOSIP_WARS 
                 0.944 
                 0.860 
                 0.880 
                 0.944 
                 0.809 
                 0.887 
               
               
                 RPS4X_UPP1 
                 0.945 
                 1.000 
                 0.600 
                 0.949 
                 0.942 
                 0.887 
               
               
                 CNOT7_CEBPB 
                 0.984 
                 1.000 
                 0.720 
                 0.852 
                 0.879 
                 0.887 
               
               
                 ARHGAP17_WARS 
                 0.978 
                 1.000 
                 0.880 
                 0.801 
                 0.776 
                 0.887 
               
               
                 UFM1_WARS 
                 0.923 
                 0.880 
                 0.760 
                 0.980 
                 0.891 
                 0.887 
               
               
                 PREPL_SQRDL 
                 0.905 
                 0.980 
                 0.680 
                 0.867 
                 1.000 
                 0.886 
               
               
                 IMP3_TAP1 
                 0.953 
                 0.920 
                 0.800 
                 0.944 
                 0.815 
                 0.886 
               
               
                 ARID1A_PCMT1 
                 0.960 
                 0.980 
                 0.680 
                 0.985 
                 0.827 
                 0.886 
               
               
                 SUCLG2_SQRDL 
                 0.977 
                 1.000 
                 0.760 
                 0.959 
                 0.733 
                 0.886 
               
               
                 RPL22_SH3GLB1 
                 0.941 
                 0.940 
                 0.680 
                 0.959 
                 0.909 
                 0.886 
               
               
                 BCL11A_WARS 
                 0.960 
                 0.660 
                 0.960 
                 0.980 
                 0.870 
                 0.886 
               
               
                 CNOT7_WARS 
                 0.969 
                 1.000 
                 0.840 
                 0.832 
                 0.788 
                 0.886 
               
               
                 ZBED5_TCIRG1 
                 0.964 
                 0.820 
                 0.760 
                 0.985 
                 0.900 
                 0.886 
               
               
                 EXOSC10_SQRDL 
                 0.974 
                 1.000 
                 0.560 
                 0.985 
                 0.909 
                 0.886 
               
               
                 AHCTF1_GNG5 
                 0.970 
                 0.640 
                 0.880 
                 0.964 
                 0.973 
                 0.885 
               
               
                 ZMYND11_FCER1G 
                 0.959 
                 0.940 
                 0.600 
                 0.980 
                 0.948 
                 0.885 
               
               
                 TOP2B_ENO1 
                 0.966 
                 0.980 
                 0.680 
                 0.964 
                 0.836 
                 0.885 
               
               
                 IMP3_IRF1 
                 0.956 
                 0.940 
                 0.840 
                 0.750 
                 0.939 
                 0.885 
               
               
                 CEP192_TAP1 
                 0.950 
                 0.920 
                 0.760 
                 0.929 
                 0.867 
                 0.885 
               
               
                 RPL9_MYD88 
                 0.943 
                 0.820 
                 0.840 
                 0.847 
                 0.973 
                 0.885 
               
               
                 RPL22_GNG5 
                 0.956 
                 0.860 
                 0.760 
                 0.929 
                 0.918 
                 0.885 
               
               
                 FNTA_MYD88 
                 0.968 
                 0.940 
                 0.640 
                 0.903 
                 0.970 
                 0.884 
               
               
                 TCF4_GNG5 
                 0.975 
                 0.800 
                 0.800 
                 0.918 
                 0.927 
                 0.884 
               
               
                 EXOSC10_TANK 
                 0.959 
                 0.920 
                 0.720 
                 0.862 
                 0.955 
                 0.883 
               
               
                 MLLT10_WARS 
                 0.908 
                 0.840 
                 0.760 
                 0.944 
                 0.964 
                 0.883 
               
               
                 TTC17_POMP 
                 0.932 
                 0.920 
                 0.640 
                 0.969 
                 0.955 
                 0.883 
               
               
                 TCF4_MYD88 
                 0.972 
                 0.860 
                 0.800 
                 0.888 
                 0.894 
                 0.883 
               
               
                 IMP3_MYD88 
                 0.958 
                 0.820 
                 0.800 
                 0.908 
                 0.927 
                 0.883 
               
               
                 TOP2B_CD63 
                 0.980 
                 1.000 
                 0.600 
                 0.929 
                 0.903 
                 0.882 
               
               
                 CEP192_RALB 
                 0.982 
                 0.840 
                 0.760 
                 0.959 
                 0.870 
                 0.882 
               
               
                 NUP160_PGD 
                 0.950 
                 0.960 
                 0.720 
                 0.944 
                 0.833 
                 0.882 
               
               
                 RPL9_SQRDL 
                 0.938 
                 0.840 
                 0.720 
                 0.918 
                 0.991 
                 0.881 
               
               
                 CEP192_PCMT1 
                 0.965 
                 0.920 
                 0.840 
                 0.893 
                 0.788 
                 0.881 
               
               
                 TCF4_SQRDL 
                 0.976 
                 0.900 
                 0.720 
                 0.939 
                 0.870 
                 0.881 
               
               
                 RPL9_GNG5 
                 0.962 
                 0.760 
                 0.800 
                 0.878 
                 1.000 
                 0.880 
               
               
                 EXOSC10_CD63 
                 0.997 
                 1.000 
                 0.560 
                 0.954 
                 0.888 
                 0.880 
               
               
                 TCF4_SH3GLB1 
                 0.979 
                 0.820 
                 0.760 
                 0.913 
                 0.927 
                 0.880 
               
               
                 ADSL_WARS 
                 0.955 
                 0.980 
                 0.840 
                 0.760 
                 0.864 
                 0.880 
               
               
                 TTC17_SH3GLB1 
                 0.972 
                 0.920 
                 0.560 
                 0.969 
                 0.976 
                 0.879 
               
               
                 ARID1A_SQRDL 
                 0.953 
                 0.940 
                 0.560 
                 0.974 
                 0.970 
                 0.879 
               
               
                 ARID1A_G6PD 
                 0.972 
                 0.780 
                 0.760 
                 0.893 
                 0.988 
                 0.879 
               
               
                 AHCTF1_TANK 
                 0.947 
                 0.700 
                 0.840 
                 0.923 
                 0.982 
                 0.878 
               
               
                 EXOSC2_CEBPB 
                 0.950 
                 1.000 
                 0.600 
                 0.923 
                 0.918 
                 0.878 
               
               
                 RPS4X_SERPINB1 
                 0.953 
                 0.980 
                 0.640 
                 0.939 
                 0.879 
                 0.878 
               
               
                 FBXO11_RALB 
                 0.946 
                 0.840 
                 0.720 
                 0.939 
                 0.945 
                 0.878 
               
               
                 TMEM50B_SQRDL 
                 0.968 
                 0.900 
                 0.680 
                 0.990 
                 0.852 
                 0.878 
               
               
                 CSNK1G2_CEBPB 
                 0.959 
                 1.000 
                 0.560 
                 0.878 
                 0.988 
                 0.877 
               
               
                 RPL15_SH3GLB1 
                 0.964 
                 0.980 
                 0.720 
                 0.990 
                 0.730 
                 0.877 
               
               
                 BCL11A_G6PD 
                 0.979 
                 0.620 
                 0.960 
                 0.954 
                 0.870 
                 0.876 
               
               
                 ZBED5_SQRDL 
                 0.963 
                 0.860 
                 0.680 
                 0.995 
                 0.885 
                 0.876 
               
               
                 ARID1A_SERPINB1 
                 0.977 
                 0.880 
                 0.640 
                 0.949 
                 0.936 
                 0.876 
               
               
                 RPS14_SH3GLB1 
                 0.954 
                 0.940 
                 0.640 
                 0.908 
                 0.939 
                 0.876 
               
               
                 EXOSC10_TAP1 
                 0.969 
                 1.000 
                 0.600 
                 0.949 
                 0.864 
                 0.876 
               
               
                 BCL11A_CEBPB 
                 0.978 
                 0.720 
                 0.720 
                 1.000 
                 0.961 
                 0.876 
               
               
                 ADSL_ATOX1 
                 0.928 
                 1.000 
                 0.600 
                 0.893 
                 0.958 
                 0.876 
               
               
                 TCF4_FCER1G 
                 0.992 
                 0.780 
                 0.760 
                 0.923 
                 0.921 
                 0.875 
               
               
                 LY9_SH3GLB1 
                 0.961 
                 0.720 
                 0.760 
                 0.964 
                 0.970 
                 0.875 
               
               
                 IMP3_GNG5 
                 0.979 
                 0.700 
                 0.800 
                 0.918 
                 0.976 
                 0.875 
               
               
                 SERTAD2_CEBPB 
                 0.979 
                 0.820 
                 0.760 
                 0.908 
                 0.906 
                 0.875 
               
               
                 AHCTF1_MYD88 
                 0.962 
                 0.640 
                 0.840 
                 0.964 
                 0.967 
                 0.875 
               
               
                 ARID1A_ENO1 
                 0.949 
                 0.800 
                 0.640 
                 0.995 
                 0.988 
                 0.874 
               
               
                 EXOSC10_UPP1 
                 0.990 
                 1.000 
                 0.560 
                 0.923 
                 0.897 
                 0.874 
               
               
                 CEP192_CSTB 
                 0.939 
                 0.760 
                 0.880 
                 0.872 
                 0.918 
                 0.874 
               
               
                 LY9_SQRDL 
                 0.967 
                 0.720 
                 0.800 
                 1.000 
                 0.882 
                 0.874 
               
               
                 LY9_TNIP1 
                 0.982 
                 0.660 
                 0.920 
                 0.903 
                 0.903 
                 0.874 
               
               
                 CNOT7_G6PD 
                 0.966 
                 0.980 
                 0.760 
                 0.857 
                 0.803 
                 0.873 
               
               
                 ARID1A_PLSCR1 
                 0.946 
                 0.960 
                 0.640 
                 0.949 
                 0.870 
                 0.873 
               
               
                 CEP192_ATOX1 
                 0.920 
                 0.920 
                 0.600 
                 0.974 
                 0.948 
                 0.873 
               
               
                 IMP3_ENO1 
                 0.983 
                 0.720 
                 0.800 
                 0.985 
                 0.876 
                 0.873 
               
               
                 ARID1A_IRF1 
                 0.923 
                 1.000 
                 0.640 
                 0.811 
                 0.988 
                 0.872 
               
               
                 EXOSC10_GNG5 
                 0.978 
                 0.840 
                 0.680 
                 0.903 
                 0.961 
                 0.872 
               
               
                 LY9_ATOX1 
                 0.953 
                 0.700 
                 0.760 
                 1.000 
                 0.948 
                 0.872 
               
               
                 FBXO11_CEBPB 
                 0.932 
                 0.880 
                 0.600 
                 0.944 
                 1.000 
                 0.871 
               
               
                 RPL9_SLAMF7 
                 0.926 
                 0.920 
                 0.760 
                 0.903 
                 0.845 
                 0.871 
               
               
                 RPL9_TNIP1 
                 0.946 
                 0.880 
                 0.800 
                 0.755 
                 0.973 
                 0.871 
               
               
                 PREPL_CD63 
                 0.946 
                 1.000 
                 0.560 
                 0.847 
                 1.000 
                 0.871 
               
               
                 ARHGAP17_SQRDL 
                 0.984 
                 0.960 
                 0.720 
                 0.837 
                 0.852 
                 0.871 
               
               
                 ZBED5_POMP 
                 0.953 
                 0.780 
                 0.680 
                 1.000 
                 0.939 
                 0.871 
               
