Patent Publication Number: US-11639527-B2

Title: Methods for nucleic acid sequencing

Description:
RELATED PATENT APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/840,009, filed Apr. 3, 2020, which is a continuation of U.S. Patent application Ser. No. 16/55,645, filed Aug. 26, 2019, which is a continuation of U.S. patent application Ser. No. 15/523,654, filed May, 2017, which is a U.S. National Stage Application pursuant to 35 U.S.C. § 371 of PCT/US2015/059309, filed Nov. 5, 2015, which claims benefit of U.S. Provisional Application No. 62/130,800, filed Mar. 10, 2015 and claims benefit of U.S. Provisional Application No. 62/075,328, filed on Nov. 5, 2014, each incorporated in its entirety by reference herein. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 30, 2021 is named 1000-739_SeqList.txt and is 65,087 bytes in size. 
     INTRODUCTION 
     Interstitial lung diseases (ILD) are a heterogeneous group of acute and chronic bilateral parenchymal pulmonary disorders with similar clinical manifestations, but a wide spectrum of severity and outcome 1,2 . Among these, idiopathic pulmonary fibrosis (IPF) is one of the most common and severe ILD, characterized by progressive fibrosis, worsening lung function and death 3-6 . Most patients diagnosed with IPF die within five years of their initial diagnosis 7,8 . However, the recent availability of two new drugs and other therapeutics in development may change this picture 9-11 , and accurate diagnosis is critical for appropriate therapeutic intervention 5,12 . 
     IPF can be challenging to diagnose. The diagnostic approach to IPF requires exclusion of other interstitial pneumonias, as well as connective tissue disease and environmental and occupational exposures 3-6 . Patients suspected of having IPF usually undergo high-resolution computed tomography (HRCT), which confirms the disease with high specificity only if the pattern of usual interstitial pneumonia (UIP) is clearly evident 5,13 . Yet, for a large number of patients, diagnosis necessitates an invasive surgical lung biopsy (SLB) to clarify the histopathologic features of interstitial pneumonia and/or UIP pattern 5,14  and the typical length of time to diagnose IPF from the onset of symptoms may be 1-2 years 15 . Discordance between pathologists occurs, and a correct diagnosis can be dependent on individual experience 16 . Despite histopathologic evaluation, a definitive diagnosis may remain elusive. Diagnostic accuracy has been shown to increase when multidisciplinary teams (MDT) of pulmonologists, radiologists, and pathologists confer 17 ; unfortunately not all patients and their physicians have access to this level of expert review by an experienced MDT. Such reviews are time consuming and require patients to be seen at regional centers of recognized expertise. 
     Accordingly, more effective methods of diagnosing IPF are required. In addition, methods of differentiating UIP from non-UIP are required. 
     SUMMARY OF THE INVENTION 
     Disclosed herein is a method for nucleic acid sequencing comprising (a) obtaining a nucleic acid sample, wherein said nucleic acid sample comprises a plurality of messenger ribonucleic acid molecules; (b) subjecting said plurality of messenger ribonucleic acid molecules to reverse transcription to yield a plurality of complementary deoxyribonucleic acid molecules; and (c) subjecting the plurality of messenger ribonucleic acid molecules or derivatives thereof to sequencing. The messenger ribonucleic acid molecules can be derived from a tissue sample of the subject. Sequencing can comprise PCR. Subjecting can comprise hybridizing a plurality of probes to said plurality of messenger ribonucleic acid molecules. The plurality of probes can be labeled with a molecular marker. 
     Herein we describe methods of and systems used for differentiating between samples as usual interstitial pneumonia (UIP) or non-UIP using classifiers whose accuracy was confirmed using expert pathology diagnoses as truth labels. While gene expression profiling studies in the scientific literature have reported differential expression between IPF and other ILD subtypes 18,19 , none have attempted to classify UIP in datasets containing other subtypes frequently present as part of the clinician&#39;s differential diagnosis. 
     In some embodiments, the present invention provides a method and/or system for detecting whether a lung tissue sample is positive for usual interstitial pneumonia (UIP) or non-usual interstitial pneumonia (non-UIP). In some embodiments a method is provided for: assaying the expression level of each of a first group of transcripts and a second group of transcripts in a test sample of a subject, wherein the first group of transcripts includes any one or more of the genes overexpressed in UIP and listed in any of Tables 5, 7, 9, 10, 11, and 12 and the second group of transcripts includes any one or more of the genes under-expressed in UIP and listed in any of Tables 5, 8, 9, 10, 11 or 12. In some embodiment, the method further provides for comparing the expression level of each of the first group of transcripts and the second group of transcripts with reference expression levels of the corresponding transcripts to (1) classify said lung tissue as usual interstitial pneumonia (UIP) if there is (a) an increase in an expression level corresponding to the first group or (b) a decrease in an expression level corresponding to the second group as compared to the reference expression levels, or (2) classify the lung tissue as non-usual interstitial pneumonia (non-UIP) if there is (c) an increase in the expression level corresponding to the second group or (d) a decrease in the expression level corresponding to the first group as compared to the reference expression levels. In some embodiments, the method further provides for determining and/or comparing sequence variants for any of the one or more genes listed in tables 5, 8, 9, 11, and/or 12. 
     In some embodiments, the present invention provides a method and/or system for detecting whether a lung tissue sample is positive for usual interstitial pneumonia (UIP) or non-usual interstitial pneumonia (non-UIP). In some embodiments, the method and/or system is used to assay by sequencing, array hybridization, or nucleic acid amplification the expression level of each of a first group of transcripts and a second group of transcripts in a test sample from a lung tissue of a subject, wherein the first group of transcripts includes any one or more of the genes over-expressed in UIP and listed in Tables 5, 7, 9, 10, 11 or 12 and the second group of transcripts includes any one or more of the genes under-expressed in UIP and listed in Tables 5, 8, 9, 10, 11 or 12. In certain embodiments, the method and/or system further compares the expression level of each of the first group of transcripts and the second group of transcripts with reference expression levels of the corresponding transcripts to (1) classify said lung tissue as usual interstitial pneumonia (UIP) if there is (a) an increase in an expression level corresponding to the first group or (b) a decrease in an expression level corresponding to the second group as compared to the reference expression levels, or (2) classify the lung tissue as non-usual interstitial pneumonia (non-UIP) if there is (c) an increase in the expression level corresponding to the second group or (d) a decrease in the expression level corresponding to the first group as compared to the reference expression levels. 
     In some embodiments, the present invention provides a method and/or system for detecting whether a test sample is positive for UIP or non-UIP by
         measuring the expression level of two or more transcripts expressed and/or determining sequence variants for one or more transcripts expressed in the sample;   using a computer generated classifier to distinguish between UIP and non-UIP;   wherein the classifier is built using a spectrum of Non-UIP pathology subtypes comprising HP, NSIP, sarcoidosis, RB, bronchiolitis, and organizing pneumonia (OP).       

     In some embodiments, the test sample is a biopsy sample or a bronchoalveolar lavage sample. In some embodiments, the test sample is fresh-frozen or fixed. 
     In some embodiments, the transcript expression levels are determined by RT-PCR, DNA microarray hybridization, RNASeq, or a combination thereof. In some embodiments, one or more of the transcripts is labeled. 
     In some embodiments, the method comprises detecting cDNA produced from RNA expressed in the test sample, wherein, optionally, the cDNA is amplified from a plurality of cDNA transcripts prior to the detecting step. 
     In some embodiments, the methods of the present invention further comprise measuring the expression level of at least one control nucleic acid in the test sample. 
     In some embodiments, the methods of the present invention classify the lung tissue as any one of interstitial lung diseases (ILD), a particular type of ILD, a non-ILD, or non-diagnostic. In particular embodiments, methods of the present invention classify the lung tissue as either idiopathic pulmonary fibrosis (IPF) or Nonspecific interstitial pneumonia (NSIP). 
     In some embodiments, the method and/or system of the present invention comprises assaying the test sample for the expression level of one or more transcripts of any one of SEQ ID NOS: 1-22. In some embodiments, the method further comprises assaying the test sample for the expression level of from 1 to 20 other genes. In some embodiments, the other genes comprise one or more, or optionally all of HMCN2, ADAMTSL1, CD79B, KEL, KLHL14, MPP2, NMNAT2, PLXDC1, CAPN9, TALDO1, PLK4, IGHV3-72, IGKV1-9, and CNTN4. 
     In some embodiments, the method and/or systems of the present invention further comprise using smoking status as a covariate during training of a UIP vs. non-UIP classifier disclosed herein, wherein, optionally, the smoking status is determined by detecting an expression profile indicative of the subject&#39;s smoker status. In some embodiments, such a classifier is used to determine whether a test sample is UIP or non-UIP. 
     In some embodiments, the method and/or systems of the present invention comprises training a UIP vs. non-UIP classifier, wherein genes that are susceptible to smoker-status bias are excluded or weighed differently than genes that are not susceptible to smoker-status bias during the classifier training. 
     In some embodiments, the present invention provides a method and/or system for detecting whether a lung tissue sample is positive for usual interstitial pneumonia (UIP) or non-usual interstitial pneumonia (non-UIP), as described herein, wherein the method comprises a first classification of a test sample as smoker or non-smoker using a first classifier trained to recognize gene signatures that distinguish smokers from non-smokers; and wherein the method further comprises a second classification of the test sample a UIP or non-UIP, wherein the second classification step uses a second or third classifier, which second and third classifiers are trained to distinguish UIP vs. non-UIP in smokers (smoker-specific classifier) and non-smokers (non-smoker-specific classifier), respectively, and wherein the second classification uses either (i) the smoker-specific classifier if the test sample is classified as smoker in the first classification or (ii) the non-smoker-specific classifier if the test sample is classified as non-smoker in the first classification. 
     In some embodiments, the present invention provides a method and/or system for detecting whether a lung tissue sample is positive for usual interstitial pneumonia (UIP) or non-usual interstitial pneumonia (non-UIP), wherein the methods comprise implementing a classifier trained using one or more feature selected from gene expression, variants, mutations, fusions, loss of heterozygoxity (LOH), and biological pathway effect. In some embodiments, the classifier is trained using features comprising gene expression, sequence variants, mutations, fusions, loss of heterozygoxity (LOH), and biological pathway effect. 
     In some embodiments, the present invention provides for assaying 2 or more different transcripts, or 3 or more, 4 or more, 5 or more, 10 or more, 15 or more, 20 or more, or more than 20 different transcripts in the first group and/or 2 or more different transcripts, or 3 or more, 4 or more, 5 or more, 10 or more, 15 or more, 20 or more, or more than 20 different transcripts in the second group. 
     In some embodiments, the method provides for detecting 2 or more different transcripts of any one of SEQ ID NOS:1-22, or 3 or more, 4 or more, 5 or more, 10 or more, 15 or more, 20 or more, or more than 20 different transcripts of any one of SEQ ID NOS:1-22. In particular embodiments, the current methods provide for assaying the test sample for the expression level of all of the transcripts of SEQ ID NOS: 1-22. In some embodiments, the method further comprises assaying the test sample for the expression level of from 1 to 20 other genes. In some embodiments, the method provides for assaying one or more of HMCN2, ADAMTSL1, CD79B, KEL, KLHL14, MPP2, NMNAT2, PLXDC1, CAPN9, TALDO1, PLK4, IGHV3-72, IGKV1-9, and CNTN4. 
     Disclosed herein is a method for determining that a subject is at risk for a non-usual interstitial pneumonia (non-UIP) subtype of a plurality of non-UIP subtypes, comprising: (a) obtaining a biological sample of said subject; (b) assaying nucleic acid molecules derived from said biological sample to identify a level of expression of at least one gene associated with said non-UIP subtype; and (c) processing said level of expression to generate a classification of said biological sample as being at risk for said non-UIP subtype. The non-UIP subtype can be hypersensitivity pneumonitis (HP), non-specific interstitial pneumonia (NSIP), sarcoidosis, respiratory bronchiolitis (RB), bronchiolitis, diffuse alveolar damage (DAD) or organizing pneumonia (OP). The biological sample can be a transbronchial biopsy sample or a bronchoalveolar lavage sample. Step (b) can comprise sequencing. Assaying can further comprise identifying a level of expression of at least one control nucleic acid molecule in said biological sample. The plurality of non-UIP subtypes can comprise hypersensitivity pneumonitis (HP), non-specific interstitial pneumonia (NSIP), sarcoidosis, respiratory bronchiolitis (RB), bronchiolitis, diffuse alveolar damage (DAD) or organizing pneumonia (OP). Step (c) can be performed using a machine learning algorithm that is trained to identify said non-UIP subtype of said plurality of non-UIP subtypes. The machine learning algorithm can be trained using features comprising gene expression variants, gene fusions, loss of heterozygosity, or biological pathway effect. The gene expression variants can be alternative splice variants. The machine learning algorithm can be trained with a training set that is independent of said biological sample. The biological sample can be fresh-frozen or fixed. The nucleic acid molecules can be ribonucleic acids (RNA) molecules, and said assaying can comprise generating complementary deoxyribonucleic acid (cDNA) molecules from said RNA molecules. The subject can be suspected of having an interstitial lung disease based at least in part on one or more clinical signs or one or more symptoms. The one or more symptoms can comprise shortness of breath or dry cough. The one or more clinical signs can comprise a result of an imaging test, a pulmonary function test, or a lung tissue analysis. The imaging test can be chest X-ray or computerized tomography. The computerized tomography can be high-resolution computerized tomography. The pulmonary function test can be spirometry, oximetry, or an exercise stress test. The lung tissue analysis can comprise histological or cytological analysis of a lung tissue sample of said subject. The method can further comprise providing a therapeutic intervention to said subject based at least in part on said classification generated in (c). 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG.  1   . Pairwise correlation on explant samples obtained from three patients diagnosed with IPF (Patients P1, P2, and P3). Locations (upper or lower, central or peripheral) are indicated for each sample. The top 200 differentially expressed genes separating IPF samples from normal lung samples were used to compute pairwise Pearson correlation coefficients and plotted as a heatmap with higher correlation represented in magenta color, and lower correlation represented in green color. Correlation between and with normal lung samples are in the 0·7 range (not shown). 
         FIGS.  2 A- 2 D . Performance of a classifier built using microarray data. ROC curves were used to characterize performance in the training set using leave-one-patient-out (LOPO) cross-validation ( FIG.  2 A ) and in the independent test set by scoring the samples with a fixed model ( FIG.  2 C ). Scores for individual samples are shown across patients in the training set ( FIG.  2 B ), and across patients in an independent test set ( FIG.  2 D ). Patient-level pathology diagnosis is shown on the x-axis. Samples with UIP pathology labels are indicated by closed circles, and non-UIP samples by pathology are shown in open triangles. A dotted horizontal line is drawn to indicate the threshold that corresponds to 92% specificity and 64% sensitivity ( FIG.  2 B ) and 92% specificity and 82% sensitivity ( FIG.  2 D ). 
         FIGS.  3 A- 3 D . Performance of classifiers built using RNASeq ( FIG.  3 A  and  FIG.  3 B ) and microarray on the matched set ( FIG.  3 C  and  FIG.  3 D ). Leave-one-patient-out (LOPO) cross-validation was performed and receiver operator characteristic (ROC) curves were produced for RNASeq ( FIG.  3 A ) and microarray ( FIG.  3 C ) classifiers. Scores for individual samples in the training sets are shown for RNASeq ( FIG.  3 B ), and microarray ( FIG.  3 D ) classification. Patient-level pathology diagnosis is shown on the x-axis. Samples with UIP pathology labels are indicated by closed circles, and non-UIP samples by pathology are shown in open triangles. A score threshold corresponding to 95% specificity is indicated as a horizontal line in  FIG.  3 B  and  FIG.  3 D . 
         FIG.  4   . Simulation study assessing the impact of mislabeling on the classification performance. The array training set (n=77) was used for this study. At a given proportion of swapped labels in the data set (x-axis), individual samples&#39; classification labels were swapped to another class label with a weight accounting for the disagreement level of three expert pathology diagnoses. Each boxplot was drawn using LOPO CV performances (AUC) from 100 repeated simulations. The finer dotted horizontal line at AUC=0.5 represents random performance, i.e., no classification, and the coarser dotted line corresponds to the classifier performance shown in  FIG.  2 A . 
         FIG.  5   . Central pathology diagnostic process for a hypothetical patient with two samples (sample A and sample B). Three expert pathologists participate in the review process. For sample-level diagnosis, the glass slides for each sample are reviewed by each pathologist (Pathologist is abbreviated as Path.). For patient-level diagnosis, glass slides from all samples (two in this exercise) are gathered and reviewed together by each pathologist. Both sample-level and patient-level diagnoses go through the same review process. A majority vote is used as the final diagnosis, unless expert pathologists disagree even after the conferral, in which case, the sample is omitted due to lack of confidence in the diagnosis. Only a single such case was observed among all banked tissues (n=128). 
         FIG.  6   . Location of lung samplings from three normal organ donors (top) and three patients diagnosed with IPF (bottom). Donors N1-N3 and P3 were female. Donors P1 and P2 were male. 
         FIG.  7 A . Illustration of a computer system usable for implementing aspects disclosed herein. 
         FIG.  7 B . Detailed illustration of the processor of the computer system of  FIG.  7 A . 
         FIG.  7 C . Detailed illustration of one non-limiting method of the present invention, wherein gene product expression data for known UIP and non-UIP samples are used to train a classifier (e.g., using a classifier training module) for differentiating UIP vs. non-UIP, wherein the classifier optionally considers smoker status as a covariant, and wherein gene product expression data from unknown samples are input into the trained classifier to identify the unknown samples as either UIP or non-UIP, and wherein the results of the classification via the classifier are defined and output via a report. 
         FIG.  8   . Differential gene expression in UIP and Non-UIP samples between smokers and non-smokers. The number of genes differentially expressed between UIP and Non UIP samples differs drastically between smokers and non-smokers. 
         FIG.  9   . Shows differential gene expression between UIP and Non-UIP samples is susceptible to smoker-status bias. Direction (i.e., over- vs. under-expression) and magnitude (circle size) of differential gene expression is confounded by smoking status. 
         FIGS.  10 A- 10 D . Examples of genes that are differentially expressed in UIP vs. Non-UIP and the effect of smoking status on expression levels.  FIG.  10 A : differential expression of IGHV3-72 in UIP vs Non-UIP smokers vs. non-smokers.  FIG.  10 B : differential expression of CPXM1 in UIP vs Non-UIP smokers vs. non-smokers.  FIG.  10 C : differential expression of BPIFA1 in UIP vs Non-UIP smokers vs. non-smokers.  FIG.  10 D : differential expression of HLA-U in UIP vs Non-UIP smokers vs. non-smokers. 
     