               
                 RPS4X_TSPO 
                 0.944 
                 0.820 
                 0.720 
                 0.944 
                 0.924 
                 0.870 
               
               
                 IMP3_G6PD 
                 0.989 
                 0.680 
                 0.840 
                 0.939 
                 0.903 
                 0.870 
               
               
                 CEP192_POMP 
                 0.932 
                 0.780 
                 0.720 
                 0.964 
                 0.955 
                 0.870 
               
               
                 TMEM5OB_CD63 
                 0.988 
                 0.860 
                 0.680 
                 0.995 
                 0.827 
                 0.870 
               
               
                 ZMYND11_ENO1 
                 0.931 
                 0.880 
                 0.600 
                 1.000 
                 0.936 
                 0.870 
               
               
                 CEP192_LAP3 
                 0.920 
                 0.860 
                 0.680 
                 0.923 
                 0.964 
                 0.869 
               
               
                 RPL9_UPP1 
                 0.948 
                 0.960 
                 0.640 
                 0.842 
                 0.958 
                 0.869 
               
               
                 TCF4_SERPINB1 
                 0.984 
                 0.920 
                 0.760 
                 0.883 
                 0.800 
                 0.869 
               
               
                 AHCTF1_PLAUR 
                 0.973 
                 0.720 
                 0.800 
                 0.857 
                 0.994 
                 0.869 
               
               
                 RPL22_WARS 
                 0.932 
                 1.000 
                 0.760 
                 0.903 
                 0.748 
                 0.869 
               
               
                 EXOSC2_POMP 
                 0.924 
                 0.900 
                 0.640 
                 0.934 
                 0.945 
                 0.869 
               
               
                 ZMYND11_SH3GLB1 
                 0.919 
                 0.920 
                 0.520 
                 0.990 
                 0.994 
                 0.869 
               
               
                 RPS14_CD63 
                 0.983 
                 0.960 
                 0.600 
                 0.949 
                 0.848 
                 0.868 
               
               
                 CAMK2G_SQRDL 
                 0.882 
                 1.000 
                 0.520 
                 0.990 
                 0.948 
                 0.868 
               
               
                 ARIH2_CEBPB 
                 0.959 
                 0.780 
                 0.680 
                 0.980 
                 0.939 
                 0.868 
               
               
                 ARID1A_NFIL3 
                 0.975 
                 0.980 
                 0.600 
                 0.791 
                 0.988 
                 0.867 
               
               
                 IMP3_POMP 
                 0.968 
                 0.760 
                 0.720 
                 0.944 
                 0.942 
                 0.867 
               
               
                 EXOSC10_ENO1 
                 0.979 
                 1.000 
                 0.560 
                 0.995 
                 0.800 
                 0.867 
               
               
                 PREPL_SH3GLB1 
                 0.922 
                 0.960 
                 0.600 
                 0.852 
                 1.000 
                 0.867 
               
               
                 TTC17_BCL6 
                 0.991 
                 0.920 
                 0.600 
                 0.903 
                 0.918 
                 0.867 
               
               
                 ZMYND11_POMP 
                 0.911 
                 0.980 
                 0.480 
                 1.000 
                 0.958 
                 0.866 
               
               
                 IMP3_RIT1 
                 0.967 
                 0.880 
                 0.760 
                 0.939 
                 0.782 
                 0.866 
               
               
                 CAMK2G_CD63 
                 0.961 
                 1.000 
                 0.480 
                 0.980 
                 0.906 
                 0.865 
               
               
                 IL10RA_CEBPB 
                 0.976 
                 0.800 
                 0.680 
                 0.985 
                 0.885 
                 0.865 
               
               
                 FNTA_TCIRG1 
                 0.951 
                 0.860 
                 0.640 
                 0.913 
                 0.961 
                 0.865 
               
               
                 CAMK2G_TCIRG1 
                 0.912 
                 0.980 
                 0.560 
                 0.959 
                 0.912 
                 0.865 
               
               
                 EXOSC10_PCMT1 
                 0.982 
                 0.980 
                 0.760 
                 0.918 
                 0.682 
                 0.865 
               
               
                 RPS14_SQRDL 
                 0.956 
                 0.940 
                 0.600 
                 0.929 
                 0.897 
                 0.864 
               
               
                 IMP3_PGD 
                 0.994 
                 0.720 
                 0.840 
                 0.949 
                 0.818 
                 0.864 
               
               
                 ZBED5_TNIP1 
                 0.987 
                 0.860 
                 0.720 
                 0.898 
                 0.855 
                 0.864 
               
               
                 CHN2_WARS 
                 0.950 
                 1.000 
                 0.640 
                 0.786 
                 0.942 
                 0.864 
               
               
                 IMP3_TCIRG1 
                 0.970 
                 0.800 
                 0.800 
                 0.908 
                 0.839 
                 0.863 
               
               
                 AHCTF1_SQRDL 
                 0.957 
                 0.660 
                 0.760 
                 0.985 
                 0.955 
                 0.863 
               
               
                 CLIP4_WARS 
                 0.927 
                 0.740 
                 0.760 
                 0.944 
                 0.942 
                 0.863 
               
               
                 NOSIP_POMP 
                 0.950 
                 0.800 
                 0.680 
                 0.980 
                 0.903 
                 0.862 
               
               
                 RPL22_SQRDL 
                 0.933 
                 0.920 
                 0.640 
                 0.985 
                 0.833 
                 0.862 
               
               
                 IMP3_VAMP3 
                 0.966 
                 0.620 
                 0.840 
                 0.934 
                 0.952 
                 0.862 
               
               
                 TTC17_TIMP2 
                 0.971 
                 0.780 
                 0.640 
                 0.990 
                 0.930 
                 0.862 
               
               
                 TTC17_SQRDL 
                 0.956 
                 0.980 
                 0.440 
                 0.995 
                 0.939 
                 0.862 
               
               
                 ARID1A_CD63 
                 0.985 
                 0.860 
                 0.520 
                 0.985 
                 0.961 
                 0.862 
               
               
                 FNTA_LAP3 
                 0.923 
                 0.960 
                 0.560 
                 0.918 
                 0.948 
                 0.862 
               
               
                 BCL11A_LAP3 
                 0.931 
                 0.680 
                 0.800 
                 0.974 
                 0.924 
                 0.862 
               
               
                 IMP3_FCER1G 
                 0.988 
                 0.680 
                 0.760 
                 0.934 
                 0.945 
                 0.861 
               
               
                 CEP192_TNIP1 
                 0.964 
                 0.860 
                 0.680 
                 0.878 
                 0.924 
                 0.861 
               
               
                 ZMYND11_SQRDL 
                 0.910 
                 0.920 
                 0.520 
                 0.995 
                 0.961 
                 0.861 
               
               
                 ZMYND11_GNG5 
                 0.935 
                 0.960 
                 0.440 
                 0.985 
                 0.985 
                 0.861 
               
               
                 ARID1A_SLAMF7 
                 0.953 
                 0.980 
                 0.640 
                 0.903 
                 0.827 
                 0.861 
               
               
                 ARID1A_TCIRG1 
                 0.964 
                 0.820 
                 0.680 
                 0.913 
                 0.924 
                 0.860 
               
               
                 ARID1A_TNIP1 
                 0.951 
                 1.000 
                 0.520 
                 0.872 
                 0.958 
                 0.860 
               
               
                 ZMYND11_PGD 
                 0.971 
                 0.940 
                 0.560 
                 0.990 
                 0.839 
                 0.860 
               
               
                 CSNK1G2_TCIRG1 
                 0.969 
                 1.000 
                 0.520 
                 0.908 
                 0.900 
                 0.859 
               
               
                 TTC17_CD63 
                 0.986 
                 0.980 
                 0.440 
                 0.969 
                 0.921 
                 0.859 
               
               
                 NUP160_RTN4 
                 0.978 
                 0.840 
                 0.720 
                 0.944 
                 0.812 
                 0.859 
               
               
                 RPL15_SQRDL 
                 0.956 
                 1.000 
                 0.760 
                 0.995 
                 0.582 
                 0.859 
               
               
                 TTC17_UPP1 
                 0.981 
                 0.940 
                 0.520 
                 0.939 
                 0.912 
                 0.858 
               
               
                 CAMK2G_FCER1G 
                 0.941 
                 0.940 
                 0.520 
                 0.954 
                 0.936 
                 0.858 
               
               
                 CEP192_TCIRG1 
                 0.966 
                 0.740 
                 0.760 
                 0.913 
                 0.912 
                 0.858 
               
               
                 IRF8_CEBPB 
                 0.984 
                 0.600 
                 0.920 
                 0.857 
                 0.930 
                 0.858 
               
               
                 CEP192_G6PD 
                 0.980 
                 0.660 
                 0.880 
                 0.898 
                 0.873 
                 0.858 
               
               
                 FBXO11_UPP1 
                 0.942 
                 0.840 
                 0.600 
                 0.929 
                 0.979 
                 0.858 
               
               
                 ARIH2_TCIRG1 
                 0.971 
                 0.700 
                 0.720 
                 0.964 
                 0.933 
                 0.858 
               
               
                 PCID2_WARS 
                 0.948 
                 0.640 
                 0.800 
                 0.923 
                 0.976 
                 0.858 
               
               
                 CAMK2G_PGD 
                 0.962 
                 0.980 
                 0.560 
                 0.985 
                 0.800 
                 0.857 
               
               
                 EXOSC10_FLII 
                 0.954 
                 0.840 
                 0.680 
                 0.934 
                 0.879 
                 0.857 
               
               
                 RPL15_CD63 
                 0.991 
                 1.000 
                 0.720 
                 0.990 
                 0.585 
                 0.857 
               
               
                 RPL22_CD63 
                 0.978 
                 0.960 
                 0.600 
                 0.959 
                 0.788 
                 0.857 
               
               
                 CNOT7_SQRDL 
                 0.956 
                 1.000 
                 0.600 
                 0.862 
                 0.867 
                 0.857 
               
               
                 FBXO11_SQRDL 
                 0.914 
                 0.860 
                 0.520 
                 0.990 
                 1.000 
                 0.857 
               
               
                 TCF4_UPP1 
                 0.988 
                 0.900 
                 0.760 
                 0.827 
                 0.809 
                 0.857 
               
               
                 PCID2_CEBPB 
                 0.953 
                 0.660 
                 0.720 
                 0.949 
                 1.000 
                 0.856 
               
               
                 CNOT7_CSTB 
                 0.953 
                 0.940 
                 0.760 
                 0.816 
                 0.812 
                 0.856 
               
               
                 ARID1A_PGD 
                 0.991 
                 0.880 
                 0.560 
                 0.964 
                 0.885 
                 0.856 
               
               
                 ARID1A_STAT3 
                 0.956 
                 0.960 
                 0.560 
                 0.913 
                 0.891 
                 0.856 
               
               
                 NOSIP_TCIRG1 
                 0.954 
                 0.720 
                 0.800 
                 0.944 
                 0.861 
                 0.856 
               
               
                 RPL9_FCER1G 
                 0.979 
                 0.740 
                 0.680 
                 0.888 
                 0.991 
                 0.856 
               
               
                 ARID1A_TRPC4AP 
                 0.946 
                 0.920 
                 0.600 
                 0.811 
                 1.000 
                 0.855 
               
               
                 ARID1A_SH3GLB1 
                 0.964 
                 0.820 
                 0.560 
                 0.944 
                 0.988 
                 0.855 
               
               
                 CEP192_RAB27A 
                 0.972 
                 0.840 
                 0.720 
                 0.832 
                 0.912 
                 0.855 
               
               
                 EXOSC10_FCER1G 
                 0.992 
                 0.880 
                 0.520 
                 0.944 
                 0.939 
                 0.855 
               
               
                 SETX_SQRDL 
                 0.965 
                 0.940 
                 0.520 
                 0.913 
                 0.936 
                 0.855 
               
               
                 CEP192_MYD88 
                 0.959 
                 0.780 
                 0.680 
                 0.883 
                 0.973 
                 0.855 
               
               
                 ARID1A_BCL6 
                 0.987 
                 0.920 
                 0.560 
                 0.888 
                 0.918 
                 0.855 
               
               
                 EXOSC2_CD63 
                 0.965 
                 0.920 
                 0.560 
                 0.949 
                 0.879 
                 0.855 
               
               
                 AHCTF1_UPP1 
                 0.974 
                 0.760 
                 0.640 
                 0.974 
                 0.924 
                 0.855 
               
               
                 IMP3_RALB 
                 0.965 
                 0.700 
                 0.840 
                 0.939 
                 0.827 
                 0.854 
               
               
                 ADK_SH3GLB1 
                 0.979 
                 1.000 
                 0.760 
                 0.878 
                 0.655 
                 0.854 
               
               
                 SUCLG2_CD63 
                 0.995 
                 0.960 
                 0.680 
                 0.923 
                 0.712 
                 0.854 
               
               
                 FNTA_WARS 
                 0.950 
                 0.960 
                 0.560 
                 0.918 
                 0.882 
                 0.854 
               
               
                 EXOSC10_TUBA1B 
                 0.981 
                 0.640 
                 0.760 
                 1.000 
                 0.888 
                 0.854 
               
               
                 IMP3_PCBP1 
                 0.975 
                 0.600 
                 0.920 
                 0.878 
                 0.894 
                 0.853 
               
               
                 ARID1A_GRINA 
                 0.941 
                 0.940 
                 0.520 
                 0.929 
                 0.936 
                 0.853 
               
               
                 TTC17_PGD 
                 0.993 
                 1.000 
                 0.480 
                 0.995 
                 0.797 
                 0.853 
               
               
                 ARID1A_TANK 
                 0.948 
                 1.000 
                 0.440 
                 0.898 
                 0.979 
                 0.853 
               
               
                 CSNK1G2_FLII 
                 0.929 
                 0.920 
                 0.640 
                 0.883 
                 0.894 
                 0.853 
               
               
                 CEP192_STAT3 
                 0.973 
                 0.900 
                 0.640 
                 0.939 
                 0.812 
                 0.853 
               
               
                 AHCTF1_SH3GLB1 
                 0.956 
                 0.620 
                 0.720 
                 0.980 
                 0.985 
                 0.852 
               
               
                 TTC17_SERPINB1 
                 0.975 
                 0.900 
                 0.520 
                 0.959 
                 0.906 
                 0.852 
               
               
                 EXOSC2_UPP1 
                 0.957 
                 0.980 
                 0.560 
                 0.888 
                 0.876 
                 0.852 
               
               
                 IMP3_TSPO 
                 0.980 
                 0.520 
                 0.880 
                 0.985 
                 0.894 
                 0.852 
               
               
                 BCL11A_TNIP1 
                 0.986 
                 0.640 
                 0.840 
                 0.878 
                 0.915 
                 0.852 
               
               
                 ADSL_ENO1 
                 0.988 
                 0.920 
                 0.640 
                 0.862 
                 0.848 
                 0.852 
               
               
                 NOSIP_SQRDL 
                 0.948 
                 0.800 
                 0.680 
                 0.990 
                 0.839 
                 0.851 
               
               
                 SERBP1_SH3GLB1 
                 0.971 
                 0.920 
                 0.600 
                 0.888 
                 0.879 
                 0.851 
               
               
                 ARID1A_NFKBIA 
                 0.993 
                 0.940 
                 0.680 
                 0.791 
                 0.852 
                 0.851 
               
               
                 RPL9_ENO1 
                 0.948 
                 0.780 
                 0.720 
                 0.888 
                 0.918 
                 0.851 
               
               
                 ARID1A_RAB27A 
                 0.960 
                 0.880 
                 0.600 
                 0.862 
                 0.952 
                 0.851 
               
               
                 RPL15_WARS 
                 0.950 
                 1.000 
                 0.840 
                 0.974 
                 0.488 
                 0.851 
               
               
                 BCL11A_CSTB 
                 0.939 
                 0.500 
                 1.000 
                 0.929 
                 0.885 
                 0.851 
               
               
                 ARID1A_SOCS3 
                 0.964 
                 0.980 
                 0.600 
                 0.760 
                 0.948 
                 0.850 
               
               
                 ARID1A_C3AR1 
                 0.993 
                 0.720 
                 0.680 
                 0.913 
                 0.945 
                 0.850 
               
               
                 RPL15_GPI 
                 0.980 
                 0.780 
                 0.800 
                 0.990 
                 0.700 
                 0.850 
               
               
                 ARIH2_TNIP1 
                 0.978 
                 0.800 
                 0.600 
                 0.908 
                 0.964 
                 0.850 
               
               
                 TOP2B_TUBA1B 
                 0.957 
                 0.680 
                 0.720 
                 0.985 
                 0.906 
                 0.849 
               
               
                 ZBED5_CD63 
                 0.988 
                 0.820 
                 0.600 
                 0.995 
                 0.842 
                 0.849 
               
               
                 TCF4_PGD 
                 0.993 
                 0.840 
                 0.760 
                 0.918 
                 0.733 
                 0.849 
               
               
                 ARID1A_MYD88 
                 0.950 
                 0.860 
                 0.560 
                 0.929 
                 0.945 
                 0.849 
               
               
                 TTC17_FCER1G 
                 0.983 
                 0.800 
                 0.560 
                 0.985 
                 0.915 
                 0.849 
               
               
                 BCL11A_POMP 
                 0.953 
                 0.540 
                 0.840 
                 0.990 
                 0.918 
                 0.848 
               
               
                 ARID1A_UPP1 
                 0.974 
                 0.860 
                 0.560 
                 0.934 
                 0.912 
                 0.848 
               
               
                 ARID1A_ERLIN1 
                 0.949 
                 0.900 
                 0.600 
                 0.990 
                 0.797 
                 0.847 
               
               
                 MGEA5_SQRDL 
                 0.877 
                 0.940 
                 0.440 
                 0.995 
                 0.982 
                 0.847 
               
               
                 NUP160_TPP1 
                 0.990 
                 0.500 
                 0.880 
                 0.903 
                 0.961 
                 0.847 
               
               
                 HLA-DPA1_CEBPB 
                 0.986 
                 0.720 
                 0.800 
                 0.872 
                 0.855 
                 0.847 
               
               
                 RPL9_SERPINB1 
                 0.952 
                 0.840 
                 0.640 
                 0.857 
                 0.942 
                 0.846 
               
               
                 SETX_CD63 
                 0.973 
                 0.820 
                 0.600 
                 0.898 
                 0.939 
                 0.846 
               
               
                 RPL9_LDHA 
                 0.960 
                 0.780 
                 0.600 
                 0.908 
                 0.982 
                 0.846 
               
               
                 EXOSC10_SERPINB1 
                 0.982 
                 0.960 
                 0.520 
                 0.929 
                 0.839 
                 0.846 
               
               
                 EXOSC10_PGD 
                 0.995 
                 1.000 
                 0.560 
                 0.964 
                 0.709 
                 0.846 
               
               
                 EXOSC10_RALB 
                 0.969 
                 0.900 
                 0.600 
                 0.944 
                 0.815 
                 0.846 
               
               
                 EXOSC10_TSPO 
                 0.981 
                 0.880 
                 0.560 
                 0.969 
                 0.836 
                 0.845 
               
               
                 ARID1A_CD55 
                 0.976 
                 0.820 
                 0.640 
                 0.821 
                 0.970 
                 0.845 
               
               
                 CHN2_FCER1G 
                 0.972 
                 0.920 
                 0.520 
                 0.827 
                 0.988 
                 0.845 
               
               
                 LY9_MYD88 
                 0.958 
                 0.620 
                 0.800 
                 0.944 
                 0.903 
                 0.845 
               
               
                 ARID1A_BCL3 
                 0.979 
                 0.940 
                 0.600 
                 0.745 
                 0.961 
                 0.845 
               
               
                 ARID1A_ETV6 
                 0.944 
                 0.880 
                 0.560 
                 0.918 
                 0.921 
                 0.845 
               
               
                 IRF8_LAP3 
                 0.933 
                 0.660 
                 0.960 
                 0.791 
                 0.879 
                 0.844 
               
               
                 TCF4_CD63 
                 0.986 
                 0.840 
                 0.680 
                 0.883 
                 0.833 
                 0.844 
               
               
                 FBXO11_MYD88 
                 0.915 
                 0.780 
                 0.600 
                 0.934 
                 0.994 
                 0.844 
               
               
                 TMEM106B_CEBPB 
                 0.974 
                 0.960 
                 0.640 
                 0.765 
                 0.882 
                 0.844 
               
               
                 RPL9_PGD 
                 0.979 
                 0.820 
                 0.680 
                 0.872 
                 0.870 
                 0.844 
               
               
                 ZNF266_CD63 
                 0.976 
                 0.820 
                 0.640 
                 0.995 
                 0.788 
                 0.844 
               
               
                 CCR7_CEBPB 
                 0.945 
                 0.620 
                 0.760 
                 0.923 
                 0.970 
                 0.844 
               
               
                 CEP192_SQRDL 
                 0.965 
                 0.760 
                 0.600 
                 0.974 
                 0.918 
                 0.844 
               
               
                 ARID1A_PRKCD 
                 0.982 
                 0.760 
                 0.600 
                 0.990 
                 0.885 
                 0.843 
               
               
                 FBXO11_SH3GLB1 
                 0.926 
                 0.760 
                 0.560 
                 0.969 
                 1.000 
                 0.843 
               
               
                 IMP3_PRKCD 
                 0.972 
                 0.700 
                 0.800 
                 0.959 
                 0.785 
                 0.843 
               
               
                 EXOSC10_GPI 
                 0.964 
                 0.760 
                 0.600 
                 0.985 
                 0.906 
                 0.843 
               
               
                 CEP192_UPP1 
                 0.988 
                 0.840 
                 0.560 
                 0.888 
                 0.939 
                 0.843 
               
               
                 BCL11A_GNG5 
                 0.975 
                 0.640 
                 0.680 
                 0.969 
                 0.948 
                 0.843 
               
               
                 ARIH2_SH3GLB1 
                 0.947 
                 0.680 
                 0.640 
                 0.985 
                 0.961 
                 0.843 
               
               
                 TOP2B_TPP1 
                 0.992 
                 0.640 
                 0.680 
                 0.985 
                 0.915 
                 0.842 
               
               
                 SEH1L_SQRDL 
                 0.961 
                 0.820 
                 0.600 
                 0.883 
                 0.942 
                 0.841 
               
               
                 ARID1A_FCER1G 
                 0.980 
                 0.780 
                 0.520 
                 0.959 
                 0.967 
                 0.841 
               
               
                 EXOSC10_ERLIN1 
                 0.986 
                 1.000 
                 0.520 
                 0.980 
                 0.715 
                 0.840 
               
               
                 ARID1A_RTN4 
                 0.988 
                 0.800 
                 0.600 
                 0.954 
                 0.858 
                 0.840 
               