    
    
     DEFINITIONS 
     “Interstitial lung disease” or “ILD” (also known as diffuse parenchymal lung disease (DPLD)) as used herein refers to a group of lung diseases affecting the interstitium (the tissue and space around the air sacs of the lungs). ILD can be classified according to a suspected or known cause, or can be idiopathic. For example, ILD can be classified as caused by inhaled substances (inorganic or organic), drug induced (e.g., antibiotics, chemotherapeutic drugs, antiarrhythmic agents, statins), associated with connective tissue disease (e.g., systemic sclerosis, polymyositis, dermatomyositis, systemic lupus erythematous, rheumatoid arthritis), associated with pulmonary infection (e.g., atypical pneumonia,  Pneumocystis  pneumonia (PCP), tuberculosis,  Chlamydia trachomatis , Respiratory Syncytial Virus), associated with a malignancy (e.g., Lymphangitic carcinomatosis), or can be idiopathic (e.g., sarcoidosis, idiopathic pulmonary fibrosis, Hamman-Rich syndrome, antisynthetase syndrome). 
     “ILD Inflammation” as used herein refers to an analytical grouping of inflammatory ILD subtypes characterized by underlying inflammation. These subtypes can be used collectively as a comparator against IPF and/or any other non-inflammation lung disease subtype. “ILD inflammation” can include HP, NSIP, sarcoidosis, and/or organizing pneumonia. 
     “Idiopathic interstitial pneumonia” or “IIP” (also referred to as noninfectious pneumonia” refers to a class of ILDs which includes, for example, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, lymphoid interstitial pneumonia, cryptogenic organizing pneumonia, and idiopathic pulmonary fibrosis. 
     “Idiopathic pulmonary fibrosis” or “IPF” as used herein refers to a chronic, progressive form of lung disease characterized by fibrosis of the supporting framework (interstitium) of the lungs. By definition, the term is used when the cause of the pulmonary fibrosis is unknown (“idiopathic”). Microscopically, lung tissue from patients having IPF shows a characteristic set of histologic/pathologic features known as usual interstitial pneumonia (UIP), which is a pathologic counterpart of IPF. 
     “Nonspecific interstitial pneumonia” or “NSIP” is a form of idiopathic interstitial pneumonia generally characterized by a cellular pattern defined by chronic inflammatory cells with collagen deposition that is consistent or patchy, and a fibrosing pattern defined by a diffuse patchy fibrosis. In contrast to UIP, there is no honeycomb appearance nor fibroblast foci that characterize usual interstitial pneumonia. 
     “Hypersensitivity pneumonitis” or “HP” refers to also called extrinsic allergic alveolitis, (EAA) refers to an inflammation of the alveoli within the lung caused by an exaggerated immune response and hypersensitivity to as a result of an inhaled antigen (e.g., organic dust). 
     “Pulmonary sarcoidosis” or “PS” refers to a syndrome involving abnormal collections of chronic inflammatory cells (granulomas) that can form as nodules. The inflammatory process for HP generally involves the alveoli, small bronchi, and small blood vessels. In acute and subacute cases of HP, physical examination usually reveals dry rales. 
     The term “microarray” refers to an ordered arrangement of hybridizable array elements, preferably polynucleotide probes, on a substrate. 
     The term “polynucleotide,” when used in singular or plural, generally refers to any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for instance, polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA including single- and double-stranded regions, single- and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or include single- and double-stranded regions. In addition, the term “polynucleotide” as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules. The regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. The term “polynucleotide” can also include DNAs (e.g., cDNAs) and RNAs that contain one or more modified bases (e.g., to provide a detectable signal, such as a fluorophore). Thus, DNAs or RNAs with backbones modified for stability or for other reasons are “polynucleotides” as that term is intended herein. Moreover, DNAs or RNAs comprising unusual bases, such as inosine, or modified bases, such as tritiated bases, are included within the term “polynucleotides” as defined herein. In general, the term “polynucleotide” embraces all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides, as well as the chemical forms of DNA and RNA characteristic of viruses and cells, including simple and complex cells. 
     The term “oligonucleotide” refers to a relatively short polynucleotide (e.g., 100, 50, 20 or fewer nucleotides) including, without limitation, single-stranded deoxyribonucleotides, single- or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNAs. Oligonucleotides, such as single-stranded DNA probe oligonucleotides, are often synthesized by chemical methods, for example using automated oligonucleotide synthesizers that are commercially available. However, oligonucleotides can be made by a variety of other methods, including in vitro recombinant DNA-mediated techniques and by expression of DNAs in cells and organisms. 
     The terms “gene product” or “expression product” are used herein interchangeably to refer to the RNA transcription products (RNA transcript) of a gene, including mRNA, and the polypeptide translation product of such RNA transcripts. A gene product can be, for example, a polynucleotide gene expression product (e.g., an unspliced RNA, an mRNA, a splice variant mRNA, a microRNA, a fragmented RNA, and the like) or a protein expression product (e.g., a mature polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide, and the like). In some embodiments the gene expression product may be a sequence variant including mutations, fusions, loss of heterozygoxity (LOH), and/or biological pathway effects. 
     The term “normalized expression level” as applied to a gene expression product refers to a level of the gene product normalized relative to one or more reference (or control) gene expression products. 
     A “reference expression level” as applied to a gene expression product refers to an expression level for one or more reference (or control) gene expression products. A “reference normalized expression level” as applied to a gene expression product refers to a normalized expression level value for one or more reference (or control) gene expression products (i.e., a normalized reference expression level). In some embodiments, a reference expression level is an expression level for one or more gene product in normal sample, as described herein. In some embodiments, a reference expression level is determined experimentally. In some embodiments, a reference expression level is a historical expression level, e.g., a database value of a reference expression level in a normal sample, which sample indicates a single reference expression level, or a summary of a plurality of reference expression levels (such as, e.g., (i) an average of two or more, preferably three or more reference expression levels from replicate analysis of the reference expression level from a single sample; (ii) an average of two or more, preferably three or more reference expression levels from analysis of the reference expression level from a plurality of different samples (e.g., normal samples); (iii) and a combination of the above mentioned steps (i) and (ii) (i.e., average of reference expression levels analyzed from a plurality of samples, wherein at least one of the reference expression levels are analyzed in replicate). In some embodiments, the “reference expression level” is an expression level of sequence variants, for example, in a sample that has been definitively determined to be UIP or non-UIP by other means (i.e. confirmed pathological diagnosis). 
     A “reference expression level value” as applied to a gene expression product refers to an expression level value for one or more reference (or control) gene expression products. A “reference normalized expression level value” as applied to a gene expression product refers to a normalized expression level value for one or more reference (or control) gene expression products. 
     “Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to re-anneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature that can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, (Wiley Interscience, 1995). 
     “Stringent conditions” or “high stringency conditions”, as defined herein, typically: (1) employ low ionic strength solutions and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3) employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt&#39;s solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodium chloride/sodium citrate) and 50% formamide at 55° C., followed by a high-stringency wash consisting of 0.1×SSC containing EDTA at 55° C. 
     “Moderately stringent conditions” may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Press, 1989), and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and % SDS) less stringent that those described above. An example of moderately stringent condition is overnight incubation at 37° C. in a solution comprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt&#39;s solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1×SSC at about 37-50° C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like. 
     “Sensitivity” as used herein refers to the proportion of true positives of the total number tested that actually have the target disorder (i.e., the proportion of patients with the target disorder who have a positive test result). “Specificity” as used herein refers to the proportion of true negatives of all the patients tested who actually do not have the target disorder (i.e., the proportion of patients without the target disorder who have a negative test result). 
     In the context of the present invention, reference to “at least one,” “at least two,” “at least five,” etc. of the genes listed in any particular gene set means any one or any and all combinations of the genes listed. 
     The terms “splicing” and “RNA splicing” are used interchangeably and refer to RNA processing that removes introns and joins exons to produce mature mRNA with continuous coding sequence that moves into the cytoplasm of a eukaryotic cell. 
     The term “exon” refers to any segment of an interrupted gene that is represented in a mature RNA product (B. Lewin, Genes 7V (Cell Press, 1990)). In theory the term “intron” refers to any segment of DNA that is transcribed but removed from within the transcript by splicing together the exons on either side of it. Operationally, exon sequences occur in the mRNA sequence of a gene as defined by Ref. SEQ ID numbers. Operationally, intron sequences are the intervening sequences within the genomic DNA of a gene, bracketed by exon sequences and usually having GT and AG splice consensus sequences at their 5′ and 3′ boundaries. 
     A “computer-based system” refers to a system of hardware, software, and data storage medium used to analyze information. Hardware of a patient computer-based system can include a central processing unit (CPU), and hardware for data input, data output (e.g., display), and data storage. The data storage medium can include any manufacture comprising a recording of the present information as described above, or a memory access device that can access such a manufacture. 
     As used herein the term “module” refers to any assembly and/or set of operatively-coupled electrical components that can include, for example, a memory, a processor, electrical traces, optical connectors, software (executing in hardware), and/or the like. For example, a module executed in the processor can be any combination of hardware-based module (e.g., a field-programmable gate array (FPGA), an application specific integrated circuit (ASIC), a digital signal processor (DSP)) and/or software-based module (e.g., a module of computer code stored in memory and/or executed at the processor) capable of performing one or more specific functions associated with that module. 
     To “record” data, programming or other information on a computer readable medium refers to a process for storing information, using any such methods as known in the art. Any convenient data storage structure may be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. 
     A “processor” or “computing means” references any hardware and/or software combination that will perform the functions required of it. For example, a suitable processor may be a programmable digital microprocessor such as available in the form of an electronic controller, mainframe, server or personal computer (desktop or portable). Where the processor is programmable, suitable programming can be communicated from a remote location to the processor, or previously saved in a computer program product (such as a portable or fixed computer readable storage medium, whether magnetic, optical or solid state device based). For example, a magnetic medium or optical disk may carry the programming, and can be read by a suitable reader communicating with each processor at its corresponding station. 
     A “test sample” is a sample of one or more cells, preferable a tissue sample (e.g., a lung tissue sample such as a transbronchial biopsy (TBB) sample) obtained from a subject. In some embodiments, a test sample is a biopsy sample obtained by any means known in the art. In particular embodiments, the test sample is a sample obtained by a video-assisted thoracoscopic surgery (VATS); a bronchoalveolar lavage (BAL); a transbronchial biopsy (TBB); or a cryo-transbronchial biopsy. In some embodiments the test sample is obtained from a patient suspected of having a lung disease, e.g., an ILD, based on clinical signs and symptoms with which the patient presents (e.g., shortness of breath (generally aggravated by exertion), dry cough), and, optionally the results of one or more of an imaging test (e.g., chest X-ray, computerized tomography (CT)), a pulmonary function test (e.g., spirometry, oximetry, exercise stress test), lung tissue analysis (e.g., histological and/or cytological analysis of samples obtained by bronchoscopy, bronchoalveolar lavage, surgical biopsy). 
     A “gene signature” is a gene expression pattern (i.e., expression level of one or more gene, or fragments thereof), which is indicative of some characteristic or phenotype. In some embodiments, gene signature refers to the expression (and/or lack of expression) of a gene, a plurality of genes, a fragment of a gene or a plurality fragments of one or more genes, which expression and/or lack of expression is indicative of UIP, Non-UIP, smoker-status, or Non-smoker-status. 
     As used herein, “is a smoker” is meant to refer to a subject who currently smokes cigarettes or a person who has smoked cigarettes in the past or a person who has the gene signature of a person who currently smokes cigarettes or has smoked cigarettes in the past. 
     As used herein, “variant”, when used to describe a feature used during training of a classifier of the present invention, refers to an alternative splice variant. 
     As used herein, “mutation”, when used to describe a feature used during training of a classifier of the present invention, refers to a sequence deviation from a known normal reference sequence. In some embodiments, the deviation is a deviation from an accepted native gene sequence according to a publically accessible database such as the UniGene database (Pontius J U, Wagner L, Schuler GD. UniGene: a unified view of the transcriptome. In: The NCBI Handbook. Bethesda (Md.): National Center for Biotechnology Information; 2003, incorporated herein), RefSeq (The NCBI handbook [Internet]. Bethesda (Md.): National Library of Medicine (US), National Center for Biotechnology Information; 2002 October Chapter 18, The Reference Sequence (RefSeq) Project, available at the world wide web address: ncbi.nlm.nih.gov/refseq/), Ensembl (EMBL, available at the world wide web address: ensembl.org/index.html), and the like. In some embodiments, the mutation includes an addition, deletion, or substitution of a sequence residue present in the reference sequence. 
     Abbreviations include: HRCT, high-resolution computed tomography; VATS, video-assisted thorascopic surgery; SLB, surgical lung biopsy; TBB, transbronchial biopsy; RB, respiratory bronchiolitis; OP, organizing pneumonia, DAD, diffuse alveolar damage, CIF/NOC, chronic interstitial fibrosis not otherwise classified; MDT, multidisciplinary team; CV, cross-validation; LOPO, leave-one-patient-out; ROC, receiver operator characteristic; AUC, area under the curve; RNASeq, RNA sequencing by next-generation sequencing technology; NGS, next-generation sequencing technology; H&amp;E, hematoxylin and eosin; FDR, false discovery rate; IRB, Institutional Review Board; ATS, American Thoracic Society; COPD, chronic obstructive pulmonary disease; KEGG, Kyoto Encyclopedia of Genes and Genomes; CI, confidence interval 
     Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. As used herein, “about” means plus or minus 10% of the indicated value. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Disclosed herein are methods of and/or systems for using a molecular signature to differentiate UIP from other ILD subtypes. The accurate diagnosis of UIP from samples where expert pathology is not available stands to benefit ILD patients by accelerating diagnosis, thus facilitating treatment decisions and reducing surgical risk to patients and costs to the healthcare system. 
     Also disclosed herein are methods of and/or systems for using the smoker or non-smoker status of a subject to improve differentiation of UIP from other ILD subtypes using a molecular signature. 
     Thus, the methods and/or systems disclosed herein provide classifiers which can differentiate UIP from non-UIP patterns based on high-dimensional transcriptional data without prior knowledge of clinical or demographic information. 
     In some embodiments, the present invention provides methods for differentiating UIP from non-UIP using a classifier that comprises or consists of one or more sequences or fragments thereof presented in any of Tables 5, 7, 8, 9, 10, 11, or 12 or at least one sequence or fragment thereof from each of Tables 5, 7, 8, 9, 10, 11 and 12. In some embodiments, the present invention provides such methods that use a classifier comprising or consisting of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the sequences provided in any one or more or all of Tables 5, 7, 8, 9, 10, 11 and 12. For example, in some embodiments, the present invention provides such methods that use classifiers comprising or consisting of at least 11, 12, 13, 14, 15, 20, 30, 50, 100, 150, 200, 250, 300, or more sequences provided in any one or more or all of Tables 5, 7, 8, 9, 10, 11 and 12, including all integers (e.g., 16, 17, 18, 19, 21, 22, 23, 24, 25 sequences, etc.) and ranges (e.g., from about 1-10 sequences from any one or more or all of Tables 5, 7, 8, 9, 10, 11, and 12, from about 10-15 sequences, 10-20 sequences, 5-30 sequences, 5-50 sequences, 10-100 sequences, 50-200 sequences, etc.) between. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of one or more of the following sequences or fragments thereof: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; or 21 of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22) in any combination. In particular aspects, such a classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of all of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of one or more of the following sequences or fragments thereof: 1) HLA-F (SEQ ID NO.:1), 2) HMCN2, 3) ADAMTSL1, 4) CD79B, 5) KEL, 6) KLHL14, 7) MPP2, 8) NMNAT2, 9) PLXDC1, 10) CAPN9, 11) TALDO1, 12) PLK4, 13) IGHV3-72, 14) IGKV1-9, and 15) CNTN4. In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; or 14 of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) HMCN2, 3) ADAMTSL1, 4) CD79B, 5) KEL, 6) KLHL14, 7) MPP2, 8) NMNAT2, 9) PLXDC1, 10) CAPN9, 11) TALDO1, 12) PLK4, 13) IGHV3-72, 14) IGKV1-9, and 15) CNTN4. In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) HMCN2, 3) ADAMTSL1, 4) CD79B, 5) KEL, 6) KLHL14, 7) MPP2, 8) NMNAT2, 9) PLXDC1, 10) CAPN9, 11) TALDO1, 12) PLK4, 13) IGHV3-72, 14) IGKV1-9, and 15) CNTN4. In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of HLA-F (SEQ ID NO.:1) or fragments thereof. In one such embodiment, the method uses a classifier comprising 1) HLA-F (SEQ ID NO.:1) and at least one of 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of HMCN2 or fragments thereof. In one such embodiment, the method uses a classifier comprising HMCN2 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of ADAMTSL1 or fragments thereof. In one such embodiment, the method uses a classifier comprising ADAMTSL1 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of CD79B or fragments thereof. In one such embodiment, the method uses a classifier comprising CD79B and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of KEL or fragments thereof. In one such embodiment, the method uses a classifier comprising KEL and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of KLHL14 or fragments thereof. In one such embodiment, the method uses a classifier comprising KLHL14 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of MPP2 or fragments thereof. In one such embodiment, the method uses a classifier comprising MPP2 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of NMNAT2 or fragments thereof. In one such embodiment, the method uses a classifier comprising NMNAT2 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of PLXDC1 or fragments thereof. In one such embodiment, the method uses a classifier comprising PLXDC1 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of CAPN9 or fragments thereof. In one such embodiment, the method uses a classifier comprising CAPN9 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.: 11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of TALDO1 or fragments thereof. In one such embodiment, the method uses a classifier comprising TALDO1 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of PLK4 or fragments thereof. In one such embodiment, the method uses a classifier comprising PLK4 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of IGHV3-72 or fragments thereof. In one such embodiment, the method uses a classifier comprising IGHV3-72 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of IGKV1-9 or fragments thereof. In one such embodiment, the method uses a classifier comprising IGKV1-9 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some particular embodiments, the present invention provides methods and/or systems for differentiating UIP from non-UIP using a classifier that comprises or consists of CNTN4 or fragments thereof. In one such embodiment, the method uses a classifier comprising CNTN4 and at least one of 1) HLA-F (SEQ ID NO.:1) 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.: 11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of 2; 3; 4; 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, 31, 32, 33, 34, or 35 of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), 22) DES (SEQ ID NO.:22), 23) HMCN2, 24) ADAMTSL1, 25) CD79B, 26) KEL, 27) KLHL14, 28) MPP2, 29) NMNAT2, 30) PLXDC1, 31) CAPN9, 32) TALDO1, 33) PLK4, 34) IGHV3-72, 35) IGKV1-9, and 36) CNTN4. In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. 
     In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier that comprises or consists of all of the following sequences: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), 22) DES (SEQ ID NO.:22), 23) HMCN2, 24) ADAMTSL1, 25) CD79B, 26) KEL, 27) KLHL14, 28) MPP2, 29) NMNAT2, 30) PLXDC1, 31) CAPN9, 32) TALDO1, 33) PLK4, 34) IGHV3-72, 35) IGKV1-9, and 36) CNTN4. In particular aspects, the classifier may contain 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes. In other aspects, the classifier may omit 1, 2, 3, 4, 5, 6, 7, 8, or more, of these genes, while optionally including other genes. In some embodiments, the present invention provides a method and/or system for differentiating UIP from non-UIP using a classifier described herein, wherein the method further comprises implementing a classifier that classifies the subject as a smoker or non-smoker. Such a smoker status classification can optionally be implemented prior to implementing a UIP vs. Non-UIP classifier, or a smoker status classification step can be built in as a covariate used during the training (e.g., using a classifier training module) of a UIP vs. Non-UIP classifier of the present invention. 
     In some embodiments, alternatively, or additionally, the method of and/or system for differentiating UIP from non-UIP using a classifier described herein further comprises a step of excluding or assigning differential weight to certain genes or variants thereof that are susceptible to smoker-status bias during the training (e.g., using a classifier training module) or implementation of the UIP vs. Non-UIP classifier. As used herein, “smoker status bias” refers to genes or variants thereof, which in non-smoker patients are differentially expressed in UIP vs. non-UIP patients, but which are not detectably differentially expressed in UIP vs. non-UIP patients that are (or have been) smokers. 
     In some embodiments, the method of and/or system for the present invention comprises a tiered classifier comprising at least a first and a second classifier, wherein the first classifier is trained (e.g., using a classifier training module) to recognize gene signatures that distinguish smokers from non-smokers, and a second classifier is trained (e.g., using a classifier training module) to distinguish UIP vs. Non UIP in smokers or non-smokers, respectively. 
     In some embodiments, the method and/or systems of the present invention comprises:
         extracting nucleic acids (e.g., RNA, such as, e.g., total RNA) from a test sample (e.g. lung tissue);   amplifying the nucleic acid to produce an expressed nucleic acid library (e.g., via polymerase chain reaction-mediated amplification of cDNAs (optionally labeled cDNAs), which cDNAs may be produced from one or more RNA sample by reverse transcription (RT-PCR));   detecting expression of one or more nucleic acid present in the nucleic acid library (e.g., detecting RNA expression profiles by measuring cDNA species produced via RT-PCR) via an array (e.g., a microarray) or via direct sequencing (e.g., RNAseq); and   determining whether the test sample is UIP or non-UIP using a trained classifier described herein.       