               
                 HERC6_LAP3 
                 0.907 
                 0.840 
                 0.560 
                 0.913 
                 0.979 
                 0.840 
               
               
                 ARID1A_FLOT1 
                 0.980 
                 0.920 
                 0.560 
                 0.913 
                 0.824 
                 0.839 
               
               
                 TCF4_PRKCD 
                 0.993 
                 0.760 
                 0.800 
                 0.898 
                 0.742 
                 0.839 
               
               
                 LY9_PLAUR 
                 0.971 
                 0.640 
                 0.760 
                 0.852 
                 0.970 
                 0.839 
               
               
                 ARID1A_NUMB 
                 0.965 
                 0.860 
                 0.520 
                 0.929 
                 0.918 
                 0.838 
               
               
                 TRAF3IP3_WARS 
                 0.949 
                 0.760 
                 0.600 
                 0.929 
                 0.955 
                 0.838 
               
               
                 CEP192_SH3GLB1 
                 0.965 
                 0.720 
                 0.600 
                 0.918 
                 0.988 
                 0.838 
               
               
                 AHCTF1_PGD 
                 0.991 
                 0.680 
                 0.720 
                 0.974 
                 0.824 
                 0.838 
               
               
                 EXOSC2_SQRDL 
                 0.924 
                 0.880 
                 0.520 
                 0.974 
                 0.891 
                 0.838 
               
               
                 FBXO11_CD63 
                 0.950 
                 0.760 
                 0.520 
                 0.964 
                 0.994 
                 0.838 
               
               
                 PCID2_POMP 
                 0.957 
                 0.520 
                 0.760 
                 0.954 
                 0.997 
                 0.838 
               
               
                 TTC17_FGR 
                 0.992 
                 0.920 
                 0.520 
                 1.000 
                 0.755 
                 0.837 
               
               
                 TROVE2_CEBPB 
                 0.979 
                 0.980 
                 0.600 
                 0.765 
                 0.861 
                 0.837 
               
               
                 ARID1A_RALB 
                 0.965 
                 0.840 
                 0.560 
                 0.944 
                 0.876 
                 0.837 
               
               
                 BCL11A_SQRDL 
                 0.973 
                 0.620 
                 0.680 
                 0.969 
                 0.939 
                 0.836 
               
               
                 IMP3_SERPINB1 
                 0.975 
                 0.720 
                 0.640 
                 0.918 
                 0.927 
                 0.836 
               
               
                 LY9_POMP 
                 0.966 
                 0.540 
                 0.760 
                 0.985 
                 0.930 
                 0.836 
               
               
                 CLIP4_CEBPB 
                 0.960 
                 0.660 
                 0.600 
                 0.959 
                 1.000 
                 0.836 
               
               
                 RPS4X_SPI1 
                 0.952 
                 0.680 
                 0.720 
                 0.923 
                 0.903 
                 0.836 
               
               
                 BCL11A_FCER1G 
                 0.990 
                 0.620 
                 0.640 
                 0.995 
                 0.930 
                 0.835 
               
               
                 EXOSC2_FCER1G 
                 0.963 
                 0.800 
                 0.600 
                 0.918 
                 0.891 
                 0.835 
               
               
                 AHCTF1_CD63 
                 0.987 
                 0.520 
                 0.760 
                 0.974 
                 0.930 
                 0.834 
               
               
                 ARIH2_SQRDL 
                 0.943 
                 0.740 
                 0.600 
                 0.985 
                 0.900 
                 0.834 
               
               
                 CEP192_LDHA 
                 0.952 
                 0.680 
                 0.640 
                 0.918 
                 0.976 
                 0.833 
               
               
                 FBXO11_SERPINB1 
                 0.943 
                 0.820 
                 0.480 
                 0.944 
                 0.976 
                 0.832 
               
               
                 IL10RA_TNIP1 
                 0.980 
                 0.840 
                 0.640 
                 0.923 
                 0.779 
                 0.832 
               
               
                 CEP192_GNG5 
                 0.964 
                 0.660 
                 0.680 
                 0.872 
                 0.985 
                 0.832 
               
               
                 ARHGAP17_CD63 
                 0.998 
                 0.960 
                 0.640 
                 0.745 
                 0.818 
                 0.832 
               
               
                 CNOT7_FCER1G 
                 0.996 
                 0.920 
                 0.520 
                 0.867 
                 0.858 
                 0.832 
               
               
                 ARIH2_G6PD 
                 0.980 
                 0.600 
                 0.680 
                 0.995 
                 0.906 
                 0.832 
               
               
                 NUP160_WAS 
                 0.960 
                 0.540 
                 0.800 
                 0.908 
                 0.952 
                 0.832 
               
               
                 LY9_CD63 
                 0.989 
                 0.500 
                 0.800 
                 0.980 
                 0.891 
                 0.832 
               
               
                 BCL11A_SH3GLB1 
                 0.980 
                 0.540 
                 0.720 
                 0.959 
                 0.961 
                 0.832 
               
               
                 ASXL2_WARS 
                 0.920 
                 0.680 
                 0.680 
                 0.888 
                 0.991 
                 0.832 
               
               
                 FBL_SQRDL 
                 0.959 
                 1.000 
                 0.520 
                 0.995 
                 0.685 
                 0.832 
               
               
                 CD52_CD63 
                 0.993 
                 0.800 
                 0.680 
                 0.929 
                 0.758 
                 0.832 
               
               
                 ADSL_POMP 
                 0.972 
                 0.900 
                 0.520 
                 0.796 
                 0.970 
                 0.832 
               
               
                 SERBP1_CD63 
                 0.991 
                 0.980 
                 0.520 
                 0.888 
                 0.779 
                 0.831 
               
               
                 ARID1A_POMP 
                 0.933 
                 0.800 
                 0.520 
                 0.969 
                 0.933 
                 0.831 
               
               
                 CHN2_SQRDL 
                 0.929 
                 1.000 
                 0.480 
                 0.770 
                 0.976 
                 0.831 
               
               
                 ARIH2_UPP1 
                 0.970 
                 0.800 
                 0.480 
                 0.990 
                 0.915 
                 0.831 
               
               
                 CEP192_VAMP3 
                 0.972 
                 0.680 
                 0.640 
                 0.908 
                 0.955 
                 0.831 
               
               
                 BCL11A_TANK 
                 0.979 
                 0.420 
                 0.880 
                 0.908 
                 0.967 
                 0.831 
               
               
                 GLG1_SQRDL 
                 0.961 
                 0.880 
                 0.560 
                 0.913 
                 0.839 
                 0.831 
               
               
                 IRF8_WARS 
                 0.966 
                 0.580 
                 0.960 
                 0.862 
                 0.785 
                 0.831 
               
               
                 HLA-DPA1_WARS 
                 0.983 
                 0.720 
                 0.840 
                 0.918 
                 0.691 
                 0.830 
               
               
                 DNAJC10_SQRDL 
                 0.952 
                 0.940 
                 0.560 
                 0.781 
                 0.918 
                 0.830 
               
               
                 ARID1A_FGR 
                 0.989 
                 0.820 
                 0.560 
                 0.944 
                 0.836 
                 0.830 
               
               
                 RPL9_TRIB1 
                 0.952 
                 0.780 
                 0.680 
                 0.806 
                 0.927 
                 0.829 
               
               
                 LY9_UPP1 
                 0.979 
                 0.600 
                 0.720 
                 0.964 
                 0.882 
                 0.829 
               
               
                 IL10RA_MYD88 
                 0.963 
                 0.740 
                 0.640 
                 0.985 
                 0.815 
                 0.829 
               
               
                 METAP1_RTN4 
                 0.965 
                 0.680 
                 0.640 
                 0.959 
                 0.891 
                 0.827 
               
               
                 BCL11A_RALB 
                 0.982 
                 0.560 
                 0.760 
                 0.990 
                 0.842 
                 0.827 
               
               
                 ARID1A_ATP2A2 
                 0.911 
                 0.860 
                 0.440 
                 0.923 
                 0.997 
                 0.826 
               
               
                 SERBP1_SQRDL 
                 0.967 
                 0.900 
                 0.560 
                 0.918 
                 0.785 
                 0.826 
               
               
                 MLLT10_CD63 
                 0.964 
                 0.720 
                 0.480 
                 0.974 
                 0.988 
                 0.825 
               
               
                 PCID2_CD63 
                 0.975 
                 0.600 
                 0.600 
                 0.954 
                 0.997 
                 0.825 
               
               
                 ARID1A_FLII 
                 0.936 
                 0.600 
                 0.760 
                 0.903 
                 0.924 
                 0.825 
               
               
                 EXOSC10_VAMP3 
                 0.969 
                 0.640 
                 0.640 
                 0.939 
                 0.924 
                 0.822 
               
               
                 CEP192_NFIL3 
                 0.980 
                 0.920 
                 0.440 
                 0.801 
                 0.970 
                 0.822 
               
               
                 ARID1A_HCK 
                 0.961 
                 0.700 
                 0.560 
                 0.964 
                 0.924 
                 0.822 
               
               
                 IMP3_SPI1 
                 0.986 
                 0.480 
                 0.840 
                 0.934 
                 0.870 
                 0.822 
               
               
                 PCID2_SQRDL 
                 0.934 
                 0.560 
                 0.640 
                 0.974 
                 1.000 
                 0.822 
               
               
                 MLLT10_PGD 
                 0.957 
                 0.760 
                 0.480 
                 0.969 
                 0.942 
                 0.822 
               
               
                 ARID1A_PLAUR 
                 0.956 
                 0.860 
                 0.560 
                 0.745 
                 0.988 
                 0.822 
               
               
                 TCF4_HCK 
                 0.970 
                 0.600 
                 0.800 
                 0.944 
                 0.794 
                 0.821 
               
               
                 TCF4_VAMP3 
                 0.977 
                 0.580 
                 0.800 
                 0.913 
                 0.836 
                 0.821 
               
               
                 EXOSC10_FGR 
                 0.991 
                 0.980 
                 0.520 
                 0.934 
                 0.682 
                 0.821 
               
               
                 ADSL_CD63 
                 0.990 
                 0.940 
                 0.480 
                 0.801 
                 0.894 
                 0.821 
               
               
                 CEP192_BCL6 
                 0.995 
                 0.780 
                 0.520 
                 0.867 
                 0.942 
                 0.821 
               
               
                 RPL9_TSPO 
                 0.950 
                 0.660 
                 0.720 
                 0.816 
                 0.958 
                 0.821 
               
               
                 FBXO11_FCER1G 
                 0.950 
                 0.720 
                 0.520 
                 0.944 
                 0.970 
                 0.821 
               
               
                 HLA-DPA1_MYD88 
                 0.980 
                 0.660 
                 0.800 
                 0.898 
                 0.764 
                 0.820 
               
               
                 CEP192_CD63 
                 0.991 
                 0.700 
                 0.560 
                 0.929 
                 0.921 
                 0.820 
               
               
                 EXOSC2_PGD 
                 0.971 
                 0.940 
                 0.480 
                 0.944 
                 0.764 
                 0.820 
               
               
                 EXOSC2_SH3GLB1 
                 0.938 
                 0.880 
                 0.480 
                 0.888 
                 0.912 
                 0.820 
               
               
                 EXOSC10_SLAMF7 
                 0.979 
                 1.000 
                 0.480 
                 0.908 
                 0.730 
                 0.819 
               
               
                 ARID1A_GNG5 
                 0.960 
                 0.820 
                 0.440 
                 0.903 
                 0.973 
                 0.819 
               
               
                 CEP192_FCER1G 
                 0.989 
                 0.720 
                 0.520 
                 0.934 
                 0.927 
                 0.818 
               
               
                 ARID1A_CCND3 
                 0.962 
                 0.600 
                 0.600 
                 0.954 
                 0.973 
                 0.818 
               
               
                 CEP192_PGD 
                 0.995 
                 0.720 
                 0.600 
                 0.969 
                 0.803 
                 0.818 
               
               
                 SERTAD2_SQRDL 
                 0.969 
                 0.640 
                 0.760 
                 0.878 
                 0.839 
                 0.817 
               
               
                 ASXL2_SH3GLB1 
                 0.943 
                 0.600 
                 0.640 
                 0.903 
                 1.000 
                 0.817 
               
               
                 BCL11A_UPP1 
                 0.989 
                 0.640 
                 0.640 
                 0.934 
                 0.882 
                 0.817 
               
               
                 ARID1A_TSPO 
                 0.973 
                 0.660 
                 0.520 
                 1.000 
                 0.930 
                 0.817 
               
               
                 ASXL2_IRF1 
                 0.912 
                 0.860 
                 0.560 
                 0.750 
                 1.000 
                 0.816 
               
               
                 TROVE2_SQRDL 
                 0.962 
                 0.940 
                 0.600 
                 0.816 
                 0.764 
                 0.816 
               
               
                 IMP3_C3AR1 
                 0.994 
                 0.580 
                 0.680 
                 0.867 
                 0.961 
                 0.816 
               
               
                 BCL11A_NFIL3 
                 0.982 
                 0.620 
                 0.640 
                 0.903 
                 0.936 
                 0.816 
               
               
                 TROVE2_SH3GLB1 
                 0.977 
                 0.900 
                 0.520 
                 0.837 
                 0.845 
                 0.816 
               
               
                 RPL9_RTN4 
                 0.994 
                 0.760 
                 0.760 
                 0.867 
                 0.697 
                 0.816 
               
               
                 SERTAD2_SH3GLB1 
                 0.970 
                 0.640 
                 0.680 
                 0.903 
                 0.885 
                 0.816 
               
               
                 ASXL2_BCL6 
                 0.975 
                 0.580 
                 0.680 
                 0.852 
                 0.991 
                 0.816 
               
               
                 ASXL2_CEBPB 
                 0.964 
                 0.680 
                 0.560 
                 0.872 
                 1.000 
                 0.815 
               
               
                 HLA-DPA1_LAP3 
                 0.950 
                 0.760 
                 0.800 
                 0.786 
                 0.779 
                 0.815 
               
               
                 CEP192_SERPINB1 
                 0.973 
                 0.740 
                 0.560 
                 0.908 
                 0.891 
                 0.814 
               
               
                 SETX_SH3GLB1 
                 0.963 
                 0.800 
                 0.480 
                 0.872 
                 0.955 
                 0.814 
               
               
                 IL10RA_SH3GLB1 
                 0.963 
                 0.680 
                 0.560 
                 0.980 
                 0.882 
                 0.813 
               
               
                 RPL9_VAMP3 
                 0.959 
                 0.520 
                 0.760 
                 0.847 
                 0.976 
                 0.812 
               
               
                 TROVE2_CD63 
                 0.985 
                 0.940 
                 0.560 
                 0.821 
                 0.755 
                 0.812 
               
               
                 CEP192_ACSL4 
                 0.983 
                 0.740 
                 0.560 
                 0.939 
                 0.833 
                 0.811 
               
               
                 ASXL2_CD63 
                 0.975 
                 0.580 
                 0.600 
                 0.903 
                 0.997 
                 0.811 
               
               
                 USP34_CD63 
                 0.947 
                 0.560 
                 0.560 
                 0.980 
                 1.000 
                 0.809 
               
               
                 ASXL2_UPP1 
                 0.964 
                 0.680 
                 0.560 
                 0.857 
                 0.985 
                 0.809 
               
               
                 ASXL2_TSPO 
                 0.962 
                 0.660 
                 0.520 
                 0.908 
                 0.994 
                 0.809 
               
               
                 CEP192_ERLIN1 
                 0.946 
                 0.800 
                 0.560 
                 0.959 
                 0.779 
                 0.809 
               
               
                 TCF4_TSPO 
                 0.983 
                 0.600 
                 0.800 
                 0.842 
                 0.818 
                 0.809 
               
               
                 ARIH2_FCER1G 
                 0.974 
                 0.540 
                 0.600 
                 0.969 
                 0.958 
                 0.808 
               
               
                 ARID1A_SORT1 
                 0.973 
                 0.760 
                 0.560 
                 0.959 
                 0.788 
                 0.808 
               
               
                 FNTA_G6PD 
                 0.967 
                 0.780 
                 0.520 
                 0.913 
                 0.855 
                 0.807 
               
               
                 RPL9_SPI1 
                 0.967 
                 0.500 
                 0.720 
                 0.888 
                 0.958 
                 0.806 
               
               
                 ARIH2_PGD 
                 0.982 
                 0.680 
                 0.640 
                 0.985 
                 0.742 
                 0.806 
               
               
                 TRAF3IP3_SQRDL 
                 0.958 
                 0.560 
                 0.560 
                 0.969 
                 0.982 
                 0.806 
               
               
                 TTC17_TSPO 
                 0.975 
                 0.780 
                 0.400 
                 1.000 
                 0.873 
                 0.806 
               
               
                 ASXL2_FGR 
                 0.975 
                 0.660 
                 0.560 
                 0.908 
                 0.924 
                 0.805 
               
               
                 LY9_PGD 
                 0.988 
                 0.500 
                 0.760 
                 0.990 
                 0.788 
                 0.805 
               
               
                 ARID1A_TIMP2 
                 0.963 
                 0.720 
                 0.480 
                 0.913 
                 0.948 
                 0.805 
               
               
                 PCID2_SH3GLB1 
                 0.951 
                 0.540 
                 0.600 
                 0.934 
                 1.000 
                 0.805 
               
               
                 ARID1A_ATP6V1B2 
                 0.976 
                 0.720 
                 0.520 
                 0.959 
                 0.848 
                 0.805 
               
               
                 BCL11A_CD63 
                 0.994 
                 0.520 
                 0.640 
                 0.954 
                 0.912 
                 0.804 
               
               
                 ARID1A_RBMS1 
                 0.974 
                 0.740 
                 0.480 
                 0.878 
                 0.942 
                 0.803 
               
               
                 HLA-DPA1_SQRDL 
                 0.976 
                 0.700 
                 0.760 
                 0.862 
                 0.715 
                 0.803 
               
               
                 IMP3_LDHA 
                 0.970 
                 0.700 
                 0.400 
                 0.964 
                 0.976 
                 0.802 
               
               
                 CNOT7_PGD 
                 0.999 
                 0.980 
                 0.480 
                 0.867 
                 0.679 
                 0.801 
               
               
                 IRF8_SQRDL 
                 0.972 
                 0.620 
                 0.720 
                 0.852 
                 0.839 
                 0.801 
               
               
                 ASXL2_TCIRG1 
                 0.954 
                 0.600 
                 0.600 
                 0.883 
                 0.967 
                 0.801 
               
               
                 BCL11A_MYD88 
                 0.966 
                 0.420 
                 0.680 
                 0.985 
                 0.942 
                 0.799 
               
               
                 CCR7_SQRDL 
                 0.942 
                 0.440 
                 0.680 
                 0.985 
                 0.942 
                 0.798 
               
               
                 ASXL2_G6PD 
                 0.956 
                 0.520 
                 0.680 
                 0.832 
                 1.000 
                 0.798 
               
               
                 ARID1A_SPI1 
                 0.978 
                 0.580 
                 0.560 
                 0.918 
                 0.948 
                 0.797 
               
               
                 ARID1A_VAMP3 
                 0.959 
                 0.540 
                 0.600 
                 0.934 
                 0.945 
                 0.796 
               
               
                 AHCTF1_BCL6 
                 0.995 
                 0.580 
                 0.480 
                 0.969 
                 0.952 
                 0.795 
               
               
                 ASXL2_KIF1B 
                 0.975 
                 0.680 
                 0.600 
                 0.929 
                 0.791 
                 0.795 
               
               
                 ASXL2_FCER1G 
                 0.972 
                 0.540 
                 0.560 
                 0.903 
                 1.000 
                 0.795 
               
               
                 IL10RA_SQRDL 
                 0.959 
                 0.680 
                 0.560 
                 0.980 
                 0.791 
                 0.794 
               
               
                 ASXL2_PGD 
                 0.979 
                 0.540 
                 0.560 
                 0.923 
                 0.964 
                 0.793 
               
               
                 CEP192_FGR 
                 0.993 
                 0.700 
                 0.600 
                 0.923 
                 0.748 
                 0.793 
               
               
                 ASXL2_SQRDL 
                 0.934 
                 0.660 
                 0.440 
                 0.923 
                 1.000 
                 0.792 
               
               
                 BCL11A_LDHA 
                 0.969 
                 0.560 
                 0.520 
                 0.959 
                 0.942 
                 0.790 
               
               
                 IRF8_POMP 
                 0.963 
                 0.560 
                 0.680 
                 0.847 
                 0.897 
                 0.789 
               
               
                 BCL11A_PGD 
                 0.994 
                 0.520 
                 0.680 
                 0.969 
                 0.782 
                 0.789 
               
               
                 ARID1A_JUNB 
                 0.981 
                 0.800 
                 0.520 
                 0.648 
                 0.994 
                 0.789 
               
               
                 CEP192_TSPO 
                 0.984 
                 0.500 
                 0.640 
                 0.934 
                 0.882 
                 0.788 
               
               
                 ASXL2_SERPINB1 
                 0.954 
                 0.660 
                 0.440 
                 0.883 
                 0.997 
                 0.787 
               
               
                 BCL11A_BCL6 
                 0.998 
                 0.560 
                 0.520 
                 0.964 
                 0.888 
                 0.786 
               
               
                 FBXO11_PGD 
                 0.962 
                 0.660 
                 0.440 
                 0.974 
                 0.885 
                 0.784 
               
               
                 BCL11A_SERPINB1 
                 0.985 
                 0.440 
                 0.680 
                 0.944 
                 0.870 
                 0.784 
               
               
                 BCL11A_ERLIN1 
                 0.979 
                 0.580 
                 0.680 
                 0.964 
                 0.712 
                 0.783 
               
               
                 ASXL2_ETV6 
                 0.928 
                 0.540 
                 0.520 
                 0.923 
                 0.991 
                 0.780 
               
               
                 ASXL2_RALB 
                 0.952 
                 0.540 
                 0.480 
                 0.944 
                 0.985 
                 0.780 
               
               
                 USP34_PGD 
                 0.960 
                 0.560 
                 0.400 
                 0.980 
                 1.000 
                 0.780 
               
               
                 ARID1A_PCBP1 
                 0.965 
                 0.660 
                 0.480 
                 0.847 
                 0.933 
                 0.777 
               
               
                 EXOSC2_TSPO 
                 0.954 
                 0.720 
                 0.400 
                 0.944 
                 0.861 
                 0.776 
               
               
                 CEP192_PRKCD 
                 0.993 
                 0.440 
                 0.720 
                 0.959 
                 0.761 
                 0.774 
               
               
                 IRF8_SH3GLB1 
                 0.985 
                 0.460 
                 0.680 
                 0.791 
                 0.933 
                 0.770 
               
               
                 ARIH2_CD63 
                 0.983 
                 0.440 
                 0.520 
                 1.000 
                 0.900 
                 0.769 
               
               
                 ARID1A_RAB7A 
                 0.962 
                 0.680 
                 0.440 
                 0.934 
                 0.827 
                 0.769 
               
               
                 TTC17_VAMP3 
                 0.968 
                 0.560 
                 0.400 
                 0.990 
                 0.924 
                 0.768 
               
               
                 ARID1A_WAS 
                 0.982 
                 0.620 
                 0.400 
                 0.908 
                 0.879 
                 0.758 
               
               
                 TTC17_WAS 
                 0.994 
                 0.580 
                 0.360 
                 1.000 
                 0.839 
                 0.755 
               
               
                 HLA-DPA1_POMP 
                 0.974 
                 0.380 
                 0.720 
                 0.872 
                 0.821 
                 0.754 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 36 
               
             
            
               
                   
               
               
                 TOP PERFORMING (BASED ON AUC) INSIRS DERIVED 
               
               
                 BIOMARKERS FOLLOWING A GREEDY SEARCH ON A 
               
               
                 COMBINED DATASET 
               
               
                 The top derived biomarker was ENTPD1:ARL6IP5 with an AUC of 0.898. 
               