     In some embodiments, the method and/or system of the present invention further comprises incorporating smoker status into the training exercise. In certain embodiments, smoker status is optionally incorporated in one of the following ways: 
     (i) by using smoking status as a covariate in a UIP or Non-UIP classifier during training (e.g., using a classifier training module). 
     (ii) by identifying a plurality of genes that are susceptible to smoker-status bias and excluding, or optionally weighing such genes differently than genes that are not susceptible to such bias, during UIP or Non-UIP classifier training (e.g., using a classifier training module).
 
(iii) by constructing a tiered classification in which an initial classifier that is trained (e.g., using a classifier training module) to recognize gene signatures that distinguish smokers from non-smokers is used to pre-classify a test sample as “smoker” or “non-smoker” based upon the gene signature of the test sample; and then, subsequent to pre-classification, a distinct classifier that was trained (e.g., using a classifier training module) to distinguish UIP vs. Non UIP in either smokers or non-smokers is implemented. For example, if the pre-classifier determines that the test sample is from a smoker, a UIP vs. Non-UIP classification is performed using a classifier trained (e.g., using a classifier training module) with UIP and Non-UIP samples from smokers. Conversely, if the pre-classifier determines that the test sample is from a non-smoker, a UIP vs. Non-UIP classification is performed using a classifier trained (e.g., using a classifier training module) with UIP and Non-UIP samples from non-smokers. In some embodiments, such smoker- or non-smoker-specific classifiers provide improved diagnostic performance due, at least in part, to a reduction in background noise caused by the inclusion of genes susceptible to smoker-status bias in the classifier training.
 
     Accordingly, the present invention also provides suitable classifiers for use in methods of differentiating UIP from non-UIP, as disclosed herein. In various embodiments, the present invention provides a classifier suitable for differentiating UIP from non-UIP, wherein the classifier is trained (e.g., using a classifier training module) using microarray or sequencing data from a sample corresponding to one or more histopathology label determined by an expert pathologist. In some embodiments, the sample is labelled UIP or Non-UIP. 
     In some embodiments, the present invention presents a classifier comprising or consisting of one or more sequences or fragments thereof presented in any of Tables 5, 7, 8, 9, 10, 11, or 12, or at least one sequence or fragment thereof from each of Tables 5, 7, 8, 9, 10, 11, or 12. In some embodiments, the present invention provides a classifier comprising or consisting of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the sequences provided in any one or more or all of Tables 5, 7, 8, 9, 10, 11 and 12. For example, in some embodiments, the present invention provides a classifier comprising or consisting of at least 11, 12, 13, 14, 15, 20, 30, 50, 100, 150, 200, 250, 300, or more sequences provided in any one or more or all of Tables 5, 7, 8, 9, 10, 11, or 12, including all integers (e.g., 16, 17, 18, 19, 21, 22, 23, 24, 25 sequences, etc.) and ranges (e.g., from about 1-10 sequences from any one or more or all of Tables 5, 7, 8, 9, 10, 11, or 12, from about 10-15 sequences, 10-20 sequences, 5-30 sequences, 5-50 sequences, 10-100 sequences, 50-200 sequences from any one or more or all of Tables 5, 7, 8, 9, 10, 11, or 12, etc.) between. In one embodiment, the present invention provides a classifier that comprises or consists of all sequences provided in Table 5, all sequences provided in Table 7, all sequences provided in Table 8, all sequences provided in Table 9, all sequences provided in table 10, all sequences provided in Table 11, or all sequences provided in Table 12. In one embodiment, the present invention provides a classifier that comprises or consists of all sequences provided in each of Tables 5, 7, 8, 9, 10, 11, or 12. 
     In some particular embodiments, the present invention provides a classifier for differentiating UIP from non-UIP, wherein the classifier comprises or consists of one or more of the following sequences or fragments thereof: 1) HLA-F (SEQ ID NO.:1), 2) CDKL2 (SEQ ID NO.:2), 3) GPR98 (SEQ ID NO.:3), 4) PRKCQ (SEQ ID NO.:4), 5) HLA-G (SEQ ID NO.:5), 6) PFKFB3 (SEQ ID NO.:6), 7) CEACAM1 (SEQ ID NO.:7), 8) RABGAP1L (SEQ ID NO.:8), 9) CD274 (SEQ ID NO.:9), 10) PRUNE2 (SEQ ID NO.:10), 11) ARAP2 (SEQ ID NO.:11), 12) DZIP1 (SEQ ID NO.:12), 13) MXRA7 (SEQ ID NO.:13), 14) PTCHD4 (SEQ ID NO.:14), 15) PDLIM3 (SEQ ID NO.:15), 16) CNN1 (SEQ ID NO.:16), 17) NIPSNAP3B (SEQ ID NO.:17), 18) PAQR7 (SEQ ID NO.:18), 19) ACTG2 (SEQ ID NO.:19), 20) NA (SEQ ID NO.:20), 21) TIMP2 (SEQ ID NO.:21), and 22) DES (SEQ ID NO.:22). In one embodiment, the classifier comprises or consists of all 22 of the above mentioned sequences. In some embodiments, the present invention provides a classifier for differentiating UIP from non-UIP, wherein the classifier comprises or consists of 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; or 21 of the abovementioned 22 sequences. In particular aspects, the classifier contains 1, 2, 3, 4, 5, 6, 7, 8, or more additional genes or fragments thereof. In other aspects, the classifier omits 1, 2, 3, 4, 5, 6, 7, 8, or more, of the abovementioned 22 sequences, while optionally including other genes. In other aspects, each of the 22 genes may be used in combination with any 1 or more, up to 20 more, of the other genes. 
     Tissue Samples 
     A lung tissue sample for use in a subject analytical or diagnostic method can be a biopsy sample (e.g., a biopsy sample obtained by video-assisted thoracoscopic surgery; VATS); a bronchoalveolar lavage (BAL) sample; a transbronchial biopsy; a cryo-transbronchial biopsy; and the like.” Lung tissue samples for analysis can be provided in a suitable preservation solution. 
     Tissue samples can be obtained from a patient suspected of having a lung disease, e.g., an ILD, based on clinical signs and symptoms with which the patient presents (e.g., shortness of breath (generally aggravated by exertion), dry cough), and, optionally the results of one or more of an imaging test (e.g., chest X-ray, computerized tomography (CT)), a pulmonary function test (e.g., spirometry, oximetry, exercise stress test), lung tissue analysis (e.g., histological and/or cytological analysis of samples obtained by bronchoscopy, bronchoalveolar lavage, surgical biopsy). 
     The lung tissue sample can be processed in any of a variety of ways. For example, the lung tissue sample can be subjected to cell lysis. The lung tissue sample can be preserved in RNAprotect solution (a solution that inhibits RNA degradation, e.g., that inhibits nuclease digestion of RNA) and subsequently subjected to cell lysis. Components such as nucleic acids and/or proteins can be enriched or isolated from the lung tissue sample, and the enriched or isolated component can be used in a subject method. Methods of enriching for and isolating components such nucleic acids and proteins are known in the art; and any known method can be used. Methods of isolating RNA for expression analysis have been described in the art. 
     In Vitro Methods of Determining Expression Product Levels 
     Additional approaches to assess expression of the panel further demonstrated the genomic signal observed in UIP vs. non-UIP classification is robust across diverse biochemical assays and detection methods. Specifically we generated RNASeq data for a subset of the cohort and evaluated performance under CV. Performance comparisons with matched array data demonstrated that classification using RNASeq data achieves similar performance to data generated from the microarray platform. 
     The general methods for determining gene expression product levels are known to the art and may include but are not limited to one or more of the following: additional cytological assays, assays for specific proteins or enzyme activities, assays for specific expression products including protein or RNA or specific RNA splice variants, in situ hybridization, whole or partial genome expression analysis, microarray hybridization assays, serial analysis of gene expression (SAGE), enzyme linked immunoabsorbance assays, mass-spectrometry, immunohistochemistry, blotting, sequencing, RNA sequencing, DNA sequencing (e.g., sequencing of cDNA obtained from RNA); Next-Gen sequencing, nanopore sequencing, pyrosequencing, or Nanostring sequencing. For example, gene expression product levels can be determined according to the methods described in Kim, et. al. (Lancet Respir Med. 2015 June; 3(6):473-82, incorporated herein in its entirety, including all supplements). As used herein, the terms “assaying” or “detecting” or “determining” are used interchangeably in reference to determining gene expression product levels, and in each case, it is contemplated that the above-mentioned methods of determining gene expression product levels are suitable for detecting or assaying gene expression product levels. Gene expression product levels may be normalized to an internal standard such as total mRNA or the expression level of a particular gene including but not limited to glyceraldehyde  3  phosphate dehydrogenase, or tubulin. 
     In various embodiments, a sample comprises cells harvested from a tissue sample (e.g., a lung tissue sample such as a TBB sample). Cells can be harvested from a sample using standard techniques known in the art or disclosed herein. For example, in one embodiment, cells are harvested by centrifuging a cell sample and resuspending the pelleted cells. The cells can be resuspended in a buffered solution such as phosphate-buffered saline (PBS). After centrifuging the cell suspension to obtain a cell pellet, the cells can be lysed to extract nucleic acid, e.g., messenger RNA. All samples obtained from a subject, including those subjected to any sort of further processing, are considered to be obtained from the subject. 
     The sample, in one embodiment, is further processed before detection of the gene expression products is performed as described herein. For example, mRNA in a cell or tissue sample can be separated from other components of the sample. The sample can be concentrated and/or purified to isolate mRNA in its non-natural state, as the mRNA is not in its natural environment. For example, studies have indicated that the higher order structure of mRNA in vivo differs from the in vitro structure of the same sequence (see, e.g., Rouskin et al. (2014). Nature 505, pp. 701-705, incorporated herein in its entirety for all purposes). 
     mRNA from the sample in one embodiment, is hybridized to a synthetic DNA probe, which in some embodiments, includes a detection moiety (e.g., detectable label, capture sequence, barcode reporting sequence). Accordingly, in these embodiments, a non-natural mRNA-cDNA complex is ultimately made and used for detection of the gene expression product. In another embodiment, mRNA from the sample is directly labeled with a detectable label, e.g., a fluorophore. In a further embodiment, the non-natural labeled-mRNA molecule is hybridized to a cDNA probe and the complex is detected. 
     In one embodiment, once the mRNA is obtained from a sample, it is converted to complementary DNA (cDNA) in a hybridization reaction or is used in a hybridization reaction together with one or more cDNA probes. cDNA does not exist in vivo and therefore is a non-natural molecule. Furthermore, cDNA-mRNA hybrids are synthetic and do not exist in vivo. Besides cDNA not existing in vivo, cDNA is necessarily different than mRNA, as it includes deoxyribonucleic acid and not ribonucleic acid. The cDNA is then amplified, for example, by the polymerase chain reaction (PCR) or other amplification method known to those of ordinary skill in the art. For example, other amplification methods that may be employed include the ligase chain reaction (LCR) (Wu and Wallace, Genomics, 4:560 (1989), Landegren et al., Science, 241:1077 (1988), incorporated by reference in its entirety for all purposes, transcription amplification (Kwoh et al.,  Proc. Natl. Acad. Sci. USA,  86:1173 (1989), incorporated by reference in its entirety for all purposes), self-sustained sequence replication (Guatelli et al.,  Proc. Nat. Acad. Sci. USA,  87:1874 (1990), incorporated by reference in its entirety for all purposes), incorporated by reference in its entirety for all purposes, and nucleic acid based sequence amplification (NASBA). Guidelines for selecting primers for PCR amplification are known to those of ordinary skill in the art. See, e.g., McPherson et al., PCR Basics: From Background to Bench, Springer-Verlag, 2000, incorporated by reference in its entirety for all purposes. The product of this amplification reaction, i.e., amplified cDNA is also necessarily a non-natural product. First, as mentioned above, cDNA is a non-natural molecule. Second, in the case of PCR, the amplification process serves to create hundreds of millions of cDNA copies for every individual cDNA molecule of starting material. The number of copies generated are far removed from the number of copies of mRNA that are present in vivo. 
     In one embodiment, cDNA is amplified with primers that introduce an additional DNA sequence (e.g., adapter, reporter, capture sequence or moiety, barcode) onto the fragments (e.g., with the use of adapter-specific primers), or mRNA or cDNA gene expression product sequences are hybridized directly to a cDNA probe comprising the additional sequence (e.g., adapter, reporter, capture sequence or moiety, barcode). Amplification and/or hybridization of mRNA to a cDNA probe therefore serves to create non-natural double stranded molecules from the non-natural single stranded cDNA, or the mRNA, by introducing additional sequences and forming non-natural hybrids. Further, as known to those of ordinary skill in the art, amplification procedures have error rates associated with them. Therefore, amplification introduces further modifications into the cDNA molecules. In one embodiment, during amplification with the adapter-specific primers, a detectable label, e.g., a fluorophore, is added to single strand cDNA molecules. Amplification therefore also serves to create DNA complexes that do not occur in nature, at least because (i) cDNA does not exist in vivo, (i) adapter sequences are added to the ends of cDNA molecules to make DNA sequences that do not exist in vivo, (ii) the error rate associated with amplification further creates DNA sequences that do not exist in vivo, (iii) the disparate structure of the cDNA molecules as compared to what exists in nature and (iv) the chemical addition of a detectable label to the cDNA molecules. 
     In some embodiments, the expression of a gene expression product of interest is detected at the nucleic acid level via detection of non-natural cDNA molecules. 
     The gene expression products described herein include RNA comprising the entire or partial sequence of any of the nucleic acid sequences of interest, or their non-natural cDNA product, obtained synthetically in vitro in a reverse transcription reaction. The term “fragment” is intended to refer to a portion of the polynucleotide that generally comprise at least 10, 15, 20, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1,000, 1,200, or 1,500 contiguous nucleotides, or up to the number of nucleotides present in a full length gene expression product polynucleotide disclosed herein. A fragment of a gene expression product polynucleotide will generally encode at least 15, 25, 30, 50, 100, 150, 200, or 250 contiguous amino acids, or up to the total number of amino acids present in a full-length gene expression product protein of the invention. 
     In certain embodiments, a gene expression profile may be obtained by whole transcriptome shotgun sequencing (“WTSS” or “RNAseq”; see, e.g., Ryan et al BioTechniques 45: 81-94), which makes the use of high-throughput sequencing technologies to sequence cDNA in order to about information about a sample&#39;s RNA content. In general terms, cDNA is made from RNA, the cDNA is amplified, and the amplification products are sequenced. 
     After amplification, the cDNA may be sequenced using any convenient method. For example, the fragments may be sequenced using Illumina&#39;s reversible terminator method, Roche&#39;s pyrosequencing method (454), Life Technologies&#39; sequencing by ligation (the SOLiD platform) or Life Technologies&#39; Ion Torrent platform. Examples of such methods are described in the following references: Margulies et al (Nature 2005 437: 376-80); Ronaghi et al (Analytical Biochemistry 1996 242: 84-9); Shendure (Science 2005 309: 1728); Imelfort et al (Brief Bioinform. 2009 10:609-18); Fox et al (Methods Mol Biol. 2009; 553:79-108); Appleby et al (Methods Mol Biol. 2009; 513: 19-39) and Morozova (Genomics. 2008 92:255-64), which are incorporated by reference for the general descriptions of the methods and the particular steps of the methods, including all starting products, reagents, and final products for each of the steps. As would be apparent, forward and reverse sequencing primer sites that compatible with a selected next generation sequencing platform can be added to the ends of the fragments during the amplification step. 
     In other embodiments, the products may be sequenced using nanopore sequencing (e.g. as described in Soni et al Clin Chem 53: 1996-2001 2007, or as described by Oxford Nanopore Technologies). Nanopore sequencing is a single-molecule sequencing technology whereby a single molecule of DNA is sequenced directly as it passes through a nanopore. A nanopore is a small hole, of the order of 1 nanometer in diameter. Immersion of a nanopore in a conducting fluid and application of a potential (voltage) across it results in a slight electrical current due to conduction of ions through the nanopore. The amount of current which flows is sensitive to the size and shape of the nanopore. As a DNA molecule passes through a nanopore, each nucleotide on the DNA molecule obstructs the nanopore to a different degree, changing the magnitude of the current through the nanopore in different degrees. Thus, this change in the current as the DNA molecule passes through the nanopore represents a reading of the DNA sequence. Nanopore sequencing technology as disclosed in U.S. Pat. Nos. 5,795,782, 6,015,714, 6,627,067, 7,238,485 and 7,258,838 and U.S. patent application publications US2006003171 and US20090029477. 
     In some embodiments, the gene expression product of the subject methods is a protein, and the amount of protein in a particular biological sample is analyzed using a classifier derived from protein data obtained from cohorts of samples. The amount of protein can be determined by one or more of the following: enzyme-linked immunosorbent assay (ELISA), mass spectrometry, blotting, or immunohistochemistry. 
     In some embodiments, gene expression product markers and alternative splicing markers may be determined by microarray analysis using, for example, Affymetrix arrays, cDNA microarrays, oligonucleotide microarrays, spotted microarrays, or other microarray products from Biorad, Agilent, or Eppendorf. Microarrays provide particular advantages because they may contain a large number of genes or alternative splice variants that may be assayed in a single experiment. In some cases, the microarray device may contain the entire human genome or transcriptome or a substantial fraction thereof allowing a comprehensive evaluation of gene expression patterns, genomic sequence, or alternative splicing. Markers may be found using standard molecular biology and microarray analysis techniques as described in Sambrook Molecular Cloning a Laboratory Manual 2001 and Baldi, P., and Hatfield, W. G., DNA Microarrays and Gene Expression 2002. 
     Microarray analysis generally begins with extracting and purifying nucleic acid from a biological sample, (e.g. a biopsy or fine needle aspirate) using methods known to the art. For expression and alternative splicing analysis it may be advantageous to extract and/or purify RNA from DNA. It may further be advantageous to extract and/or purify niRNA from other forms of RNA such as tRNA and rRNA. 
     Purified nucleic acid may further be labeled with a fluorescent label, radionuclide, or chemical label such as biotin, digoxigenin, or digoxin for example by reverse transcription, polymerase chain reaction (PCR), ligation, chemical reaction or other techniques. The labeling can be direct or indirect which may further require a coupling stage. The coupling stage can occur before hybridization, for example, using aminoallyl-UTP and NHS amino-reactive dyes (like cyanine dyes) or after, for example, using biotin and labelled streptavidin. In one example, modified nucleotides (e.g. at a 1 aaUTP: 4 TTP ratio) are added enzymatically at a lower rate compared to normal nucleotides, typically resulting in 1 every 60 bases (measured with a spectrophotometer). The aaDNA may then be purified with, for example, a column or a diafiltration device. The aminoallyl group is an amine group on a long linker attached to the nucleobase, which reacts with a reactive label (e.g. a fluorescent dye). 
     The labeled samples may then be mixed with a hybridization solution which may contain sodium dodecyl sulfate (SDS), SSC, dextran sulfate, a blocking agent (such as COT1 DNA, salmon sperm DNA, calf thymus DNA, PolyA or PolyT), Denhardt&#39;s solution, formamine, or a combination thereof. 
     A hybridization probe is a fragment of DNA or RNA of variable length, which is used to detect in DNA or RNA samples the presence of nucleotide sequences (the DNA target) that are complementary to the sequence in the probe. The probe thereby hybridizes to single-stranded nucleic acid (DNA or RNA) whose base sequence allows probe-target base pairing due to complementarity between the probe and target. The labeled probe is first denatured (by heating or under alkaline conditions) into single DNA strands and then hybridized to the target DNA. 
     To detect hybridization of the probe to its target sequence, the probe is tagged (or labeled) with a molecular marker; commonly used markers are 32P or Digoxigenin, which is nonradioactive antibody-based marker. DNA sequences or RNA transcripts that have moderate to high sequence complementarity (e.g. at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more complementarity) to the probe are then detected by visualizing the hybridized probe via autoradiography or other imaging techniques. Detection of sequences with moderate or high complementarity depends on how stringent the hybridization conditions were applied; high stringency, such as high hybridization temperature and low salt in hybridization buffers, permits only hybridization between nucleic acid sequences that are highly similar, whereas low stringency, such as lower temperature and high salt, allows hybridization when the sequences are less similar. Hybridization probes used in DNA microarrays refer to DNA covalently attached to an inert surface, such as coated glass slides or gene chips, and to which a mobile cDNA target is hybridized. 
     A mix comprising target nucleic acid to be hybridized to probes on an array may be denatured by heat or chemical means and added to a port in a microarray. The holes may then be sealed and the microarray hybridized, for example, in a hybridization oven, where the microarray is mixed by rotation, or in a mixer. After an overnight hybridization, non-specific binding may be washed off (e.g. with SDS and SSC). The microarray may then be dried and scanned in a machine comprising a laser that excites the dye and a detector that measures emission by the dye. The image may be overlaid with a template grid and the intensities of the features (e.g. a feature comprising several pixels) may be quantified. 
     Various kits can be used for the amplification of nucleic acid and probe generation of the subject methods. Examples of kit that can be used in the present invention include but are not limited to Nugen WT-Ovation FFPE kit, cDNA amplification kit with Nugen Exon Module and Frag/Label module. The NuGEN WT-Ovation™. FFPE System V2 is a whole transcriptome amplification system that enables conducting global gene expression analysis on the vast archives of small and degraded RNA derived from FFPE samples. The system is comprised of reagents and a protocol required for amplification of as little as 50 ng of total FFPE RNA. The protocol can be used for qPCR, sample archiving, fragmentation, and labeling. The amplified cDNA can be fragmented and labeled in less than two hours for GeneChip™. 3′ expression array analysis using NuGEN&#39;s FL-Ovation™. cDNA Biotin Module V2. For analysis using Affymetrix GeneChip™. Exon and Gene ST arrays, the amplified cDNA can be used with the WT-Ovation Exon Module, then fragmented and labeled using the FL-Ovation™. cDNA Biotin Module V2. For analysis on Agilent arrays, the amplified cDNA can be fragmented and labeled using NuGEN&#39;s FL-Ovation™. cDNA Fluorescent Module. 
     In some embodiments, Ambion WT-expression kit can be used. Ambion WT-expression kit allows amplification of total RNA directly without a separate ribosomal RNA (rRNA) depletion step. With the Ambion™ WT Expression Kit, samples as small as 50 ng of total RNA can be analyzed on Affymetrix™. GeneChip™ Human, Mouse, and Rat Exon and Gene 1.0 ST Arrays. In addition to the lower input RNA requirement and high concordance between the Affymetrix™ method and TaqMan™ real-time PCR data, the Ambion™. WT Expression Kit provides a significant increase in sensitivity. For example, a greater number of probe sets detected above background can be obtained at the exon level with the Ambion™. WT Expression Kit as a result of an increased signal-to-noise ratio. Ambion™-expression kit may be used in combination with additional Affymetrix labeling kit. In some embodiments, AmpTec Trinucleotide Nano mRNA Amplification kit (6299-A15) can be used in the subject methods. The ExpressArt™ TRinucleotide mRNA amplification Nano kit is suitable for a wide range, from 1 ng to 700 ng of input total RNA. According to the amount of input total RNA and the required yields of aRNA, it can be used for 1-round (input &gt;300 ng total RNA) or 2-rounds (minimal input amount 1 ng total RNA), with aRNA yields in the range of &gt;10 μg. AmpTec&#39;s proprietary TRinucleotide priming technology results in preferential amplification of mRNAs (independent of the universal eukaryotic 3′-poly(A)-sequence), combined with selection against rRNAs. More information on AmpTec Trinucleotide Nano mRNA Amplification kit can be obtained at www.amp-tec.com/products.htm. This kit can be used in combination with cDNA conversion kit and Affymetrix labeling kit. 
     The raw data may then be normalized, for example, by subtracting the background intensity and then dividing the intensities making either the total intensity of the features on each channel equal or the intensities of a reference gene and then the t-value for all the intensities may be calculated. More sophisticated methods, include z-ratio, loess and lowess regression and RMA (robust multichip analysis), such as for Affymetrix chips. 
     In some embodiments, the above described methods may be used for determining transcript expression levels for training (e.g., using a classifier training module) a classifier to differentiate whether a subject is a smoker or non-smoker. In some embodiments, the above described methods may be used for determining transcript expression levels for training (e.g., using a classifier training module) a classifier to differentiate whether a subject has UIP or non-UIP. 
     Data Analysis 
     (i) Comparison of Sample to Normal 
     In some embodiments, results of molecular profiling performed on a sample from a subject (“test sample”) may be compared to a biological sample that is known or suspected to be normal (“normal sample”). In some embodiments, a normal sample is a sample that does not comprise or is expected to not comprise an ILD, or conditions under evaluation, or would test negative in the molecular profiling assay for the one or more ILDs under evaluation. In some embodiments, a normal sample is that which is or is expected to be free of any ILD, or a sample that would test negative for any ILD in the molecular profiling assay. The normal sample may be from a different subject from the subject being tested, or from the same subject. In some cases, the normal sample is a lung tissue sample obtained from a subject such as the subject being tested for example. The normal sample may be assayed at the same time, or at a different time from the test sample. In some embodiments, a normal sample is a sample that is known or suspected to be from a non-smoker. In particular embodiments, the normal sample is a sample that has been confirmed by at least two expert pathologists to be Non-UIP. In particular embodiments, the normal sample is a sample that has been confirmed by at least two expert pathologists to be Non-IPF. 
     The results of an assay on the test sample may be compared to the results of the same assay on a sample having a known disease state (e.g., normal, affected by a selected ILD (e.g., IPF, NSIP, etc.), smoker, non-smoker). In some cases the results of the assay on the normal sample are from a database, or a reference. In some cases, the results of the assay on the normal sample are a known or generally accepted value or range of values by those skilled in the art. In some cases the comparison is qualitative. In other cases the comparison is quantitative. In some cases, qualitative or quantitative comparisons may involve but are not limited to one or more of the following: comparing fluorescence values, spot intensities, absorbance values, chemiluminescent signals, histograms, critical threshold values, statistical significance values, gene product expression levels, gene product expression level changes, alternative exon usage, changes in alternative exon usage, protein levels, DNA polymorphisms, copy number variations, indications of the presence or absence of one or more DNA markers or regions, or nucleic acid sequences. 
     (ii) Evaluation of Results 
     In some embodiments, the molecular profiling results are evaluated using methods known to the art for correlating gene product expression levels or alternative exon usage with specific phenotypes such as a particular ILD, or normalcy (e.g. disease or condition free). In some cases, a specified statistical confidence level may be determined in order to provide a diagnostic confidence level. For example, it may be determined that a confidence level of greater than 90% may be a useful predictor of the presence of an ILD or of a smoker or non-smoker status. In other embodiments, more or less stringent confidence levels may be chosen. For example, a confidence level of about or at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, 99.5%, or 99.9% may be chosen as a useful phenotypic predictor. The confidence level provided may in some cases be related to the quality of the sample, the quality of the data, the quality of the analysis, the specific methods used, and/or the number of gene expression products analyzed. The specified confidence level for providing a diagnosis may be chosen on the basis of the expected number of false positives or false negatives and/or cost. Methods for choosing parameters for achieving a specified confidence level or for identifying markers with diagnostic power include but are not limited to Receiver Operating Characteristic (ROC) curve analysis, binormal ROC, principal component analysis, partial least squares analysis, singular value decomposition, least absolute shrinkage and selection operator analysis, least angle regression, and the threshold gradient directed regularization method. 
     (iii) Data Analysis 
     Raw gene expression level and alternative splicing data may in some cases be improved through the application of methods and/or processes designed to normalize and or improve the reliability of the data. In some embodiments of the present disclosure the data analysis requires a computer or other device, machine or apparatus for application of the various methods and/or processes described herein due to the large number of individual data points that are processed. A “machine learning classifier” refers to a computational-based prediction data structure or method, employed for characterizing a gene expression profile. The signals corresponding to certain expression levels, which are obtained by, e.g., microarray-based hybridization assays, are typically subjected to the classifier to classify the expression profile. Supervised learning generally involves “training” a classifier to recognize the distinctions among classes and then “testing” the accuracy of the classifier on an independent test set. For new, unknown samples the classifier can be used to predict the class in which the samples belong. In various embodiments, such training is be achieved, e.g., using a classifier training module. 
     In some cases, the robust multi-array average (RMA) method may be used to normalize raw data. The RMA method begins by computing background-corrected intensities for each matched cell on a number of microarrays. The background corrected values are restricted to positive values as described by Irizarry et al. Biostatistics 2003 Apr. 4 (2): 249-64. After background correction, the base-2 logarithm of each background corrected matched-cell intensity is then obtained. The back-ground corrected, log-transformed, matched intensity on each microarray is then normalized using the quantile normalization method in which for each input array and each probe expression value, the array percentile probe value is replaced with the average of all array percentile points, this method is more completely described by Bolstad et al. Bioinformatics 2003. Following quantile normalization, the normalized data may then be fit to a linear model to obtain an expression measure for each probe on each microarray. Tukey&#39;s median polish algorithm (Tukey, J. W., Exploratory Data Analysis. 1977) may then be used to determine the log-scale expression level for the normalized probe set data. 
     Various other software and/or hardware modules or processes may be implemented. In certain methods, feature selection and model estimation may be performed by logistic regression with lasso penalty using glmnet (Friedman J, Hastie T, Tibshirani R. Regularization Paths for Generalized Linear Models via Coordinate Descent. Journal of statistical software 2010; 33(1): 1-22). Raw reads may be aligned using TopHat (Trapnell C, Pachter L, Salzberg S L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 2009; 25(9): 1105-11.). Gene counts may be obtained using HTSeq (Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data.  Bioinformatics  2014.) and normalized using DESeq (Love M I, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2; 2014). In methods, top features (N ranging from 10 to 200) were used to train a linear support vector machine (SVM) (Suykens J A K, Vandewalle J. Least Squares Support Vector Machine Classifiers.  Neural Processing Letters  1999; 9(3): 293-300) using the e1071 library (Meyer D. Support vector machines: the interface to libsvm in package e1071. 2014.). Confidence intervals may be computed using the pROC package (Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves.  BMC bioinformatics  2011; 12: 77) 
     In addition, data may be filtered to remove data that may be considered suspect. In some embodiments, data deriving from microarray probes that have fewer than about 4, 5, 6, 7 or 8 guanosine+cytosine nucleotides may be considered to be unreliable due to their aberrant hybridization propensity or secondary structure issues. Similarly, data deriving from microarray probes that have more than about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 guanosine+cytosine nucleotides may be considered unreliable due to their aberrant hybridization propensity or secondary structure issues. 
     In some cases, unreliable probe sets may be selected for exclusion from data analysis by ranking probe-set reliability against a series of reference datasets. For example, RefSeq or Ensembl (EMBL) are considered very high quality reference datasets. Data from probe sets matching RefSeq or Ensembl sequences may in some cases be specifically included in microarray analysis experiments due to their expected high reliability. Similarly data from probe-sets matching less reliable reference datasets may be excluded from further analysis, or considered on a case by case basis for inclusion. In some cases, the Ensembl high throughput cDNA (HTC) and/or mRNA reference datasets may be used to determine the probe-set reliability separately or together. In other cases, probe-set reliability may be ranked. For example, probes and/or probe-sets that match perfectly to all reference datasets such as for example RefSeq, HTC, HTSeq, and mRNA, may be ranked as most reliable (1). Furthermore, probes and/or probe-sets that match two out of three reference datasets may be ranked as next most reliable (2), probes and/or probe-sets that match one out of three reference datasets may be ranked next (3) and probes and/or probe sets that match no reference datasets may be ranked last (4). Probes and or probe-sets may then be included or excluded from analysis based on their ranking. For example, one may choose to include data from category 1, 2, 3, and 4 probe-sets; category 1, 2, and 3 probe-sets; category 1 and 2 probe-sets; or category 1 probe-sets for further analysis. In another example, probe-sets may be ranked by the number of base pair mismatches to reference dataset entries. It is understood that there are many methods understood in the art for assessing the reliability of a given probe and/or probe-set for molecular profiling and the methods of the present disclosure encompass any of these methods and combinations thereof. 
     In some embodiments of the present invention, data from probe-sets may be excluded from analysis if they are not expressed or expressed at an undetectable level (not above background). A probe-set is judged to be expressed above background if for any group:
 