               
                 Incremental AUC increases can be made with the addition of further 
               
               
                 derived biomarkers as indicated. 
               
            
           
           
               
               
               
               
            
               
                   
                 Derived Biomarker 
                 AUC 
                 Increased AUC 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 ENTPD1_ARL6IP5 
                 0.898 
                 0.037 
               
               
                   
                 TNFSF8_HEATR1 
                 0.935 
                 0.013 
               
               
                   
                 ADAM19_POLR2A 
                 0.948 
                 0.007 
               
               
                   
                 SYNE2_VPS13C 
                 0.955 
                 0.004 
               
               
                   
                 TNFSF8_NIP7 
                 0.959 
                 0.002 
               
               
                   
                 CDA_EFHD2 
                 0.962 
                 0.000 
               
               
                   
                 ADAM19_MLLT10 
                 0.962 
                 0.000 
               
               
                   
                 PTGS1 + ENTPD1 
                 0.962 
                 0.001 
               
               
                   
                 ADAM19_EXOC7 
                 0.963 
                 0.002 
               
               
                   
                 CDA_PTGS1 
                 0.965 
                 −0.965 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 37 
               
             
            
               
                   
               
               
                 INSIRS NUMERATORS AND DENOMINATORS APPEARING MORE 
               
               
                 THAN TWICE IN THE 164 DERIVED BIOMARKERS WITH A MEAN 
               
               
                 AUC &gt; 0.82 IN THE VALIDATION DATASETS. 
               
               
                 inSIRS numerators and denominators appearing more than once in 
               
               
                 derived biomarkers with an AUC &gt; 0.85 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Numerator 
                 # 
                 Denominator 
                 # 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 TNFSF8 
                 90 
                 MACF1 
                 8 
               
               
                   
                 ADAM19 
                 17 
                 ARL6IP5 
                 6 
               
               
                   
                 VNN3 
                 12 
                 TRAPPC2 
                 5 
               
               
                   
                 RGS2 
                 11 
                 KRIT1 
                 3 
               
               
                   
                 GAB2 
                 8 
                 RBM26 
                 3 
               
               
                   
                 STK17B 
                 4 
                 SYT11 
                 3 
               
               
                   
                 ENTPD1 
                 3 
                 YTHDC2 
                 3 
               
               
                   
                 IGF2R 
                 3 
                 CDKN1B 
                 2 
               
               
                   
                 SYNE2 
                 3 
                 CYSLTR1 
                 2 
               
               
                   
                 CDA 
                 2 
                 FCF1 
                 2 
               
               
                   
                 MXD1 
                 2 
                 LARP1 
                 2 
               
               
                   
                   
                   
                 MLLT10 
                 2 
               
               
                   
                   
                   
                 PHC3 
                 2 
               
               
                   
                   
                   
                 S100PBP 
                 2 
               
               
                   
                   
                   
                 THOC2 
                 2 
               
               
                   
                   
                   
                 ZNF507 
                 2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 38 
               
             
            
               
                   
               
               
                 TABLE OF INDIVIDUAL PERFORMANCE, IN DESCENDING AUC, OF 164 INSIRS DERIVED BIOMARKERS WITH 
               
               
                 AN AVERAGE AUC &gt;0.82 ACROSS EACH OF SIX NON-INFECTIOUS SYSTEMIC INFLAMMATION DATASETS. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Children 
                   
                   
                   
                 Acute 
                 Adult 
                   
               
               
                   
                 Sepsis/ 
                 Auto- 
                   
                   
                 Respiratory 
                 Sepsis/ 
                   
               
               
                   
                 SIRS 
                 immunity 
                 Trauma 
                 Anaphylaxis 
                 Inflammation 
                 SIRS 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Derived Biomarker 
                 GAPPSS 
                 GSE17755 
                 GSE36809 
                 GSE47655 
                 GSE63990 
                 GSE74224 
                 MEAN 
               
               
                 TNFSF8_VEZT 
                 0.885 
                 NA 
                 0.987 
                 0.951 
                 0.816 
                 0.926 
                 0.904 
               
               
                 TNFSF8_HEATR1 
                 0.882 
                 NA 
                 0.978 
                 0.840 
                 0.897 
                 0.907 
                 0.893 
               
               
                 TNFSF8_THOC2 
                 0.939 
                 NA 
                 0.977 
                 0.852 
                 0.780 
                 0.936 
                 0.889 
               
               
                 TNFSF8_NIP7 
                 0.897 
                 NA 
                 0.947 
                 0.840 
                 0.823 
                 0.961 
                 0.885 
               
               
                 TNFSF8_MLLT10 
                 0.859 
                 NA 
                 0.966 
                 0.901 
                 0.819 
                 0.905 
                 0.882 
               
               
                 TNFSF8_EIF5B 
                 0.900 
                 NA 
                 0.994 
                 0.926 
                 0.766 
                 0.873 
                 0.882 
               
               
                 TNFSF8_LRRC8D 
                 0.927 
                 NA 
                 0.984 
                 0.852 
                 0.778 
                 0.904 
                 0.881 
               
               
                 TNFSF8_RNMT 
                 0.906 
                 NA 
                 0.994 
                 0.914 
                 0.741 
                 0.889 
                 0.879 
               
               
                 STK17B_ARL6IP5 
                 0.948 
                 0.988 
                 0.996 
                 0.901 
                 0.537 
                 0.927 
                 0.879 
               
               
                 ENTPD1_ARL6IP5 
                 0.858 
                 0.974 
                 1.000 
                 0.951 
                 0.621 
                 0.899 
                 0.878 
               
               
                 TNFSF8_CD84 
                 0.885 
                 NA 
                 0.982 
                 0.951 
                 0.789 
                 0.841 
                 0.878 
               
               
                 TNFSF8_PWP1 
                 0.861 
                 NA 
                 0.996 
                 0.889 
                 0.773 
                 0.910 
                 0.877 
               
               
                 TNFSF8_IPO7 
                 0.879 
                 NA 
                 0.994 
                 0.901 
                 0.720 
                 0.936 
                 0.876 
               
               
                 ADAM19_EXOC7 
                 0.942 
                 NA 
                 0.987 
                 0.790 
                 0.805 
                 0.902 
                 0.875 
               
               
                 TNFSF8_ARHGAP5 
                 0.891 
                 NA 
                 0.989 
                 0.975 
                 0.643 
                 0.909 
                 0.874 
               
               
                 TNFSF8_RMND1 
                 0.898 
                 NA 
                 0.983 
                 0.877 
                 0.775 
                 0.877 
                 0.874 
               
               
                 TNFSF8_IDE 
                 0.867 
                 NA 
                 0.964 
                 0.852 
                 0.796 
                 0.931 
                 0.873 
               
               
                 TNFSF8_TBCE 
                 0.900 
                 NA 
                 0.974 
                 0.864 
                 0.784 
                 0.877 
                 0.873 
               
               
                 TNFSF8_G3BP1 
                 0.748 
                 NA 
                 0.991 
                 0.914 
                 0.834 
                 0.919 
                 0.873 
               
               
                 TNFSF8_CDK6 
                 0.873 
                 NA 
                 0.993 
                 0.840 
                 0.783 
                 0.916 
                 0.872 
               
               
                 TNFSF8_MANEA 
                 0.885 
                 NA 
                 0.963 
                 0.877 
                 0.716 
                 0.944 
                 0.870 
               
               
                 TNFSF8_CKAP2 
                 0.876 
                 NA 
                 0.972 
                 0.926 
                 0.683 
                 0.927 
                 0.869 
               
               
                 TNFSF8_ZNF507 
                 0.870 
                 NA 
                 0.987 
                 0.901 
                 0.755 
                 0.870 
                 0.869 
               
               
                 TNFSF8_GGPS1 
                 0.912 
                 NA 
                 0.954 
                 0.827 
                 0.797 
                 0.892 
                 0.868 
               
               
                 TNFSF8_XPO4 
                 0.885 
                 NA 
                 0.985 
                 0.877 
                 0.717 
                 0.924 
                 0.867 
               
               
                 TNFSF8_PHC3 
                 0.845 
                 NA 
                 0.983 
                 0.864 
                 0.823 
                 0.863 
                 0.867 
               
               
                 TNFSF8_ASCC3 
                 0.879 
                 NA 
                 0.967 
                 0.901 
                 0.667 
                 0.954 
                 0.866 
               
               
                 TNFSF8_NOL10 
                 0.876 
                 NA 
                 0.963 
                 0.864 
                 0.783 
                 0.885 
                 0.866 
               
               
                 TNFSF8_ANK3 
                 0.879 
                 NA 
                 0.966 
                 0.901 
                 0.785 
                 0.855 
                 0.866 
               
               
                 TNFSF8_SMC3 
                 0.888 
                 NA 
                 0.959 
                 0.914 
                 0.718 
                 0.885 
                 0.866 
               
               
                 TNFSF8_REPS1 
                 0.924 
                 NA 
                 0.992 
                 0.802 
                 0.766 
                 0.890 
                 0.866 
               
               
                 TNFSF8_C14orf1 
                 0.900 
                 NA 
                 0.972 
                 0.840 
                 0.766 
                 0.892 
                 0.866 
               
               
                 TNFSF8_FUT8 
                 0.933 
                 NA 
                 0.994 
                 0.914 
                 0.622 
                 0.907 
                 0.866 
               
               
                 TNFSF8_VPS13A 
                 0.888 
                 NA 
                 0.978 
                 0.877 
                 0.728 
                 0.897 
                 0.865 
               
               
                 TNFSF8_RAD50 
                 0.894 
                 NA 
                 0.993 
                 0.852 
                 0.755 
                 0.865 
                 0.864 
               
               
                 TNFSF8_ESF1 
                 0.903 
                 NA 
                 0.990 
                 0.901 
                 0.734 
                 0.824 
                 0.862 
               
               
                 TNFSF8_MRPS10 
                 0.880 
                 NA 
                 0.946 
                 0.852 
                 0.738 
                 0.929 
                 0.862 
               
               
                 CDA_EFHD2 
                 0.976 
                 NA 
                 0.994 
                 0.926 
                 0.608 
                 0.834 
                 0.862 
               
               
                 TNFSF8_SLC35A3 
                 0.861 
                 NA 
                 0.982 
                 0.889 
                 0.761 
                 0.851 
                 0.862 
               