Integral from TO to Infinity of the standard normal distribution&lt;Significance (0.01)
 
     Where: T0=Sqr(GroupSize) (T−P)/Sqr(Pvar); GroupSize=Number of CEL files in the group, T=Average of probe scores in probe-set, P=Average of Background probes averages of GC content, and Pvar=Sum of Background probe variances/(Number of probes in probe-set) 2, 
     This allows including probe-sets in which the average of probe-sets in a group is greater than the average expression of background probes of similar GC content as the probe-set probes as the center of background for the probe-set and enables one to derive the probe-set dispersion from the background probe-set variance. 
     In some embodiments of the present disclosure, probe-sets that exhibit no, or low variance may be excluded from further analysis. Low-variance probe-sets are excluded from the analysis via a Chi-Square test. A probe-set is considered to be low-variance if its transformed variance is to the left of the 99 percent confidence interval of the Chi-Squared distribution with (N−1) degrees of freedom. (N−1)*Probe-set Variance/(Gene Probe-set Variance). about.Chi-Sq(N−1) where N is the number of input CEL files, (N−1) is the degrees of freedom for the Chi-Squared distribution, and the “probe-set variance for the gene” is the average of probe-set variances across the gene. In some embodiments of the present invention, probe-sets for a given gene or transcript cluster may be excluded from further analysis if they contain less than a minimum number of probes that pass through the previously described filter steps for GC content, reliability, variance and the like. For example in some embodiments, probe-sets for a given gene or transcript cluster may be excluded from further analysis if they contain less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or less than about 20 probes. 
     Methods of data analysis of gene expression levels or of alternative splicing may further include the use of a feature selection method and/or process as provided herein. In some embodiments of the present invention, feature selection is provided by use of the LIMMA software package (Smyth, G. K. (2005). Limma: linear models for microarray data. In: Bioinformatics and Computational Biology Solutions using R and Bioconductor, R. Gentleman, V. Carey, S. Dudoit, R. Irizarry, W. Huber (eds.), Springer, New York, pages 397-420). 
     Methods of data analysis of gene expression levels and or of alternative splicing may further include the use of a pre-classifier method and/or process (e.g., implemented by a pre-classifier analysis module). For example, a method and/or process may use a cell-specific molecular fingerprint to pre-classify the samples according to their composition and then apply a correction/normalization factor. This data/information may then be fed in to a final classification method and/or process which would incorporate that information to aid in the final diagnosis. 
     In certain embodiments, the methods of the present invention include the use of a pre-classifier method and/or process (e.g., implemented by a pre-classifier analysis module) that uses a molecular fingerprint to pre-classify the samples as smoker or non-smoker prior to application of a UIP/non-UIP classifier of the present invention. 
     Methods of data analysis of gene expression levels and/or of alternative splicing may further include the use of a classifier method and/or process (e.g., implemented by a classifier analysis module) as provided herein. In some embodiments of the present invention a diagonal linear discriminant analysis, k-nearest neighbor classifier, support vector machine (SVM) classifier, linear support vector machine, random forest classifier, or a probabilistic model-based method or a combination thereof is provided for classification of microarray data. In some embodiments, identified markers that distinguish samples (e.g. first ILD from second ILD, normal vs. ILD) or distinguish subtypes (e.g. IPF vs. NSIP) are selected based on statistical significance of the difference in expression levels between classes of interest. In some cases, the statistical significance is adjusted by applying a Benjamin Hochberg or another correction for false discovery rate (FDR). 
     In some cases, the classifier may be supplemented with a meta-analysis approach such as that described by Fishel and Kaufman et al. 2007 Bioinformatics 23(13): 1599-606. In some cases, the classifier may be supplemented with a meta-analysis approach such as a repeatability analysis. In some cases, the repeatability analysis selects markers that appear in at least one predictive expression product marker set. 
     Methods for deriving and applying posterior probabilities to the analysis of microarray data are known in the art and have been described for example in Smyth, G. K. 2004 Stat. Appi. Genet. Mol. Biol. 3: Article  3 . In some cases, the posterior probabilities may be used to rank the markers provided by the classifier. In some cases, markers may be ranked according to their posterior probabilities and those that pass a chosen threshold may be chosen as markers whose differential expression is indicative of or diagnostic for samples that are for example IPF or NSIP. Illustrative threshold values include prior probabilities of 0.7, 0.75, 0.8, 0.85, 0.9, 0.925, 0.95, 0.975, 0.98, 0.985, 0.99, 0.995 or higher. 
     A statistical evaluation of the results of the molecular profiling may provide, but is not limited to providing, a quantitative value or values indicative of one or more of the following: the likelihood of diagnostic accuracy; the likelihood of an ILD; the likelihood of a particular ILD; the likelihood of the success of a particular therapeutic intervention, the likelihood the subject is a smoker, and the likelihood the subject is a non-smoker. Thus a physician, who is not likely to be trained in genetics or molecular biology, need not understand the raw data. Rather, the data is presented directly to the physician in its most useful form to guide patient care. The results of the molecular profiling can be statistically evaluated using a number of methods known to the art including, but not limited to: the students T test, the two sided T test, pearson rank sum analysis, hidden markov model analysis, analysis of q-q plots, principal component analysis, one way ANOVA, two way ANOVA, LIMMA and the like. 
     In some embodiments of the present invention, the use of molecular profiling alone or in combination with cytological analysis may provide a classification, identification, or diagnosis that is between about 85% accurate and about 99% or about 100% accurate. In some cases, the molecular profiling process and/or cytology provide a classification, identification, diagnosis of an ILD that is about, or at least about 85%, 86%, 87%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.75%, 99.8%, 99.85%, or 99.9% accurate. In some embodiments, the molecular profiling process and/or cytology provide a classification, identification, or diagnosis of the presence of a particular ILD type (e.g. IPF; NSIP; HP) that is about, or at least about 85%, 86%, 87%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.75%, 99.8%, 99.85%, or 99.9% accurate. 
     In some cases, accuracy may be determined by tracking the subject over time to determine the accuracy of the original diagnosis. In other cases, accuracy may be established in a deterministic manner or using statistical methods. For example, receiver operator characteristic (ROC) analysis may be used to determine the optimal assay parameters to achieve a specific level of accuracy, specificity, positive predictive value, negative predictive value, and/or false discovery rate. 
     In some embodiments of the present disclosure, gene expression products and compositions of nucleotides encoding for such products which are determined to exhibit the greatest difference in expression level or the greatest difference in alternative splicing between a first ILD and a second ILD (e.g., between IPF and NSIP), between ILD and normal, and/or between smoker and non-smoker may be chosen for use as molecular profiling reagents of the present disclosure. Such gene expression products may be particularly useful by providing a wider dynamic range, greater signal to noise, improved diagnostic power, lower likelihood of false positives or false negative, or a greater statistical confidence level than other methods known or used in the art. 
     In other embodiments of the present invention, the use of molecular profiling alone or in combination with cytological analysis may reduce the number of samples scored as non-diagnostic by about, or at least about 100%, 99%, 95%, 90%, 80%, 75%, 70%, 65%, or about 60% when compared to the use of standard cytological techniques known to the art. In some cases, the methods of the present invention may reduce the number of samples scored as intermediate or suspicious by about, or at least about 100%, 99%, 98%, 97%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, or about 60%, when compared to the standard cytological methods used in the art. 
     In some cases the results of the molecular profiling assays, are entered into a database for access by representatives or agents of a molecular profiling business, the individual, a medical provider, or insurance provider. In some cases assay results include sample classification, identification, or diagnosis by a representative, agent or consultant of the business, such as a medical professional. In other cases, a computer analysis of the data is provided automatically. In some cases the molecular profiling business may bill the individual, insurance provider, medical provider, researcher, or government entity for one or more of the following: molecular profiling assays performed, consulting services, data analysis, reporting of results, or database access. 
     In some embodiments of the present invention, the results of the molecular profiling are presented as a report on a computer screen or as a paper record. In some cases, the report may include, but is not limited to, such information as one or more of the following: the number of genes differentially expressed, the suitability of the original sample, the number of genes showing differential alternative splicing, a diagnosis, a statistical confidence for the diagnosis, the likelihood the subject is a smoker, the likelihood of an ILD, and indicated therapies. 
     (iv) Categorization of Samples Based on Molecular Profiling Results 
     The results of the molecular profiling may be classified into one of the following: smoker, non-smoker, ILD, a particular type of ILD, a non-ILD, or non-diagnostic (providing inadequate information concerning the presence or absence of an ILD). In some cases, the results of the molecular profiling may be classified into IPF versus NSIP categories. In particular cases, the results may be classified as UIP or non-UIP. 
     In some embodiments of the present invention, results are classified using a trained classifier. Trained classifiers of the present invention implement methods and/or processes that have been developed using a reference set of known ILD and normal samples, known smoker and non-smoker samples, or combinations of known ILD and normal samples from smokers and/or non-smokers including, but not limited to, samples with one or more histopathologies. In some embodiments, training (e.g., using a classifier training module) comprises comparison of gene expression product levels in a first set biomarkers from a first ILD to gene expression product levels in a second set of biomarkers from a second ILD, where the first set of biomarkers includes at least one biomarker that is not in the second set. In some embodiments, training (e.g., using a classifier training module) comprises comparison of gene expression product levels in a first set biomarkers from a first ILD that is non-UIP to gene expression product levels in a second set of biomarkers from a second ILD that is UIP, where the first set of biomarkers includes at least one biomarker that is not in the second set. In some embodiments, training (e.g., using a classifier training module) further comprises comparison of gene expression product levels in a first set biomarkers from a first subject that is a smoker to gene expression product levels in a second set of biomarkers from a second subject that is a non-smoker, where the first set of biomarkers includes at least one biomarker that is not in the second set. In some embodiments, either the entire classifier or portions of the classifier can be trained (e.g., using a classifier training module) using comparisons of expression levels of biomarker panels within a classification panel against all other biomarker panels (or all other biomarker signatures) used in the classifier. 
     Classifiers suitable for categorization of samples include but are not limited to k-nearest neighbor classifiers, support vector machines, linear discriminant analysis, diagonal linear discriminant analysis, updown, naive Bayesian classifiers, neural network classifiers, hidden Markov model classifiers, genetic classifiers, or any combination thereof. 
     In some cases, trained classifiers of the present invention may incorporate data other than gene expression or alternative splicing data such as but not limited to DNA polymorphism data, sequencing data, scoring or diagnosis by cytologists or pathologists of the present invention, information provided by the pre-classifier method and/or process of the present disclosure, or information about the medical history of the subject of the present disclosure. 
     When classifying a biological sample for diagnosis of ILD, there are typically two possible outcomes from a binary classifier. Similarly, when classifying a biological sample for diagnosis of smoker, there are typically two possible outcomes from a binary classifier. When a binary classifier is compared with actual true values (e.g., values from a biological sample), there are typically four possible outcomes. If the outcome from a prediction is p (where “p” is a positive classifier output, such as a particular ILD) and the actual value is also p, then it is called a true positive (TP); however if the actual value is n then it is said to be a false positive (FP). Conversely, a true negative has occurred when both the prediction outcome and the actual value are n (where “n” is a negative classifier output, such as no ILD, or absence of a particular disease tissue as described herein), and false negative is when the prediction outcome is n while the actual value is p. In one embodiment, consider a diagnostic test that seeks to determine whether a person has a certain disease. A false positive in this case occurs when the person tests positive, but actually does not have the disease. A false negative, on the other hand, occurs when the person tests negative, suggesting they are healthy, when they actually do have the disease. In some embodiments, a Receiver Operator Characteristic (ROC) curve assuming real-world prevalence of subtypes can be generated by re-sampling errors achieved on available samples in relevant proportions. 
     The positive predictive value (PPV), or precision rate, or post-test probability of disease, is the proportion of patients with positive test results who are correctly diagnosed. It is the most important measure of a diagnostic method as it reflects the probability that a positive test reflects the underlying condition being tested for. Its value does however depend on the prevalence of the disease, which may vary. In one example, FP (false positive); TN (true negative); TP (true positive); FN (false negative). False positive rate (α)=FP/(FP+TN)-specificity; False negative rate (β)=FN/(TP+FN)−sensitivity; Power=sensitivity=1−β; Likelihood-ratio positive=sensitivity/(1−specificity); Likelihood-ratio negative=(1−sensitivity)/specificity. 
     The negative predictive value is the proportion of patients with negative test results who are correctly diagnosed. PPV and NPV measurements can be derived using appropriate disease subtype prevalence estimates. An estimate of the pooled disease prevalence can be calculated from the pool of indeterminates which roughly classify into B vs M by surgery. For subtype specific estimates, in some embodiments, disease prevalence may sometimes be incalculable because there are not any available samples. In these cases, the subtype disease prevalence can be substituted by the pooled disease prevalence estimate. 
     In some embodiments, the level of expression products or alternative exon usage is indicative of one or the following: IPF, NSIP, or HP. 
     In some embodiments, the level of expression products or alternative exon usage is indicative that the subject is a smoker or a non-smoker. 
     In some embodiments, the results of the expression analysis of the subject methods provide a statistical confidence level that a given diagnosis is correct. In some embodiments, such statistical confidence level is at least about, or more than about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% 99.5%, or more. 
     Reports 
     A subject method and/or system may include generating a report that provides an indication that a sample (a lung tissue sample) is an ILD sample (e.g., using a report module). A subject diagnostic method can include generating a report that provides an indication as to whether an individual being tested has an ILD. A subject diagnostic method can include generating a report that provides an indication as to whether an individual being tested is, or is not a smoker. A subject method (or report module) can include generating a report that provides an indication as to whether an individual being tested has IPF (and not, e.g., an ILD other than IPF; e.g., the report can indicate that the individual has IPF and not NSIP). 
     In some embodiments, a subject method of diagnosing an ILD involves generating a report (e.g., using a report module). Such a report can include information such as a likelihood that the patient has an ILD; a likelihood that the patient is a smoker; a recommendation regarding further evaluation; a recommendation regarding therapeutic drug and/or device intervention; and the like. 
     For example, the methods disclosed herein can further include a step of generating or outputting a report providing the results of a subject diagnostic method, which report can be provided in the form of an electronic medium (e.g., an electronic display on a computer monitor), or in the form of a tangible medium (e.g., a report printed on paper or other tangible medium). An assessment as to the results of a subject diagnostic method (e.g., a likelihood that an individual has an ILD; a likelihood that an individual has IPF; a likelihood that an individual is a smoker) can be referred to as a “report” or, simply, a “score.” A person or entity that prepares a report (“report generator”) may also perform steps such as sample gathering, sample processing, and the like. Alternatively, an entity other than the report generator can perform steps such as sample gathering, sample processing, and the like. A diagnostic assessment report can be provided to a user. A “user” can be a health professional (e.g., a clinician, a laboratory technician, a physician (e.g., a cardiologist), etc.). 
     A subject report can further include one or more of: 1) service provider information; 2) patient data; 3) data regarding the expression level of a given gene product or set of gene products, a score or classifier decision; 4) follow-up evaluation recommendations; 5) therapeutic intervention or recommendations; and 6) other features. 
     Further Evaluation 
     Based on the expression level of a given gene product or set of gene products, and/or based on a report (as described above), a physician or other qualified medical personnel can determine whether further evaluation of the test subject (the patient) is required. Further evaluation can include, e.g., spirometry. 
     Therapeutic Intervention 
     Based on the expression level of a given gene product or set of gene products, and/or based on a report (as described above), a physician or other qualified medical personnel can determine whether appropriate therapeutic intervention is advised. 
     Therapeutic intervention includes drug-based therapeutic intervention, device-based therapeutic intervention, and surgical intervention. Where a report indicates a likelihood that an individual has IPF, drug-based therapeutic intervention includes, e.g., administering to the individual an effective amount of pirfenidone, prednisone, azathioprine, or N-acetylcysteine. Surgical intervention includes, e.g., arterial bypass surgery. 
     Computer-Implemented Methods, Systems and Devices 
     Therapeutic Intervention 
     The methods of the present disclosure can be computer-implemented, such that method steps (e.g., assaying, comparing, calculating, and the like) are be automated in whole or in part. 
     Accordingly, the present disclosure provides methods, computer systems, devices and the like in connection with computer-implemented methods of facilitating a diagnosis of an interstitial lung disease (e.g., a diagnosis of IPF, NSIP, HP, etc.), including differential diagnosis. 
     The present disclosure further provides methods, computer systems, devices and the like in connection with computer-implemented methods of facilitating determination of smoker status (e.g., smoker vs. non-smoker). 
     The present disclosure further provides methods, computer systems, devices and the like in connection with computer-implemented methods of facilitating a diagnosis of an interstitial lung disease (e.g., a diagnosis of IPF, NSIP, HP, etc.), including differential diagnosis, wherein the methods further comprise determining a subjects smoker status (smoker vs. non-smoker) and incorporating smoker status into the determination of the subjects interstitial lung disease diagnosis. In some embodiments, (i) smoker status is incorporated into the interstitial lung disease diagnosis as a covariate in the model used during training (e.g., using a classifier training module). This approach boosts signal-to-noise ratio, particularly in data derived from smokers (were noise is higher) and allows data derived from smokers and non-smokers to be combined and used simultaneously. In some embodiments, (ii) smoker status is incorporated into the interstitial lung disease diagnosis by identifying one or more genes that are susceptible to smoker status bias and excluding such genes or weighing such genes differently than other genes that are not susceptible to smoker-status during interstitial lung disease diagnosis classifier training. In some embodiments, (iii) smoker status is incorporated into the interstitial lung disease diagnosis by constructing a tiered classification in which an initial classifier is trained to recognize the gene signatures that distinguish smokers from non-smokers (e.g., using a classifier training module). Once patient samples are pre-classified as “smoker” or “non-smoker” (e.g., using a pre-classifier analysis module), distinct classifiers that were each trained to distinguish UIP vs. Non UIP in smokers or non-smokers, respectively can be implemented to diagnose interstitial lung disease. In still further embodiments, such methods comprising the step of incorporating smoker status into the determination of the subjects interstitial lung disease diagnosis include a combination of one or more of the above mentioned means of such incorporation (i.e., a combination of two or more of embodiments (i) to (iii) in the instant paragraph. 
     For example, the method steps, including obtaining values for biomarker levels, comparing normalized biomarker (gene) expression levels to a control level, calculating the likelihood of an ILD (and optionally the likelihood a subject is a smoker), generating a report, and the like, can be completely or partially performed by a computer program product. Values obtained can be stored electronically, e.g., in a database, and can be subjected to a classifier executed by a programmed computer (e.g., using a classifier analysis module). 
     For example, the methods and/or systems of the present disclosure can involve inputting a biomarker level (e.g., a normalized expression level of a gene product) into a classifier analysis module to execute a method and/or process to perform the comparing and calculating step(s) described herein, and generate a report (e.g., using a report module) as described herein, e.g., by displaying or printing a report to an output device at a location local or remote to the computer. The output to the report can be a score (e.g., numerical score (representative of a numerical value) or a non-numerical score (e.g., non-numerical output (e.g., “IPF”, “No evidence of IPF”) representative of a numerical value or range of numerical values. In other aspects, the output may indicate “UIP” vs. “non-UIP.” In other aspects, the output may indicate “Smoker” vs. “Non-smoker” 
     The present disclosure thus provides a computer program product including a computer readable storage medium having software and/or hardware modules stored on it. The software and/or hardware modules can, when executed by a processor, execute relevant calculations based on values obtained from analysis of one or more biological sample (e.g., lung tissue sample) from an individual. The computer program product has stored therein a computer program for performing the calculation(s). 
     The present disclosure provides systems for executing the program described above, which system generally includes: a) a central computing environment or processor executing software and/or hardware modules; b) an input device, operatively connected to the computing environment, to receive patient data, wherein the patient data can include, for example, biomarker level or other value obtained from an assay using a biological sample from the patient, as described above; c) an output device, connected to the computing environment, to provide information to a user (e.g., medical personnel); and d) a method and/or process executed by the central computing environment (e.g., a processor), where the method and/or process is executed based on the data received by the input device, and wherein the method and/or process calculates a value, which value is indicative of the likelihood the subject has an ILD, as described herein. 
     The present disclosure also provides systems for executing the program described above, which system generally includes: a) a central computing environment or processor executing software and/or hardware modules; b) an input device, operatively connected to the computing environment, to receive patient data, wherein the patient data can include, for example, biomarker level or other value obtained from an assay using a biological sample from the patient, as described above; c) an output device, connected to the computing environment, to provide information to a user (e.g., medical personnel); and d) a method and/or process executed by the central computing environment (e.g., a processor), where the method and/or process is executed based on the data received by the input device, wherein the method and/or process calculates a value, which value is indicative of the likelihood the subject has an ILD, as described herein, and wherein the method and/or process uses smoking status (smoker vs. non-smoker) as a covariate in the model used during training. In some embodiments, the method and/or process excludes or weighs one or more gene that is susceptible to smoker status bias differently during classifier training to enrich the feature space used for training with genes that are not confounded or affected by smoking status. 
     In still further embodiments, the present disclosure provides systems for executing the program described above, which system generally includes: a) a central computing environment or processor executing software and/or hardware modules; b) an input device, operatively connected to the computing environment, to receive patient data, wherein the patient data can include, for example, biomarker level or other value obtained from an assay using a biological sample from the patient, as described above; c) an output device, connected to the computing environment, to provide information to a user (e.g., medical personnel); and d) a first method and/or process executed by the central computing environment (e.g., a processor), where the first method and/or process is executed based on the data received by the input device, wherein the first method and/or process calculates a value, which value is indicative of the likelihood a subject is a smoker or a non-smoker, as described herein, wherein the subject&#39;s status as a smoker or non-smoker causes the first method and/or process to apply a second method and/or process specifically trained (e.g., using a classifier training module) to distinguish UIP vs. Non UIP in smokers or non-smokers, respectively and e) wherein the second method and/or process is executed by the central computing environment (e.g., a processor), where the second method and/or process is executed based on the data received by the input device, and wherein the second method and/or process calculates a value, which value is indicative of the likelihood the subject has an ILD, as described herein, 
     Computer Systems 
       FIG.  7 A  illustrates a processing system  100  including at least one processor  102 , or processing unit or plurality of processors, memory  104 , at least one input device  106  and at least one output device  108 , coupled together via a bus or group of buses  110 . Processing system can be implemented on any suitable device, such as, for example, a host device, a personal computer, a handheld or laptop device, a personal digital assistant, a multiprocessor system, a microprocessor-based system, a programmable consumer electronic device, a minicomputer, a server computer, a web server computer, a mainframe computer, and/or a distributed computing environment that includes any of the above systems or devices 
     In certain embodiments, input device  106  and output device  108  can be the same device. An interface  112  can also be provided for coupling the processing system  100  to one or more peripheral devices, for example interface  112  can be a PCI card or PC card. At least one storage device  114  which houses at least one database  116  can also be provided. 
     The memory  104  can be any form of memory device, for example, volatile or nonvolatile memory, solid state storage devices, magnetic devices, etc. For example, in some embodiments, the memory  104  can be a random access memory (RAM), a memory buffer, a hard drive, a read-only memory (ROM), an erasable programmable read-only memory (EPROM), a database, and/or the like. 
     The processor  102  can include more than one distinct processing device, for example to handle different functions within the processing system  100 . The processor  100  can be any suitable processing device configured to run or execute a set of instructions or code (e.g., stored in the memory) such as a general-purpose processor (GPP), a central processing unit (CPU), an accelerated processing unit (APU), a graphics processor unit (GPU), an Application Specific Integrated Circuit (ASIC), and/or the like. Such a processor  100  can run or execute a set of instructions or code stored in the memory associated with using a personal computer application, a mobile application, an internet web browser, a cellular and/or wireless communication (via a network), and/or the like. More specifically, the processor can execute a set of instructions or code stored in the memory  104  associated with analyzing and classifying data, as described herein. 
     Input device  106  receives input data  118  and can comprise, for example, a keyboard, a pointer device such as a pen-like device or a mouse, audio receiving device for voice controlled activation such as a microphone, data receiver or antenna such as a modem or wireless data adaptor, data acquisition card, etc. Input data  118  can come from different sources, for example keyboard instructions in conjunction with data received via a network. 
     Output device  108  produces or generates output data  120  and can comprise, for example, a display device or monitor in which case output data  120  is visual, a printer in which case output data  120  is printed, a port for example a USB port, a peripheral component adaptor, a data transmitter or antenna such as a modem or wireless network adaptor, etc. Output data  120  can be distinct and derived from different output devices, for example a visual display on a monitor in conjunction with data transmitted to a network. A user can view data output, or an interpretation of the data output, on, for example, a monitor or using a printer. 
     In some embodiments, the input device  106  and/or the output device  108  can be a communication interface configured to send and/or receive data via a network. More specifically, in such embodiments, the processing system  100  can act as a host device to one or more client devices (not shown in  FIG.  7 A ). As such, the processing system  100  can send data to (e.g., output data  120 ) and receive data from (e.g., input data  118 ) the client devices. Such a communication interface can be any suitable module and/or device that can place the processing system  100  in communication with a client device such as one or more network interface cards or the like. Such a network interface card can include, for example, an Ethernet port, a WiFi® radio, a Bluetooth® radio, a near field communication (NFC) radio, and/or a cellular radio that can place the client device  150  in communication with the host device  110  via a network or the like. 
     The storage device  114  can be any form of data or information storage means, for example, volatile or non-volatile memory, solid state storage devices, magnetic devices, etc. For example, in some embodiments, the storage device  114  can be a random access memory (RAM), a memory buffer, a hard drive, a read-only memory (ROM), an erasable programmable read-only memory (EPROM), a database, and/or the like. 
     In use, the processing system  100  is adapted to allow data or information to be stored in and/or retrieved from, via wired or wireless communication means, at least one database  116 . The interface  112  may allow wired and/or wireless communication between the processing unit  102  and peripheral components that may serve a specialized purpose. In general, the processor  102  can receive instructions as input data  118  via input device  106  and can display processed results or other output to a user by utilizing output device  108 . More than one input device  106  and/or output device  108  can be provided. The processing system  100  may be any suitable form of terminal, server, specialized hardware, or the like. The processing system  100  may be a part of a networked communications system. 
     Processing system  100  can connect to a network, for example, a local area network (LAN), a virtual network such as a virtual local area network (VLAN), a wide area network (WAN), a metropolitan area network (MAN), a worldwide interoperability for microwave access network (WiMAX), a cellular network, the Internet, and/or any other suitable network implemented as a wired and/or wireless network. For instance, when used in a LAN networking environment, the computing system environment  100  is connected to the LAN through a network interface or adapter. When used in a WAN networking environment, the computing system environment typically includes a modem or other means for establishing communications over the WAN, such as the Internet. The modem, which may be internal or external, may be connected to a system bus via a user input interface, or via another appropriate mechanism. In a networked environment, program modules depicted relative to the computing system environment  100 , or portions thereof, may be stored in a remote memory storage device. It is to be appreciated that the illustrated network connections of  FIG.  7    are examples and other means of establishing a communications link between multiple computers may be used. 
     Input data  118  and output data  120  can be communicated to other devices via the network. The transfer of information and/or data over the network can be achieved using wired communications means or wireless communications means. A server can facilitate the transfer of data between the network and one or more databases. A server and one or more databases provide an example of an information source. 
     Thus, the processing computing system environment  100  illustrated in  FIG.  7 A  may operate in a networked environment using logical connections to one or more remote computers. The remote computer may be a personal computer, a server, a router, a network PC, a peer device, or other common network node, and typically includes many or all of the elements described above. 
       FIG.  7 B  illustrates the processor  102  of  FIG.  7 A  in greater detail. The processor  102  can be configured to execute specific modules. The modules can be, for example, hardware modules, software modules stored in the memory  104  and/or executed in the processor  102 , and/or any combination thereof. For example, as shown in  FIG.  7 B , the processor  102  includes and/or executes a pre-classifier analysis module  130 , a classifier training module  132 , a classifier analysis module  134  and a report module  136 . As shown in  FIG.  7 B , the pre-classifier analysis module  130 , the classifier training module  132 , the classifier analysis module  134  and the report module  136  can be connected and/or electrically coupled. As such, signals can be sent between the pre-classifier analysis module  130 , the classifier training module  132 , the classifier analysis module  134  and the report module  136 . 
     The classifier training module  132  can be configured to receive a corpora of data (e.g. gene expression data, sequencing data) and train a classifier. For example, clinical annotation data from samples previously identified as UIP and non-UIP (e.g., by an expert) can be received by the input device  106  and used by the classifier training module  132  to identify correlations between the samples previously identified as UIP and non-UIP. For example, expert TBB histopathology labels (i.e., UIP or Non UIP), expert HRCT labels, and/or expert patient-level clinical outcome labels can be obtained and used alone or in combination to train the classifier using microarray and/or sequencing data. The feature space used can include gene expression, variants, mutations, fusions, loss of heterozygoxity (LOH), biological pathway effect and/or any other dimension of the data that can be extracted as a feature for the purposes of training a machine-learning algorithm. In some embodiments, the feature space used for training a UIP vs. Non-UIP classifier, a smoker vs. Non-smoker classifier, or a UIP vs. Non-UIP and smoker vs. Non-smoker classifier includes gene expression, variants, mutations, fusions, loss of heterozygoxity (LOH), and biological pathway effect. In some embodiments, the feature space used for training a UIP vs. Non-UIP classifier, a smoker vs. Non-smoker classifier, or a UIP vs. Non-UIP and smoker vs. Non-smoker classifier includes gene expression and variant dimensions. 
     In some embodiments, the classifier training module  132  can train a smoker classifier and a non-smoker classifier based on an indication associated with whether a received sample is associated with a smoker or non-smoker. In other embodiments, the smoker/non-smoker can be used as an attribute (a model covariate) to train a single classifier. After the classifier is trained, it can be used to identify and/or classify newly received and unknown samples as described herein. 
     The pre-classifier analysis module  130  can identify whether a sample is associated with a smoker or a non-smoker. Specifically, the pre-classifier analysis module  130  can use any suitable method to identify and/or classify a sample as coming from an individual that smokes (or has a past history of heavy smoking) versus an individual that does not smoke (or has no smoking history). The classification can be done in any suitable manner such as, receiving an indication from a user, identification of genes that are susceptible to smoker-status bias, using a machine-learning classifier, and/or any other suitable method described herein. 
     The classifier analysis module  134  can input the sample into the classifier to identify and/or classify the received sample as associated with UIP and non-UIP. Specifically, the classifier analysis module  134  can use a trained classifier to identify whether the sample indicates UIP or non-UIP. In some embodiments, the classifier analysis module  134  can indicate a percentage or confidence score of the sample being associated with UIP or non-UIP. In some embodiments, the classifier analysis module  134  can execute two separate classifiers: one for smoker samples and the other for non-smoker samples (as determined by the pre-classifier analysis module  130 ). In other embodiments, a single classifier is executed for both smoker and non-smoker samples with an input for smoker status. 
     The report module  136  can be configured to generate any suitable report based on the outcome of the classifier analysis module  134  as described in further detail herein. In some cases, the report may include, but is not limited to, such information as one or more of the following: the number of genes differentially expressed, the suitability of the original sample, the number of genes showing differential alternative splicing, a diagnosis, a statistical confidence for the diagnosis, the likelihood the subject is a smoker, the likelihood of an ILD, and indicated therapies. 
       FIG.  7 C  illustrates a flow chart of one non-limiting embodiment of the present invention wherein gene product expression data for known UIP and non-UIP samples are used to train (e.g., using a classifier training module) a classifier for differentiating UIP vs. non-UIP, wherein the classifier optionally considers smoker status as a covariant, and wherein gene product expression data from unknown samples are input into the trained classifier to identify the unknown samples as either UIP or non-UIP, and wherein the results of the classification via the classifier are defined and output via a report. 
     Certain embodiments may be described with reference to acts and symbolic representations of operations that are performed by one or more computing devices, such as the computing system environment  100  of  FIG.  7 A . As such, it will be understood that such acts and operations, which are at times referred to as being computer-executed, include the manipulation by the processor of the computer of electrical signals representing data in a structured form. This manipulation transforms the data or maintains them at locations in the memory system of the computer, which reconfigures or otherwise alters the operation of the computer in a manner understood by those skilled in the art. The data structures in which data is maintained are physical locations of the memory that have particular properties defined by the format of the data. However, while an embodiment is being described in the foregoing context, it is not meant to be limiting as those of skill in the art will appreciate that the acts and operations described hereinafter may also be implemented in hardware. 
     Embodiments may be implemented with numerous other general-purpose or special-purpose computing devices and computing system environments or configurations. Examples of other computing systems, environments, and configurations that may be suitable for use with an embodiment include, but are not limited to, personal computers, handheld or laptop devices, personal digital assistants, multiprocessor systems, microprocessor-based systems, programmable consumer electronics, network, minicomputers, server computers, web server computers, mainframe computers, and distributed computing environments that include any of the above systems or devices. 
     Embodiments may be described in a general context of computer-executable instructions, such as hardware and/or software modules. An embodiment may also be practiced in a distributed computing environment where tasks are performed by remote processing devices that are linked through a communications network. In a distributed computing environment, program modules may be located in both local and remote computer storage media including memory storage devices. 
     Computer Program Products 
     The present disclosure provides computer program products that, when executed on a programmable computer such as that described above with reference to  FIG.  7   , can carry out the methods of the present disclosure. As discussed above, the subject matter described herein may be embodied in systems, apparatus, methods, and/or articles depending on the desired configuration. These various implementations may include implementation in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which may be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device (e.g. video camera, microphone, joystick, keyboard, and/or mouse), and at least one output device (e.g. display monitor, printer, etc.). 
     Computer programs (also known as programs, software, software applications, applications, components, or code) include instructions for a programmable processor, and may be implemented in a high-level procedural and/or object-oriented programming language, and/or in assembly/machine language. As used herein, the term “machine-readable medium” refers to any computer program product, apparatus and/or device (e.g., magnetic discs, optical disks, memory, etc.) used to provide machine instructions and/or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. 
     It will be apparent from this description that aspects of the present disclosure may be embodied, at least in part, in software, hardware, firmware, or any combination thereof. Thus, the techniques described herein are not limited to any specific combination of hardware circuitry and/or software, or to any particular source for the instructions executed by a computer or other data processing system. Rather, these techniques may be carried out in a computer system or other data processing system in response to one or more processors, such as a microprocessor, executing sequences of instructions stored in memory or other computer-readable medium including any type of ROM, RAM, cache memory, network memory, floppy disks, hard drive disk (HDD), solid-state devices (SSD), optical disk, CD-ROM, and magnetic-optical disk, EPROMs, EEPROMs, flash memory, or any other type of media suitable for storing instructions in electronic format. 
     In addition, the processor(s) may be, or may include, one or more programmable general-purpose or special-purpose microprocessors, digital signal processors (DSPs), programmable controllers, application specific integrated circuits (ASICs), programmable logic devices (PLDs), trusted platform modules (TPMs), or the like, or a combination of such devices. In alternative embodiments, special-purpose hardware such as logic circuits or other hardwired circuitry may be used in combination with software instructions to implement the techniques described herein. 
     Arrays and Kits 
     The present disclosure provides arrays and kits for use in carrying out a subject evaluating method or a subject diagnostic method. 
     Arrays 
     A subject array can comprise a plurality of nucleic acids, each of which hybridizes to a gene differentially expressed in a cell present in a tissue sample obtained from an individual being tested for an ILD. 
     A subject array can comprise a plurality of nucleic acids, each of which hybridizes to a gene differentially expressed in a cell present in a tissue sample obtained from an individual being tested for smoker status. 
     A subject array can comprise a plurality of nucleic acids, each of which hybridizes to a gene differentially expressed in a cell present in a tissue sample obtained from an individual being tested for both smoker status and an ILD. 
     A subject array can comprise a plurality of member nucleic acids, each of which member nucleic acids hybridizes to a different gene product. In some cases, two or more member nucleic acids hybridize to the same gene product; e.g., in some cases 2, 3, 4, 5, 6, 7, 8, 9, 10, or more member nucleic acids hybridize to the same gene product. A member nucleic acid can have a length of from about 5 nucleotides (nt) to about 100 nt, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 18, 19, 20, 20-25, 25-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100 nt. A nucleic acid can have one or more phosphate backbone modifications. 
     A subject array can include from about 10 to about 10 5  unique member nucleic acids, or more than 10 5  unique member nucleic acids. For example, a subject array can include from about 10 to about 10 2 , from about 10 2  to about 10 3 , from about 10 3  to about 10 4 , from about 10 4  to about 10 5 , or more than 10 5 , unique member nucleic acids. 
     