               
                 ADAM19_TMEM87A 
                 0.942 
                 NA 
                 0.999 
                 0.864 
                 0.657 
                 0.878 
                 0.861 
               
               
                 TNFSF8_LANCL1 
                 0.891 
                 NA 
                 0.999 
                 0.815 
                 0.750 
                 0.900 
                 0.861 
               
               
                 ADAM19_ERCC4 
                 0.936 
                 NA 
                 0.990 
                 0.852 
                 0.653 
                 0.912 
                 0.861 
               
               
                 TNFSF8_CD28 
                 0.942 
                 NA 
                 1.000 
                 0.840 
                 0.692 
                 0.870 
                 0.860 
               
               
                 ADAM19_MLLT10 
                 0.939 
                 NA 
                 1.000 
                 0.926 
                 0.647 
                 0.828 
                 0.860 
               
               
                 TNFSF8_IQCB1 
                 0.903 
                 NA 
                 0.963 
                 0.852 
                 0.711 
                 0.907 
                 0.860 
               
               
                 TNFSF8_FASTKD2 
                 0.891 
                 NA 
                 0.995 
                 0.877 
                 0.680 
                 0.897 
                 0.859 
               
               
                 TNFSF8_RDX 
                 0.842 
                 NA 
                 0.921 
                 0.790 
                 0.801 
                 0.968 
                 0.858 
               
               
                 TNFSF8_MTO1 
                 0.879 
                 NA 
                 0.969 
                 0.877 
                 0.713 
                 0.894 
                 0.858 
               
               
                 IQSEC1_MACF1 
                 0.945 
                 NA 
                 0.994 
                 0.877 
                 0.663 
                 0.845 
                 0.858 
               
               
                 TNFSF8_SMC6 
                 0.876 
                 NA 
                 0.951 
                 0.926 
                 0.684 
                 0.887 
                 0.858 
               
               
                 TNFSF8_NEK1 
                 0.867 
                 NA 
                 0.963 
                 0.914 
                 0.765 
                 0.813 
                 0.857 
               
               
                 TNFSF8_ZNF562 
                 0.855 
                 NA 
                 0.968 
                 0.864 
                 0.720 
                 0.914 
                 0.856 
               
               
                 TNFSF8_PEX1 
                 0.897 
                 NA 
                 0.966 
                 0.765 
                 0.814 
                 0.877 
                 0.856 
               
               
                 ADAM19_SIDT2 
                 0.952 
                 NA 
                 0.993 
                 0.938 
                 0.628 
                 0.816 
                 0.856 
               
               
                 TNFSF8_METTL5 
                 0.939 
                 NA 
                 0.973 
                 0.765 
                 0.775 
                 0.856 
                 0.856 
               
               
                 CYP4F3_TRAPPC2 
                 0.967 
                 NA 
                 0.903 
                 0.926 
                 0.706 
                 0.814 
                 0.855 
               
               
                 TNFSF8_KRIT1 
                 0.864 
                 NA 
                 0.935 
                 0.901 
                 0.721 
                 0.895 
                 0.855 
               
               
                 TNFSF8_YEATS4 
                 0.906 
                 NA 
                 0.947 
                 0.877 
                 0.736 
                 0.843 
                 0.855 
               
               
                 TNFSF8_CLUAP1 
                 0.902 
                 NA 
                 0.980 
                 0.877 
                 0.672 
                 0.885 
                 0.854 
               
               
                 TNFSF8_LARP4 
                 0.876 
                 NA 
                 0.979 
                 0.753 
                 0.767 
                 0.939 
                 0.854 
               
               
                 TNFSF8_SLC35D1 
                 0.873 
                 NA 
                 0.996 
                 0.802 
                 0.743 
                 0.895 
                 0.854 
               
               
                 SYNE2_RBM26 
                 0.897 
                 NA 
                 0.910 
                 0.901 
                 0.691 
                 0.887 
                 0.853 
               
               
                 TNFSF8_CD40LG 
                 0.888 
                 NA 
                 0.973 
                 0.914 
                 0.655 
                 0.880 
                 0.853 
               
               
                 VNN3_CYSLTR1 
                 0.855 
                 NA 
                 0.972 
                 0.963 
                 0.713 
                 0.792 
                 0.852 
               
               
                 TNFSF8_SYT11 
                 0.882 
                 NA 
                 0.927 
                 0.778 
                 0.770 
                 0.934 
                 0.852 
               
               
                 TNFSF8_RIOK2 
                 0.888 
                 NA 
                 0.972 
                 0.802 
                 0.731 
                 0.904 
                 0.852 
               
               
                 TNFSF8_BZW2 
                 0.918 
                 NA 
                 0.996 
                 0.778 
                 0.701 
                 0.914 
                 0.852 
               
               
                 TNFSF8_LARP1 
                 0.830 
                 NA 
                 0.982 
                 0.840 
                 0.719 
                 0.916 
                 0.852 
               
               
                 ADAM19_SYT11 
                 0.939 
                 NA 
                 1.000 
                 0.815 
                 0.599 
                 0.932 
                 0.851 
               
               
                 TNFSF8_NCBP1 
                 0.877 
                 NA 
                 0.915 
                 0.778 
                 0.785 
                 0.936 
                 0.851 
               
               
                 ADAM19_MACF1 
                 0.958 
                 NA 
                 1.000 
                 0.827 
                 0.592 
                 0.914 
                 0.851 
               
               
                 TNFSF8_NOL8 
                 0.885 
                 NA 
                 0.993 
                 0.864 
                 0.629 
                 0.929 
                 0.851 
               
               
                 TNFSF8_KIAA0391 
                 0.942 
                 NA 
                 0.922 
                 0.802 
                 0.745 
                 0.880 
                 0.851 
               
               
                 TNFSF8_HIBCH 
                 0.900 
                 NA 
                 0.919 
                 0.815 
                 0.813 
                 0.834 
                 0.850 
               
               
                 TNFSF8_MYO9A 
                 0.888 
                 NA 
                 0.951 
                 0.827 
                 0.697 
                 0.927 
                 0.849 
               
               
                 EXTL3_CYSLTR1 
                 0.876 
                 NA 
                 0.951 
                 0.889 
                 0.784 
                 0.780 
                 0.849 
               
               
                 CLEC4E_ARL6IP5 
                 0.800 
                 0.977 
                 0.998 
                 0.938 
                 0.511 
                 0.904 
                 0.849 
               
               
                 VNN3_MACF1 
                 0.879 
                 NA 
                 0.950 
                 0.914 
                 0.706 
                 0.828 
                 0.849 
               
               
                 ADAM19_MTRR 
                 0.945 
                 NA 
                 0.993 
                 0.790 
                 0.584 
                 0.956 
                 0.849 
               
               
                 TNFSF8_SUPT7L 
                 0.891 
                 NA 
                 0.960 
                 0.790 
                 0.728 
                 0.905 
                 0.849 
               
               
                 ADAM19_TFIP11 
                 0.958 
                 NA 
                 0.928 
                 0.901 
                 0.603 
                 0.883 
                 0.849 
               
               
                 TNFSF8_ARL6IP5 
                 0.839 
                 NA 
                 0.967 
                 0.852 
                 0.681 
                 0.932 
                 0.848 
               
               
                 TNFSF8_ENOSF1 
                 0.900 
                 NA 
                 0.983 
                 0.802 
                 0.756 
                 0.846 
                 0.848 
               
               
                 TNFSF8_ADSL 
                 0.939 
                 NA 
                 0.998 
                 0.790 
                 0.638 
                 0.907 
                 0.848 
               
               
                 TNFSF8_TGS1 
                 0.864 
                 NA 
                 0.889 
                 0.914 
                 0.708 
                 0.900 
                 0.848 
               
               
                 GAB2_TRAPPC2 
                 0.876 
                 NA 
                 0.988 
                 0.914 
                 0.577 
                 0.910 
                 0.848 
               
               
                 TNFSF8_NR2C1 
                 0.924 
                 NA 
                 0.988 
                 0.753 
                 0.713 
                 0.900 
                 0.847 
               
               
                 TNFSF8_ZMYND11 
                 0.858 
                 NA 
                 0.998 
                 0.802 
                 0.745 
                 0.878 
                 0.847 
               
               
                 TNFSF8_NGDN 
                 0.924 
                 NA 
                 0.973 
                 0.864 
                 0.689 
                 0.819 
                 0.847 
               
               
                 TNFSF8_PRKAB2 
                 0.888 
                 NA 
                 0.981 
                 0.778 
                 0.737 
                 0.890 
                 0.847 
               
               
                 TNFSF8_MDH1 
                 0.933 
                 NA 
                 0.980 
                 0.802 
                 0.626 
                 0.931 
                 0.847 
               
               
                 IGF2R_MACF1 
                 0.912 
                 NA 
                 0.986 
                 0.901 
                 0.642 
                 0.826 
                 0.846 
               
               
                 ADAM19_RRAGC 
                 0.955 
                 NA 
                 0.941 
                 0.914 
                 0.543 
                 0.910 
                 0.846 
               
               
                 STK17B_YTHDC2 
                 0.870 
                 NA 
                 0.990 
                 0.926 
                 0.551 
                 0.919 
                 0.846 
               
               
                 TNFSF8_GOLPH3L 
                 0.903 
                 NA 
                 0.991 
                 0.840 
                 0.625 
                 0.910 
                 0.846 
               
               
                 TNFSF8_BRCC3 
                 0.879 
                 NA 
                 0.957 
                 0.778 
                 0.764 
                 0.883 
                 0.846 
               
               
                 TNFSF8_NFX1 
                 0.888 
                 NA 
                 0.994 
                 0.815 
                 0.666 
                 0.907 
                 0.846 
               
               
                 VNN3_ATP8A1 
                 0.845 
                 NA 
                 0.992 
                 0.914 
                 0.685 
                 0.824 
                 0.845 
               
               
                 TNFSF8_IKBKAP 
                 0.897 
                 NA 
                 0.989 
                 0.778 
                 0.671 
                 0.929 
                 0.845 
               
               
                 TNFSF8_TRIP11 
                 0.864 
                 NA 
                 0.901 
                 0.889 
                 0.788 
                 0.816 
                 0.845 
               
               
                 RGS2_TRAPPC2 
                 0.809 
                 NA 
                 0.959 
                 0.963 
                 0.612 
                 0.905 
                 0.845 
               
               
                 TNFSF8_TCF12 
                 0.856 
                 NA 
                 0.958 
                 0.778 
                 0.721 
                 0.944 
                 0.845 
               
               
                 TNFSF8_WDR70 
                 0.897 
                 NA 
                 0.981 
                 0.704 
                 0.791 
                 0.887 
                 0.845 
               
               
                 TNFSF8_KLHL20 
                 0.870 
                 NA 
                 0.954 
                 0.765 
                 0.766 
                 0.905 
                 0.845 
               
               
                 CDA_PTGS1 
                 0.939 
                 0.770 
                 0.983 
                 0.951 
                 0.546 
                 0.912 
                 0.845 
               
               
                 MXD1_TRAPPC2 
                 0.836 
                 NA 
                 0.998 
                 0.988 
                 0.548 
                 0.883 
                 0.844 
               
               
                 RGS2_RBM26 
                 0.809 
                 NA 
                 0.999 
                 0.975 
                 0.642 
                 0.814 
                 0.844 
               
               
                 IGF2R_NOTCH2 
                 0.924 
                 NA 
                 0.962 
                 0.963 
                 0.551 
                 0.863 
                 0.844 
               
               
                 TNFSF8_HLTF 
                 0.882 
                 NA 
                 0.965 
                 0.778 
                 0.761 
                 0.867 
                 0.844 
               