       
         
           
               
             
               
                   
               
               
                 Abbreviations 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 adj.P.Value.edgeR: 
                 False discovery rate adjusted p value of RNAseq gene 
               
               
                   
                 expression data using edgeR analysis. 
               
               
                 adj.P.Value.microarray 
                 False discovery rate adjusted p value of RNAseq gene 
               
               
                   
                 expression data using microarray analysis 
               
               
                 adj.P.Value.npSeq: 
                 False discovery rate adjusted p value of RNAseq gene 
               
               
                   
                 expression data using npSeq analysis 
               
               
                 BRONCH: 
                 Broncholitis 
               
               
                 CIF-NOC 
                 Chronic Interstitial Fibrosis Not Otherwise Classified 
               
               
                 edgeR: 
                 an R package for the significance analysis of sequencing data 
               
               
                 Ensembl ID: 
                 Gene Identifier from Ensembl Genome Browser database 
               
               
                 FDR: 
                 False Discovery Rate, an adjusted p value that limits the 
               
               
                   
                 possibility that the results are random due to the large 
               
               
                   
                 number of genes simultaneously evaluated. 
               
               
                 Gene Symbol: 
                 Gene Identifier from HUGO Gene Nomenclature Committee 
               
               
                 logFC.edgeR: 
                 Log2 fold change of RNAseq gene expression data using 
               
               
                   
                 edgeR analysis 
               
               
                 logFC.microarray: 
                 Log2 fold change of RNAseq gene expression data using 
               
               
                   
                 LIMMA microarray analysis 
               
               
                 logFC.npSeq: 
                 Log2 fold change of RNAseq gene expression data using 
               
               
                   
                 npSeq analysis 
               
               
                 microarray: 
                 Gene expression analysis using gene arrays such as from 
               
               
                   
                 Affymetrix. 
               
               
                 NML: 
                 Normal Lung, usually obtained from human lung donor 
               
               
                   
                 tissue that was ultimately never transplanted 
               
               
                 npSeq: 
                 an R package for the significance analysis of sequencing data 
               
               
                 NSIP: 
                 Non Specific Interstitial Pneumonia 
               
               
                 OP: 
                 Organizing Pneumonia 
               
               
                 P.value.edgeR: 
                 p value of RNAseq gene expression data using edgeR analysis 
               
               
                 P.value.microarray: 
                 p value of RNAseq gene expression data using LIMMA microarray 
               
               
                   
                 analysis 
               
               
                 P.value.npSeqp: 
                 value of RNAseq gene expression data using npSeq analysis 
               
               
                 RB: 
                 Respiratory Broncholitis 
               
               
                 REST: 
                 A combination of all other ILDs except the subtype it is being 
               
               
                   
                 compared to. Usually HP and NSIP, BRONCH, CIF-NOC, OP, 
               
               
                   
                 RB and SARC. 
               
               
                 SARC: 
                 Sarcoidosis 
               
               
                 SQC: 
                 Squamous Cell Carcinoma 
               
               
                 TCID: 
                 “TCID” or “Transcript Cluster Identifier” refers to a gene 
               
               
                   
                 level identifier used by all Affymetrix microarrays. Each TCID is 
               
               
                   
                 associated with a fixed reference number that identifies a set of 
               
               
                   
                 specific probes having sequences for a specific gene. Such specific 
               
               
                   
                 probes are present on a given array commercially available from 
               
               
                   
                 Affymetrix. TCID numbers thus refer to a gene product(s) of a 
               
               
                   
                 specific gene, and can be found, e.g., at the following world wide 
               
               
                   
                 web address: affymetrix.com/the sequences of which probes and 
               
               
                   
                 gene products are hereby incorporation herein in their entirety. 
               
               
                 UIP: 
                 Usual Interstitial Pneumonia; the HRCT or histopathology pattern 
               
               
                   
                 observed in IPF 
               
               
                 LIMMA: 
                 Linear Models for Microarray Data; an R package for the 
               
               
                   
                 significance analysis of microarray data. 
               
               
                   
               
               
                 “ENSEMBL ID” refers to a gene identifier number from the Ensembl Genome Browser database (see world wide web address: ensembl.org/index.html, incorporate herein). Each identifier begins with the letters ENSG to denote “Ensembl Gene”. Each ENSEMBL ID number (i.e., each “gene” in the Ensembl database) refers to a gene defined by a specific start and stop position on a particular human chromosome, and therefore defines a specific locus of the human genome. As one of average skill in the art would fully appreciate, all of the gene symbols disclosed herein refer to gene sequences, which are readily available on publically available databases, e.g., UniGene database (Pontius J U, Wagner L, Schuler G D. UniGene: a unified view of the transcriptome. In: The NCBI Handbook. Bethesda (MD): National Center for Biotechnology Information; 2003, available at the world wide web address ncbi.nlm.nih.gov/unigene, incorporated herein), RefSeq (The NCBI handbook [Internet], Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2002 October Chapter 18, The Reference Sequence (RefSeq) Project, available at the world wide web address: ncbi.nlm.nih.gov/refseq/, incorporate herein), Ensembl (EMBL, available at the world wide web address: ensembl.org/index.html, incorporated herein), and the like. The sequences of the genes disclosed herein via their gene symbols, Ensembl IDs, and Entrez IDs are herein incorporated in their entirety. 
               
            
           
         
       
     
     All references, patents, and patent applications cited herein are incorporated in their entirety for all purposes. 
     EXAMPLES 
     Example 1 
     Sample Collection, Pathology Diagnosis, and Labeling 
     Video-assisted thoracoscopic surgery (VATS) specimens were prospectively collected as a part of an Institutional Review Board (IRB) approved ongoing multi-center clinical protocol, BRonchial sAmple collection for a noVel gEnomic test (BRAVE), sponsored by Veracyte, Inc. (South San Francisco, Calif.). Additional VATS and surgical lung biopsy specimens were obtained from banked sources. 
     Following surgery, histology slides were collected, de-identified, and submitted to expert pathology review. Selected slides were scanned to construct a permanent digital file of microscopic images (Aperio, Vista, Calif.). Slides were evaluated according to the central pathology diagnostic process described in  FIG.  5   , resulting in both sample-level and patient-level pathology diagnoses. Pathology categories are summarized in Table 3. A patient can have more than one sample-level diagnosis (i.e. one per VATS sample per patient, most often one from each of the lower and upper lobes of the right lung), but can only have one patient-level diagnosis. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 List of all pathology diagnoses considered in 
               
               
                 our central pathology diagnostic process. 
               
            
           
           
               
               
            
               
                 Diagnosis 
                 Abbreviation 
               
               
                   
               
               
                 Classic Usual Interstitial Pneumonia 
                 Classic UIP 
               
               
                 Difficult Usual Interstitial Pneumonia 
                 Difficult UIP 
               
               
                 Favor Usual Interstitial Pneumonia 
                 Favor UIP 
               
               
                 Cellular Non-specific Interstitial Pneumonia 
                 Cellular NSIP 
               
               
                 Fibrotic Non-specific Interstitial Pneumonia 
                 Fibrotic NSIP 
               
               
                 Both cellular and fibrotic Non-specific Interstitial 
                 Both cellular 
               
               
                   
                 and fibrotic 
               
               
                 Pneumonia 
                 NSIP 
               
               
                 Favor Non-specific Interstitial Pneumonia 
                 Favor NSIP 
               
               
                 Hypersensitivity Pneumonitis 
                 HP 
               
               
                 Favor Hypersensitivity Pneumonitis 
                 Favor HP 
               
               
                 Chronic Interstitial Fibrosis, Not Otherwise Classified 
                 CIF/NOC 
               
               
                 Organizing Pneumonia 
                 OP 
               
               
                 Diffuse Alveolar Damage 
                 DAD 
               
               
                 Respiratory Bronchiolitis 
                 RB 
               
               
                 Smoking-Related Interstitial Fibrosis 
                 SRIF 
               
               
                 Emphysema 
                 Emphysema 
               
               
                 Bronchiolitis 
                 Bronchiolitis 
               
               
                 Sarcoidosis 
                 Sarcoidosis 
               
               
                 Lymphangioleiomyomatosis 
                 LAM 
               
               
                 Langerhans cell histiocytosis 
                 LCH 
               
               
                 Eosinophilic Pneumonia 
                 EP 
               
               
                 Non-diagnostic 
                 ND 
               
               
                 Other 
                 Other 
               
               
                   
               
            
           
         
       
     
     Most diagnostic terminologies follow American Thoracic Society (ATS) 2011 or 2013 guidelines 5,6 , but a few changes were made by the expert pathologist panel to better characterize features at the lobe level. In particular, ‘Classic UIP’ and ‘Difficult UIP’ were included instead of ‘Definite UIP’ and ‘Probable UIP’ as described in the ATS 2011 guidelines. Chronic Interstitial Fibrosis, Not Otherwise Classified (CIF/NOC) corresponds to unclassifiable fibrotic ILD. Three subcategories of CIF/NOC, ‘Favor UIP’, ‘Favor NSIP’, and ‘Favor HP’, were defined to specify cases of unclassifiable fibrosis which, in the judgment of the expert pathology panel, exhibit features suggestive of UIP, non-specific interstitial pneumonia (NSIP), or hypersensitivity pneumonitis (HP). A diagnosis of Smoking-Related Interstitial Fibrosis (SRIF) is also included 20 . 
     For classification, sample-level pathology diagnoses were converted into binary class labels (UIP and non-UIP). Among the pathology diagnosis categories (Table 3), the ‘UIP’ class includes (1) UIP, (2) Classic UIP, (3) Difficult UIP, and (4) CIF/NOC, Favor UIP. All other pathology diagnoses except Non-diagnostic (ND) were assigned to the ‘non-UIP’ class. 
     Example 2 
     Sample Processing 
     Frozen tissue samples were mounted for sectioning using Tissue-Tek O.C.T. medium (Sakura Finetek U.S.A.) and 2×20 μm sections generated using a CM1800 cryostat (Leica Biosystems, Buffalo Grove, Ill.). Tissue curls were immediately immersed in RNAprotect (QIAGEN, Valencia, Calif.), incubated overnight at 4° C. and stored at −80° C. until extraction. Whenever possible, adjacent 5 μm tissue curls were mounted onto glass slides and processed for hematoxylin and eosin (H&amp;E) staining following standard procedures. 
     Nucleic acids were extracted using the AllPrep Micro Kit (QIAGEN) according to manufacturer&#39;s guidelines. Total RNA yield and quality was determined using Quant-it (Invitrogen) and Pico BioAnalyzer kits (Agilent). Fifteen nanograms of total RNA were amplified using Ovation FFPE WTA System (NuGEN, San Carlos, Calif.), hybridized to GeneChip Gene ST 1.0 (Affymetrix, Santa Clara, Calif.) microarrays, processed and scanned according to the manufacturer&#39;s protocols. Expression data was normalized by Robust Multi-array Average (RMA). 
     Example 3 
     Next-Generation RNA Sequencing 
     Whole transcriptome RNA sequencing was performed on select samples at a targeted minimum read depth of 80 million paired-end reads per sample. Briefly, 10 ng of total RNA was amplified using the Ovation RNASeq System v2 (NuGEN, San Carlos, Calif.) and TruSeq (Illumina, San Diego, Calif.) sequencing libraries were prepared and sequenced on an Illumina HiSeq according to manufacturer&#39;s instructions. Raw reads were aligned to the hg19 genome assembly using TopHat2. Gene counts were obtained using HTSeq and normalized in Bioconductor using the varianceStabilizingTransformation function in the DESeq2 package. Raw counts and normalized expression levels were obtained for 55,097 transcripts. 
     Example 4 
     Cohort Selection and Classifier Training 
     The study cohort initially included both banked (n=128) and prospectively collected BRAVE (n=38) tissues. Banked samples with poor cellularity on H&amp;E staining (n=4 from a single patient) or normal lung tissue appearance (n=1) were excluded, as were samples diagnosed as ‘unclassifiable fibrotic ILD’ i.e. CIF/NOC (n=3) or samples that lacked pathology agreement by at least two pathologists (n=29). For BRAVE samples, CIF/NOC samples were not excluded. Only one BRAVE cohort sample was omitted, due to missing central pathology diagnosis. Processed RNA samples with residual genomic DNA contamination (n=2) or low RNA quality (RNA integrity number (RIN)&lt;4) (n=1) were also excluded. After all exclusions, 125 samples from 86 patients remained for use in classification. The age, gender, smoking history and pathology diagnoses of included patients are summarized in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Cohort summary. Within each set of microarray data or RNASeq data, clinical factors such 
               
               
                 as age, gender and smoking history are summarized across patients. In addition, samples 
               
               
                 are summarized by sample-level pathology diagnosis (counts without parenthesis), and patients 
               
               
                 are summarized by patient-level pathology diagnosis (counts within parenthesis). Zeros 
               
               
                 in either case are due to discordance between sample-level and patient-level pathology; 
               
               
                 counts will therefore not be additive. Of the 36 samples in the RNASeq training set, 22 
               
               
                 overlap with the microarray training set and 14 overlap with the microarray test set. 
               
            
           
           
               
               
               
            
               
                   
                 Microarray 
                 RNASeq 
               
            
           
           
               
               
               
               
               
               
            
               
                 Category 
                 Sub-category 
                 All 
                 Training 
                 Test 
                 Training 
               
               
                   
               
               
                 Size 
                 Patient 
                 86 
                 54 
                 32 
                 29 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Age 
                 Mean (range) 
                 57.9 
                 (25-83) 
                 58.9 
                 (25-83) 
                 56.3 
                 (32-76) 
                 60.5 
                 (32-80) 
               
               
                 Gender 
                 Male 
                 32 
                 (37.2%) 
                 22 
                 (40.7%) 
                 10 
                 (31.2%) 
                 16 
                 (55.2%) 
               
               
                   
                 Female 
                 54 
                 (62.8%) 
                 32 
                 (59.3%) 
                 22 
                 (68.8%) 
                 13 
                 (44.8%) 
               
               
                 Smoking 
                 Yes 
                 45 
                 (52.3%) 
                 33 
                 (61.1%) 
                 12 
                 (37.5%) 
                 15 
                 (51.7%) 
               
               
                   
                 No 
                 38 
                 (44.2%) 
                 19 
                 (35.2%) 
                 19 
                 (59.4%) 
                 14 
                 (48.3%) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Unknown 
                 3 
                 (3.5%) 
                 2 
                 (3.7%) 
                 1 
                 (3.1%) 
                  0 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Pathology 
                 UIP 
                 45 
                 (30) 
                 28 
                 (18) 
                 17 
                 (12) 
                 14 
                 (14) 
               
               
                 diagnosis 
                 Classic UIP 
                 8 
                 (5) 
                 5 
                 (4) 
                 3 
                 (1) 
                 2 
                 (0) 
               
               
                   
                 Difficult UIP 
                 5 
                 (2) 
                 3 
                 (1) 
                 2 
                 (1) 
                 1 
                 (0) 
               
               
                   
                 Favor UIP 
                 3 
                 (1) 
                 3 
                 (1) 
                 0 
                 (0) 
                 0 
                 (0) 
               
               
                   
                 Fibrotic NSIP 
                 2 
                 (0) 
                 0 
                 (0) 
                 2 
                 (0) 
                 0 
                 (0) 
               
               
                   
                 Cellular NSIP 
                 7 
                 (0) 
                 5 
                 (0) 
                 2 
                 (0) 
                 2 
                 (0) 
               
               
                   
                 Both cellular and fibrotic 
                 14 
                 (0) 
                 9 
                 (0) 
                 5 
                 (0) 
                 3 
                 (0) 
               
               
                   
                 NSIP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 NSIP 
                 0 
                 (15) 
                 0 
                 (10) 
                 0 
                 (5) 
                 0 
                 (5) 
               
               
                   
                 Favor HP 
                 2 
                 (1) 
                 0 
                 (0) 
                 2 
                 (1) 
                 0 
                 (0) 
               
               
                   
                 HP 
                 16 
                 (14) 
                 11 
                 (10) 
                 5 
                 (4) 
                 3 
                 (2) 
               
               
                   
                 Unclassifiable fibrotic 
                 4 
                 (5) 
                 2 
                 (3) 
                 2 
                 (2) 
                 0 
                 (0) 
               
               
                   
                 ILD 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Sarcoidosis 
                 4 
                 (4) 
                 2 
                 (2) 
                 2 
                 (2) 
                 2 
                 (2) 
               
               
                   
                 RB 
                 4 
                 (2) 
                 0 
                 (1) 
                 4 
                 (1) 
                 3 
                 (1) 
               
               
                   
                 OP 
                 2 
                 (1) 
                 2 
                 (1) 
                 0 
                 (0) 
                 1 
                 (1) 
               
               
                   
                 SRIF 
                 1 
                 (1) 
                 0 
                 (0) 
                 1 
                 (1) 
                 1 
                 (1) 
               
               
                   
                 Bronchiolitis 
                 1 
                 (1) 
                 1 
                 (1) 
                 0 
                 (0) 
                 1 
                 (1) 
               
               
                   
                 Emphysema 
                 2 
                 (0) 
                 2 
                 (0) 
                 0 
                 (0) 
                 0 
                 (0) 
               
               
                   
                 DAD 
                 0 
                 (1) 
                 0 
                 (0) 
                 0 
                 (1) 
                 0 
                 (1) 
               
               
                   
                 Other 
                 5 
                 (3) 
                 4 
                 (2) 
                 1 
                 (1) 
                 3 
                 (1) 
               
               
                   
                 Total 
                 125 
                 (86) 
                 77 
                 (54) 
                 48 
                 (32) 
                 36 
                 (29) 
               
               
                   
               
            
           
         
       
     
     125 samples (86 patients) were available for microarray classification. The 86 patients were randomized into training and test sets while controlling for patient-level pathology subtype bias (Table 1). The microarray training set consists of 77 samples (39 UIP and 38 non-UIP) from 54 patients. The microarray test set consists of 48 samples (22 UIP vs. 26 non-UIP) from 32 patients. 
     RNASeq data was generated for a subset of 36 samples (17 UIP and 19 non-UIP) from 29 patients (Table 1), representing a spectrum of ILD subtypes. Among the 36 samples, 22 overlap with the microarray training set and 14 overlap with the microarray test set. Due to the small sample size of this dataset, classification performance was evaluated by cross-validation (CV) only. 
     Example 5 
     Training Models, Classification, Feature Selection 
     All statistical analyses were carried out using R version 3.0.1 21 . For the microarray classifier, genes differentially expressed between UIP and non-UIP classes were ranked by limma, then the top 200 genes with lowest false discovery rate (FDR) 0·0003) were carried forward as candidate genes for model building. Several models were built using different methods, and the one with the lowest error was chosen. Feature selection and model estimation were performed by logistic regression with lasso penalty using glmnet. For the RNASeq classifier, genes were ranked by FDR resulting from a Wald-style test implemented in the DESeq2 package on the raw count data. The top features (N ranging from 10 to 200) were used to train a linear support vector machine (SVM) using the e1071 library on the normalized expression data. 
     Classifier performance was evaluated by CV and, when available, by an independent test set. To minimize over-fitting, a single patient was maintained as the smallest unit when defining the training/test set and the CV partition; i.e. all samples belonging to the same patient were held together as a group in the training/test set or in CV partitions. The CV methods used include leave-one-patient-out (LOPO) and 10-fold patient-level CV. 
     Performance was reported as the area under the curve (AUC), and specificity (1·0—false positive rate) and sensitivity (1·0—false negative rate) at a given score threshold. We set the score threshold to require at least &gt;90% specificity. For each performance measurement, 95% confidence intervals were computed using 2000 stratified bootstrap replicates and the pROC package and reported as [CI lower-upper]. 
     Example 6 
     Spatial Heterogeneity in Samplings from Explanted Lungs 
     A total of 60 samplings from three normal lung donors (n=7) and three lungs from patients diagnosed with IPF (n=53) were analyzed using genome-wide microarray data. Intact normal and diseased lungs obtained during transplant procedures were collected following a protocol approved by the Institutional Review Board (IRB) of Inova Fairfax, Falls Church, Va. The upper and lower lobes of explanted lungs from three normal donors and three patients diagnosed with IPF were sampled centrally and peripherally. The location and number of the explant samples is illustrated in  FIG.  6   . Surgical pathology and final clinical diagnoses were provided by the originating institutions. Pathology over-reads by three expert pathologists unanimously confirmed UIP in all three IPF patient explant lungs. 
     Gene expression was evaluated in seven normal and 53 IPF explant lung samples. Genes differentially expressed between normal and IPF patient explant samples were identified and ranked by false discovery rate (FDR) using the R limma package (Smyth, G. K. (2005)). The top 200 genes differentially expressed between UIP and non-UIP classes in the microarray training set are shown in Table 12. Using the top 200 genes with the lowest FDR adjusted P-values (&lt;1·45e-07), the Pearson correlation coefficient was calculated for all pairs of 53 UIP samples. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Top 200 genes differentially expressed between UIP and non-UIP classes in the microarray 
               
               
                 training set, with indication of 22 genes used by the microarray classifier. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 FDR 
                   
                   
               
               
                   
                 GENE 
                   
                   
                   
                 adjusted 
                   
                 Used by 
               
               
                 TCID 
                 SYMBOL 
                 logFC 
                 MedExpr.UIP 
                 MedExpr.NonUIP 
                 p-value 
                 rank 
                 Classifier 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 8117760 
                 HLA-F 
                 −0.48 
                 9.02 
                 9.53 
                 2.35E−09 
                 1 
                 Used 
               
               
                 8177717 
                 HLA-F 
                 −0.50 
                 9.35 
                 9.94 
                 2.35E−09 
                 2 
               
               
                 8179019 
                 HLA-F 
                 −0.50 
                 9.31 
                 9.83 
                 2.35E−09 
                 3 
               
               
                 8101031 
                 CDKL2 
                 −0.95 
                 7.31 
                 8.16 
                 1.29E−07 
                 4 
                 Used 
               
               
                 8106827 
                 GPR98 
                 −0.77 
                 6.11 
                 6.74 
                 2.16E−07 
                 5 
                 Used 
               
               
                 8100026 
                 ATP8A1 
                 −0.65 
                 7.63 
                 8.17 
                 9.86E−07 
                 6 
               
               
                 7931930 
                 PRKCQ 
                 −0.64 
                 6.78 
                 7.40 
                 1.81E−06 
                 7 
                 Used 
               
               
                 8135661 
                 CFTR 
                 −1.00 
                 6.50 
                 7.56 
                 2.37E−06 
                 8 
               
               
                 8177725 
                 HLA-G 
                 −0.29 
                 10.67 
                 10.89 
                 2.37E−06 
                 9 
                 Used 
               
               
                 8179034 
                 HLA-G 
                 −0.29 
                 10.67 
                 10.89 
                 2.37E−06 
                 10 
               
               
                 8123246 
                 SLC22A3 
                 −0.94 
                 6.90 
                 7.85 
                 2.37E−06 
                 11 
               
               
                 8118571 
                 PSMB9 
                 −0.53 
                 10.04 
                 10.68 
                 2.37E−06 
                 12 
               
               
                 8178211 
                 PSMB9 
                 −0.53 
                 10.04 
                 10.68 
                 2.37E−06 
                 13 
               
               
                 8179495 
                 PSMB9 
                 −0.53 
                 10.04 
                 10.68 
                 2.37E−06 
                 14 
               
               
                 8065719 
                 PXMP4 
                 −0.67 
                 7.12 
                 7.94 
                 2.37E−06 
                 15 
               
               
                 7926037 
                 PFKFB3 
                 −0.45 
                 7.66 
                 8.10 
                 2.81E−06 
                 16 
                 Used 
               
               
                 8037205 
                 CEACAM1 
                 −0.41 
                 6.47 
                 6.97 
                 3.04E−06 
                 17 
                 Used 
               
               
                 8178489 
                 HLA-C 
                 −0.36 
                 11.26 
                 11.64 
                 3.04E−06 
                 18 
               
               
                 7917561 
                 GBP4 
                 −0.87 
                 8.49 
                 9.57 
                 3.59E−06 
                 19 
               
               
                 7968678 
                 FREM2 
                 −1.08 
                 6.67 
                 7.72 
                 3.88E−06 
                 20 
               
               
                 7907492 
                 RABGAP1L 
                 −0.32 
                 8.01 
                 8.33 
                 3.88E−06 
                 21 
                 Used 
               
               
                 8124901 
                 HLA-C 
                 −0.35 
                 11.27 
                 11.61 
                 3.89E−06 
                 22 
               
               
                 8096682 
                 ARHGEF38 
                 −0.78 
                 6.52 
                 7.21 
                 3.89E−06 
                 23 
               
               
                 8049187 
                 EFHD1 
                 0.36 
                 7.69 
                 7.30 
                 4.36E−06 
                 24 
               
               
                 8117890 
                 HLA-B 
                 −0.28 
                 10.64 
                 10.89 
                 4.54E−06 
                 25 
               
               
                 8179731 
                 HLA-B 
                 −0.26 
                 11.89 
                 12.09 
                 4.54E−06 
                 26 
               
               
                 8154233 
                 CD274 
                 −0.84 
                 6.35 
                 7.14 
                 4.54E−06 
                 27 
                 Used 
               
               
                 8177788 
                 HLA-E 
                 −0.29 
                 10.68 
                 10.94 
                 4.54E−06 
                 28 
               
               
                 8179103 
                 HLA-E 
                 −0.29 
                 10.68 
                 10.94 
                 4.54E−06 
                 29 
               
               
                 8117777 
                 HLA-H 
                 −0.24 
                 9.99 
                 10.21 
                 4.89E−06 
                 30 
               
               
                 7981290 
                 WARS 
                 −0.55 
                 9.39 
                 9.97 
                 5.08E−06 
                 31 
               
               
                 8177732 
                 HLA-A 
                 −0.27 
                 11.72 
                 12.01 
                 5.30E−06 
                 32 
               
               
                 7965565 
                 USP44 
                 −0.71 
                 5.92 
                 6.68 
                 5.30E−06 
                 33 
               
               
                 8125512 
                 TAP1 
                 −0.55 
                 8.54 
                 9.14 
                 5.30E−06 
                 34 
               
               
                 8178867 
                 TAP1 
                 −0.55 
                 8.54 
                 9.14 
                 5.50E−06 
                 35 
               
               
                 8180061 
                 TAP1 
                 −0.55 
                 8.54 
                 9.14 
                 5.30E−06 
                 36 
               
               
                 8022145 
                 L3MBTL4 
                 −0.37 
                 6.74 
                 7.07 
                 5.37E−06 
                 37 
               
               
                 8106098 
                 MAP1B 
                 0.68 
                 8.77 
                 8.00 
                 5.37E−06 
                 38 
               
               
                 7934719 
                 SFTPD 
                 −0.71 
                 9.02 
                 9.63 
                 5.75E−06 
                 39 
               