               
                 TNFSF8_BCKDHB 
                 0.873 
                 NA 
                 0.919 
                 0.815 
                 0.797 
                 0.858 
                 0.844 
               
               
                 MXD1_RCBTB2 
                 0.852 
                 NA 
                 0.979 
                 0.963 
                 0.581 
                 0.885 
                 0.844 
               
               
                 TNFSF8_AGA 
                 0.894 
                 NA 
                 0.894 
                 0.815 
                 0.728 
                 0.922 
                 0.843 
               
               
                 TNFSF8_AGPAT5 
                 0.876 
                 NA 
                 0.999 
                 0.815 
                 0.671 
                 0.892 
                 0.843 
               
               
                 TNFSF8_TTC27 
                 0.891 
                 NA 
                 0.997 
                 0.802 
                 0.658 
                 0.902 
                 0.842 
               
               
                 TNFSF8_TTC17 
                 0.815 
                 NA 
                 0.918 
                 0.802 
                 0.769 
                 0.938 
                 0.842 
               
               
                 TNFSF8_S100PBP 
                 0.885 
                 NA 
                 0.971 
                 0.889 
                 0.605 
                 0.900 
                 0.842 
               
               
                 TNFSF8_PRPF39 
                 0.879 
                 NA 
                 0.980 
                 0.790 
                 0.666 
                 0.927 
                 0.842 
               
               
                 TNFSF8_MACF1 
                 0.845 
                 NA 
                 0.954 
                 0.790 
                 0.757 
                 0.897 
                 0.841 
               
               
                 ENTPD1_MACF1 
                 0.791 
                 NA 
                 0.999 
                 0.877 
                 0.659 
                 0.914 
                 0.841 
               
               
                 MYH9_MACF1 
                 0.855 
                 NA 
                 0.990 
                 0.926 
                 0.753 
                 0.720 
                 0.841 
               
               
                 ENTPD1_SYT11 
                 0.764 
                 0.868 
                 0.999 
                 0.901 
                 0.630 
                 0.907 
                 0.841 
               
               
                 SYNE2_VPS13C 
                 0.885 
                 NA 
                 0.962 
                 0.864 
                 0.579 
                 0.944 
                 0.841 
               
               
                 VNN3_RAB11FIP2 
                 0.852 
                 NA 
                 0.965 
                 0.938 
                 0.646 
                 0.831 
                 0.840 
               
               
                 GAB2_RNF170 
                 0.906 
                 NA 
                 0.997 
                 0.901 
                 0.581 
                 0.838 
                 0.840 
               
               
                 ADAM19_PSMD5 
                 0.945 
                 NA 
                 1.000 
                 0.827 
                 0.551 
                 0.909 
                 0.839 
               
               
                 ADAM19_DIAPH2 
                 0.939 
                 NA 
                 0.974 
                 0.877 
                 0.500 
                 0.926 
                 0.839 
               
               
                 GAB2_FCF1 
                 0.900 
                 NA 
                 0.980 
                 0.889 
                 0.566 
                 0.880 
                 0.838 
               
               
                 IGF2R_TCF7L2 
                 0.900 
                 NA 
                 0.967 
                 0.864 
                 0.680 
                 0.806 
                 0.838 
               
               
                 VNN3_THOC2 
                 0.839 
                 NA 
                 0.986 
                 0.938 
                 0.652 
                 0.804 
                 0.838 
               
               
                 ADAM19_PLCL2 
                 0.939 
                 NA 
                 0.995 
                 0.901 
                 0.577 
                 0.813 
                 0.838 
               
               
                 ADAM19_LARP1 
                 0.947 
                 NA 
                 0.998 
                 0.827 
                 0.579 
                 0.865 
                 0.837 
               
               
                 RGS2_MACF1 
                 0.821 
                 NA 
                 0.976 
                 0.840 
                 0.673 
                 0.900 
                 0.837 
               
               
                 TNFSF8_RFC1 
                 0.870 
                 NA 
                 0.967 
                 0.840 
                 0.673 
                 0.867 
                 0.837 
               
               
                 VNN3_CDKN1B 
                 0.861 
                 NA 
                 0.967 
                 0.951 
                 0.678 
                 0.764 
                 0.837 
               
               
                 ADAM19_POLR2A 
                 0.970 
                 NA 
                 0.996 
                 0.778 
                 0.576 
                 0.899 
                 0.837 
               
               
                 HEBP2_ARL6IP5 
                 0.800 
                 0.974 
                 0.993 
                 0.914 
                 0.544 
                 0.828 
                 0.836 
               
               
                 VNN3_TIA1 
                 0.852 
                 NA 
                 0.986 
                 0.951 
                 0.654 
                 0.764 
                 0.836 
               
               
                 RGS2_ATXN3 
                 0.809 
                 NA 
                 0.993 
                 1.000 
                 0.624 
                 0.780 
                 0.835 
               
               
                 RGS2_CLOCK 
                 0.809 
                 NA 
                 0.997 
                 0.951 
                 0.572 
                 0.875 
                 0.835 
               
               
                 TNFSF8_EFTUD1 
                 0.882 
                 NA 
                 0.986 
                 0.753 
                 0.685 
                 0.902 
                 0.835 
               
               
                 GAB2_KLHL24 
                 0.891 
                 NA 
                 0.923 
                 0.926 
                 0.688 
                 0.764 
                 0.835 
               
               
                 VNN3_YTHDC2 
                 0.858 
                 NA 
                 0.972 
                 0.938 
                 0.660 
                 0.774 
                 0.834 
               
               
                 VNN3_KRIT1 
                 0.855 
                 NA 
                 0.971 
                 0.951 
                 0.657 
                 0.769 
                 0.834 
               
               
                 RGS2_S100PBP 
                 0.809 
                 NA 
                 0.992 
                 0.963 
                 0.542 
                 0.883 
                 0.834 
               
               
                 VNN3_TRAPPC2 
                 0.848 
                 NA 
                 0.949 
                 0.951 
                 0.645 
                 0.802 
                 0.833 
               
               
                 GAB2_BTN2A1 
                 0.915 
                 NA 
                 0.965 
                 0.889 
                 0.548 
                 0.875 
                 0.833 
               
               
                 ADAM19_HRH4 
                 0.939 
                 NA 
                 0.983 
                 0.926 
                 0.608 
                 0.740 
                 0.833 
               
               
                 GAB2_ADRBK2 
                 0.903 
                 NA 
                 0.995 
                 0.889 
                 0.517 
                 0.887 
                 0.832 
               
               
                 KCMF1_ARL6IP5 
                 0.858 
                 0.974 
                 0.999 
                 0.914 
                 0.589 
                 0.694 
                 0.832 
               
               
                 VNN3_RBM26 
                 0.842 
                 NA 
                 0.993 
                 0.938 
                 0.679 
                 0.736 
                 0.832 
               
               
                 ADAM19_SLCO3A1 
                 0.945 
                 NA 
                 0.965 
                 0.827 
                 0.499 
                 0.951 
                 0.831 
               
               
                 STK17B_RABGAP1L 
                 0.892 
                 NA 
                 0.988 
                 0.901 
                 0.598 
                 0.802 
                 0.831 
               
               
                 GAB2_PRUNE 
                 0.906 
                 NA 
                 0.965 
                 0.901 
                 0.540 
                 0.865 
                 0.830 
               
               
                 RGS2_ZNF507 
                 0.809 
                 NA 
                 0.998 
                 0.938 
                 0.602 
                 0.818 
                 0.829 
               
               
                 RGS2_ARHGEF6 
                 0.809 
                 NA 
                 0.987 
                 0.975 
                 0.501 
                 0.895 
                 0.829 
               
               
                 RGS2_PHC3 
                 0.809 
                 NA 
                 0.996 
                 0.938 
                 0.626 
                 0.797 
                 0.828 
               
               
                 GAB2_CREB1 
                 0.891 
                 NA 
                 0.995 
                 0.926 
                 0.570 
                 0.784 
                 0.828 
               
               
                 VNN3_VPS13B 
                 0.845 
                 NA 
                 0.928 
                 0.938 
                 0.648 
                 0.804 
                 0.828 
               
               
                 PELI1_CDKN1B 
                 0.906 
                 NA 
                 0.923 
                 0.963 
                 0.490 
                 0.880 
                 0.827 
               
               
                 RGS2_YTHDC2 
                 0.809 
                 NA 
                 0.980 
                 0.864 
                 0.628 
                 0.865 
                 0.825 
               
               
                 STK17B_TLK1 
                 0.879 
                 NA 
                 0.972 
                 0.901 
                 0.473 
                 0.909 
                 0.823 
               
               
                 RGS2_FCF1 
                 0.809 
                 NA 
                 0.968 
                 0.951 
                 0.576 
                 0.826 
                 0.823 
               
               
                 SYNE2_KRIT1 
                 0.900 
                 NA 
                 0.800 
                 0.926 
                 0.650 
                 0.855 
                 0.822 
               
               
                 HAL_CPA3 
                 0.835 
                 NA 
                 0.923 
                 0.963 
                 0.540 
                 0.860 
                 0.820 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 INTERPRETATION OF RESULTS OBTAINED WHEN USING 
               
               
                 A COMBINATION OF BASIRS AND BACTERIAL DETECTION 
               
            
           
           
               
               
            
               
                   
                 Bacterial Pathogen Antigen 
               
            
           
           
               
               
               
            
               
                 Host Immune Response 
                 Positive 
                 Negative 
               
               
                   
               
               
                 Positive 
                 Confirmed BaSIRS 
                 Organism did not grow? 
               
               
                   
                   
                 Organism not present? 
               
               
                 Negative 
                 Contaminant? 
                 Confirmed inSIRS 
               
               
                   
                 Commensal? 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 40 
               
             
            
               
                   
               
               
                 INTERPRETATION OF RESULTS OBTAINED WHEN USING 
               
               
                 A COMBINATION OF VASIRS AND VIRUS DETECTION 
               
            
           
           
               
               
            
               
                 Host Immune 
                 Viral Pathogen Antigen 
               
            
           
           
               
               
               
            
               
                 Response 
                 Positive 
                 Negative 
               
               
                   
               
               
                 Positive 
                 Confirmed VaSIRS 
                 Assay not sensitive enough? 
               
               
                   
                   
                 Organism not present? 
               
               
                   
                   
                 Not enough sample taken? 
               
               
                   
                   
                 Wrong assay performed? 
               
               
                   
                   
                 Antibodies not yet produced? 
               
               
                 Negative 
                 Commensal? 
                 Confirmed inSIRS 
               
               
                   
                 Residual antibody? 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 41 
               
             
            
               
                   
               
               
                 INTERPRETATION OF RESULTS OBTAINED WHEN USING 
               
               
                 A COMBINATION OF PASIRS AND PROTOZOAN DETECTION 
               
            
           
           
               
               
            
               
                 Host Immune 
                 Protozoal Pathogen Antigen 
               
            
           
           
               
               
               
            
               
                 Response 
                 Positive 
                 Negative 
               
               
                   
               
               
                 Positive 
                 Confirmed PaSIRS 
                 Assay not sensitive enough? 
               
               
                   
                   
                 Organism not present? 
               
               
                   
                   
                 Not enough sample taken? 
               
               
                   
                   
                 Wrong assay performed? 
               
               
                   
                   
                 Antibodies not yet produced? 
               
               
                 Negative 
                 Commensal? 
                 Confirmed inSIRS 
               
               
                   
                 Residual antibody?