               
                 7905929 
                 EFNA1 
                 −0.51 
                 7.67 
                 8.14 
                 5.88E−06 
                 40 
               
               
                 7917516 
                 GBP1 
                 −0.62 
                 9.37 
                 10.05 
                 6.11E−06 
                 41 
               
               
                 8161865 
                 PRUNE2 
                 0.79 
                 7.44 
                 6.75 
                 7.05E−06 
                 42 
                 Used 
               
               
                 8044353 
                 ACOXL 
                 −0.68 
                 6.13 
                 6.74 
                 7.10E−06 
                 43 
               
               
                 8057418 
                 ZNF385B 
                 −0.71 
                 6.95 
                 7.71 
                 7.15E−06 
                 44 
               
               
                 8101131 
                 CXCL11 
                 −1.44 
                 5.33 
                 6.99 
                 8.16E−06 
                 45 
               
               
                 8058498 
                 FZD5 
                 −0.52 
                 7.72 
                 8.27 
                 8.87E−06 
                 46 
               
               
                 8082100 
                 PARP14 
                 −0.36 
                 8.93 
                 9.25 
                 9.55E−06 
                 47 
               
               
                 8001007 
                 PRSS8 
                 −0.51 
                 7.39 
                 7.89 
                 9.85E−06 
                 48 
               
               
                 8099760 
                 ARAP2 
                 −0.41 
                 7.55 
                 7.90 
                 1.06E−05 
                 49 
                 Used 
               
               
                 7914950 
                 CSF3R 
                 −0.45 
                 7.12 
                 7.60 
                 1.14E−05 
                 50 
               
               
                 7972336 
                 DZIP1 
                 0.33 
                 7.72 
                 7.47 
                 1.16E−05 
                 51 
                 Used 
               
               
                 8014591 
                 HNF1B 
                 −0.53 
                 6.88 
                 7.33 
                 1.20E−05 
                 52 
               
               
                 8151423 
                 JPH1 
                 −0.52 
                 6.68 
                 7.17 
                 1.21E−05 
                 53 
               
               
                 8056217 
                 MXRA7 
                 0.40 
                 8.58 
                 8.29 
                 1.21E−05 
                 54 
                 Used 
               
               
                 8117861 
                 HLA-L 
                 −0.24 
                 6.64 
                 6.89 
                 1.25E−05 
                 55 
               
               
                 8179080 
                 HLA-L 
                 −0.24 
                 6.64 
                 6.89 
                 1.25E−05 
                 56 
               
               
                 7976443 
                 IFI27 
                 −0.57 
                 9.21 
                 9.74 
                 1.54E−05 
                 57 
               
               
                 8022022 
                 LPIN2 
                 −0.30 
                 8.06 
                 8.37 
                 1.55E−05 
                 58 
               
               
                 7997593 
                 ATP2C2 
                 −0.46 
                 6.73 
                 7.13 
                 1.62E−05 
                 59 
               
               
                 8054846 
                 SCTR 
                 −0.48 
                 6.23 
                 6.74 
                 1.72E−05 
                 60 
               
               
                 8178498 
                 HLA-B 
                 −0.26 
                 11.86 
                 12.07 
                 1.87E−05 
                 61 
               
               
                 8140971 
                 SAMD9L 
                 −0.48 
                 8.09 
                 8.52 
                 2.12E−05 
                 62 
               
               
                 7931728 
                 LARP4B 
                 −0.28 
                 8.76 
                 9.07 
                 2.15E−05 
                 63 
               
               
                 8058857 
                 IGFBP5 
                 0.62 
                 10.41 
                 9.73 
                 2.15E−05 
                 64 
               
               
                 7946504 
                 TMEM41B 
                 −0.39 
                 7.58 
                 7.95 
                 2.61E−05 
                 65 
               
               
                 8057744 
                 STAT1 
                 −0.60 
                 9.64 
                 10.45 
                 2.72E−05 
                 66 
               
               
                 8107129 
                 SLCO4C1 
                 −1.08 
                 7.96 
                 8.93 
                 2.72E−05 
                 67 
               
               
                 8109938 
                 RANBP17 
                 −0.58 
                 6.10 
                 6.71 
                 2.72E−05 
                 68 
               
               
                 7934271 
                 PLA2G12B 
                 −0.40 
                 6.37 
                 6.79 
                 2.72E−05 
                 69 
               
               
                 8126855 
                 PTCHD4 
                 0.31 
                 6.51 
                 6.22 
                 2.72E−05 
                 70 
               
               
                 8097829 
                 FHDC1 
                 −0.54 
                 6.39 
                 6.91 
                 2.80E−05 
                 71 
               
               
                 8140478 
                 GSAP 
                 −0.50 
                 7.87 
                 8.41 
                 2.82E−05 
                 72 
               
               
                 8079334 
                 LIMD1 
                 −0.34 
                 7.37 
                 7.66 
                 2.83E−05 
                 73 
               
               
                 7992828 
                 IL32 
                 −0.47 
                 8.23 
                 8.83 
                 2.83E−05 
                 74 
               
               
                 8103563 
                 DDX60 
                 −0.43 
                 7.34 
                 7.80 
                 2.83E−05 
                 75 
               
               
                 8082928 
                 CLDN18 
                 −1.10 
                 8.77 
                 9.84 
                 2.83E−05 
                 76 
               
               
                 7970716 
                 LNX2 
                 −0.46 
                 8.40 
                 8.79 
                 3.01E−05 
                 77 
               
               
                 7944739 
                 CRTAM 
                 −0.62 
                 5.05 
                 5.69 
                 3.07E−05 
                 78 
               
               
                 8089026 
                 STX19 
                 −0.49 
                 5.91 
                 6.36 
                 3.18E−05 
                 79 
               
               
                 8079377 
                 CXCR6 
                 −0.46 
                 5.75 
                 6.17 
                 3.22E−05 
                 80 
               
               
                 7956120 
                 ERBB3 
                 −0.65 
                 7.37 
                 7.96 
                 3.67E−05 
                 81 
               
               
                 7981514 
                 AHNAK2 
                 0.54 
                 7.30 
                 6.80 
                 3.84E−05 
                 82 
               
               
                 8134036 
                 STEAP2 
                 0.66 
                 9.18 
                 8.42 
                 3.87E−05 
                 83 
               
               
                 8109639 
                 PTTG1 
                 −0.67 
                 7.91 
                 8.53 
                 3.89E−05 
                 84 
               
               
                 8101118 
                 CXCL9 
                 −1.55 
                 7.35 
                 9.08 
                 4.07E−05 
                 85 
               
               
                 7919984 
                 SELENBP1 
                 −0.44 
                 8.87 
                 9.25 
                 4.25E−05 
                 86 
               
               
                 8108724 
                 PCDHB10 
                 0.61 
                 5.78 
                 5.12 
                 4.27E−05 
                 87 
               
               
                 8126853 
                 PTCHD4 
                 0.75 
                 7.02 
                 6.07 
                 4.27E−05 
                 88 
                 Used 
               
               
                 8134384 
                 DYNG1I1 
                 0.23 
                 5.71 
                 5.43 
                 4.52E−05 
                 89 
               
               
                 7935535 
                 CRTAC1 
                 −0.68 
                 6.04 
                 6.73 
                 4.73E−05 
                 90 
               
               
                 8097080 
                 SYNPO2 
                 0.89 
                 9.20 
                 8.26 
                 4.73E−05 
                 91 
               
               
                 8129410 
                 THEMIS 
                 −0.85 
                 6.35 
                 7.33 
                 4.73E−05 
                 92 
               
               
                 7968035 
                 SPATA13 
                 −0.24 
                 6.85 
                 7.12 
                 4.83E−05 
                 93 
               
               
                 8104022 
                 PDLIM3 
                 0.58 
                 8.33 
                 7.63 
                 5.03E−05 
                 94 
                 Used 
               
               
                 8125545 
                 HLA-DOA 
                 −0.48 
                 8.31 
                 8.98 
                 5.03E−05 
                 95 
               
               
                 8115147 
                 CD74 
                 −0.20 
                 12.35 
                 12.54 
                 5.03E−05 
                 96 
               
               
                 8144758 
                 ZDHHC2 
                 −0.31 
                 7.85 
                 8.21 
                 5.03E−05 
                 97 
               
               
                 7910466 
                 CAPN9 
                 −0.71 
                 5.34 
                 6.15 
                 5.03E−05 
                 98 
               
               
                 8124911 
                 HLA-B 
                 −0.25 
                 11.87 
                 12.05 
                 5.12E−05 
                 99 
               
               
                 7938834 
                 NAV2 
                 −0.36 
                 7.79 
                 8.04 
                 5.18E−05 
                 100 
               
               
                 8146092 
                 IDO1 
                 −1.21 
                 6.59 
                 8.00 
                 5.43E−05 
                 101 
               
               
                 8117800 
                 HLA-A 
                 −0.25 
                 11.70 
                 11.94 
                 5.43E−05 
                 102 
               
               
                 8025918 
                 CNN1 
                 0.86 
                 8.39 
                 7.52 
                 5.43E−05 
                 103 
                 Used 
               
               
                 8020847 
                 DTNA 
                 0.42 
                 7.10 
                 6.70 
                 5.52E−05 
                 104 
               
               
                 7934411 
                 USP54 
                 −0.43 
                 7.89 
                 8.31 
                 5.61E−05 
                 105 
               
               
                 8101126 
                 CXCL10 
                 −1.70 
                 6.30 
                 8.19 
                 5.61E−05 
                 106 
               
               
                 7993458 
                 C16orf45 
                 0.39 
                 7.38 
                 7.02 
                 5.62E−05 
                 107 
               
               
                 8157027 
                 NIPSNAP3B 
                 0.29 
                 5.25 
                 4.98 
                 5.62E−05 
                 108 
                 Used 
               
               
                 8007931 
                 ITGB3 
                 0.40 
                 6.54 
                 6.10 
                 5.62E−05 
                 109 
               
               
                 7947248 
                 KIF18A 
                 −0.48 
                 5.00 
                 5.51 
                 6.16E−05 
                 110 
               
               
                 7978360 
                 GZMH 
                 −0.58 
                 6.95 
                 7.54 
                 6.51E−05 
                 111 
               
               
                 8142997 
                 PLXNA4 
                 0.44 
                 6.55 
                 6.07 
                 6.64E−05 
                 112 
               
               
                 8125993 
                 ETV7 
                 −0.28 
                 5.78 
                 6.03 
                 6.97E−05 
                 113 
               
               
                 8149725 
                 PEBP4 
                 −1.05 
                 8.77 
                 9.75 
                 7.36E−05 
                 114 
               
               
                 8178295 
                 UBD 
                 −0.74 
                 7.87 
                 8.57 
                 7.36E−05 
                 115 
               
               
                 8122986 
                 SNX9 
                 0.28 
                 8.54 
                 8.22 
                 7.50E−05 
                 116 
               
               
                 8154981 
                 UXC13B 
                 −0.49 
                 8.16 
                 8.62 
                 7.50E−05 
                 117 
               
               
                 8175369 
                 MAP7D3 
                 0.55 
                 8.76 
                 8.26 
                 8.13E−05 
                 118 
               
               
                 8091600 
                 PLCH1 
                 −0.62 
                 6.84 
                 7.31 
                 8.13E−05 
                 119 
               
               
                 8124650 
                 UBD 
                 −0.75 
                 7.99 
                 8.74 
                 8.22E−05 
                 120 
               
               
                 8161044 
                 TPM2 
                 0.60 
                 10.51 
                 9.89 
                 8.37E−05 
                 121 
               
               
                 8002218 
                 ESRP2 
                 −0.41 
                 7.21 
                 7.56 
                 8.37E−05 
                 122 
               
               
                 8180093 
                 HLA-DOA 
                 −0.45 
                 8.07 
                 8.59 
                 8.37E−05 
                 123 
               
               
                 8136473 
                 TRIM24 
                 −0.28 
                 8.33 
                 8.58 
                 8.41E−05 
                 124 
               
               
                 7956856 
                 MSRB3 
                 0.44 
                 7.99 
                 7.55 
                 8.49E−05 
                 125 
               
               
                 8035304 
                 BST2 
                 −0.50 
                 8.02 
                 8.52 
                 8.49E−05 
                 126 
               
               
                 8072710 
                 APOL6 
                 −0.37 
                 8.35 
                 8.84 
                 8.51E−05 
                 127 
               
               
                 8052882 
                 ADD2 
                 0.28 
                 5.63 
                 5.38 
                 8.58E−05 
                 128 
               
               
                 7958019 
                 DRAM1 
                 −0.52 
                 8.60 
                 9.13 
                 9.18E−05 
                 129 
               
               
                 8069565 
                 BTG3 
                 −0.38 
                 8.02 
                 8.40 
                 9.23E−05 
                 130 
               
               
                 8114010 
                 IRF1 
                 −0.53 
                 7.62 
                 8.14 
                 9.28E−05 
                 131 
               
               
                 7986446 
                 ALDH1A3 
                 0.49 
                 8.01 
                 7.51 
                 9.28E−05 
                 132 
               
               
                 8068583 
                 KCNJ15 
                 −0.76 
                 8.89 
                 9.53 
                 9.68E−05 
                 133 
               
               
                 7909586 
                 PPP2R5A 
                 −0.37 
                 7.92 
                 8.32 
                 1.05E−04 
                 134 
               
               
                 8178220 
                 HLA-DPB1 
                 −0.54 
                 9.76 
                 10.34 
                 1.06E−04 
                 135 
               
               
                 8116932 
                 PHACTR1 
                 −0.38 
                 7.38 
                 7.81 
                 1.15E−04 
                 136 
               
               
                 8136095 
                 AHCYL2 
                 −0.57 
                 8.98 
                 9.39 
                 1.23E−04 
                 137 
               
               
                 8073088 
                 APOBEC3G 
                 −0.53 
                 7.17 
                 7.77 
                 1.31E−04 
                 138 
               
               
                 8109462 
                 CNOT8 
                 −0.26 
                 8.54 
                 8.78 
                 1.33E−04 
                 139 
               
               
                 8006608 
                 CCL4L1 
                 −0.64 
                 6.44 
                 7.12 
                 1.39E−04 
                 140 
               
               
                 8083709 
                 SMC4 
                 −0.29 
                 8.48 
                 8.78 
                 1.41E−04 
                 141 
               
               
                 8138489 
                 CDCA7L 
                 −0.44 
                 7.79 
                 8.21 
                 1.45E−04 
                 142 
               
               
                 7913858 
                 PAQR7 
                 0.22 
                 6.58 
                 6.38 
                 1.46E−04 
                 143 
               
               
                 8148070 
                 COL14A1 
                 0.71 
                 9.87 
                 9.29 
                 1.48E−04 
                 144 
               
               
                 8096314 
                 PKD2 
                 0.32 
                 8.43 
                 8.07 
                 1.50E−04 
                 145 
               
               
                 8014349 
                 CCL15-CCL14 
                 0.69 
                 9.75 
                 9.08 
                 1.57E−04 
                 146 
               
               
                 7919314 
                 FMO5 
                 −0.68 
                 7.05 
                 7.69 
                 1.58E−04 
                 147 
               
               
                 8006621 
                 CCL4L1 
                 −0.75 
                 7.10 
                 7.93 
                 1.61E−04 
                 148 
               
               
                 8019651 
                 CCL4L1 
                 −0.75 
                 7.10 
                 7.93 
                 1.61E−04 
                 149 
               
               
                 8089299 
                 CD47 
                 −0.25 
                 10.44 
                 10.72 
                 1.61E−04 
                 150 
               
               
                 7904106 
                 MAGI3 
                 −0.42 
                 7.60 
                 7.99 
                 1.71E−04 
                 151 
               
               
                 8008321 
                 ACSF2 
                 −0.34 
                 6.38 
                 6.73 
                 1.75E−04 
                 152 
               
               
                 8005048 
                 MYOCD 
                 0.92 
                 7.04 
                 6.16 
                 1.77E−04 
                 153 
               
               
                 8042788 
                 ACTG2 
                 0.98 
                 10.11 
                 9.21 
                 1.79E−04 
                 154 
                 Used 
               
               
                 7929466 
                 CYP2C18 
                 −0.35 
                 5.09 
                 5.39 
                 1.84E−04 
                 155 
               
               
                 8129888 
                 NHSL1 
                 −0.41 
                 8.14 
                 8.57 
                 1.99E−04 
                 156 
               
               
                 8173924 
                 NA 
                 −0.95 
                 5.22 
                 6.25 
                 2.03E−04 
                 157 
                 Used 
               
               
                 7923958 
                 C1orf116 
                 −0.74 
                 8.38 
                 9.00 
                 2.07E−04 
                 158 
               
               
                 7979269 
                 GCH1 
                 −0.42 
                 6.93 
                 7.36 
                 2.16E−04 
                 159 
               
               
                 8020495 
                 CABLES1 
                 −0.37 
                 7.82 
                 8.21 
                 2.17E−04 
                 160 
               
               
                 7919645 
                 SV2A 
                 0.28 
                 6.06 
                 5.82 
                 2.18E−04 
                 161 
               
               
                 8077458 
                 EDEM1 
                 −0.33 
                 7.97 
                 8.32 
                 2.18E−04 
                 162 
               
               
                 8117476 
                 BTN3A3 
                 −0.40 
                 8.58 
                 9.00 
                 2.24E−04 
                 163 
               
               
                 8021376 
                 NEDD4L 
                 −0.66 
                 8.35 
                 8.94 
                 2.25E−04 
                 164 
               
               
                 8056457 
                 SCN1A 
                 −0.52 
                 4.80 
                 5.29 
                 2.25E−04 
                 165 
               
               
                 8150962 
                 TOX 
                 −0.51 
                 8.15 
                 8.60 
                 2.25E−04 
                 166 
               
               
                 8058591 
                 ACADL 
                 −1.01 
                 6.63 
                 7.62 
                 2.26E−04 
                 167 
               
               
                 8126653 
                 MRPL14 
                 −0.37 
                 9.31 
                 9.62 
                 2.29E−04 
                 168 
               
               
                 8098611 
                 TLR3 
                 −0.44 
                 8.52 
                 8.89 
                 2.29E−04 
                 169 
               
               
                 8066822 
                 SULF2 
                 0.54 
                 8.51 
                 7.83 
                 2.29E−04 
                 170 
               
               
                 8109507 
                 ITK 
                 −0.60 
                 6.14 
                 6.97 
                 2.30E−04 
                 171 
               
               
                 8099506 
                 TAPT1 
                 −0.32 
                 7.42 
                 7.70 
                 2.32E−04 
                 172 
               
               
                 7973564 
                 PSME1 
                 −0.19 
                 9.85 
                 10.07 
                 2.34E−04 
                 173 
               
               
                 7897044 
                 PRKCZ 
                 −0.47 
                 7.44 
                 7.85 
                 2.48E−04 
                 174 
               
               
                 7974080 
                 MIA2 
                 −0.31 
                 4.02 
                 4.26 
                 2.56E−04 
                 175 
               
               
                 7917576 
                 GBP5 
                 −0.98 
                 7.57 
                 8.74 
                 2.57E−04 
                 176 
               
               
                 8085774 
                 ZNF385D 
                 0.99 
                 7.66 
                 6.39 
                 2.58E−04 
                 177 
               
               
                 7923386 
                 LMOD1 
                 0.69 
                 7.68 
                 7.05 
                 2.58E−04 
                 178 
               
               
                 8073522 
                 SREBF2 
                 −0.28 
                 8.20 
                 8.44 
                 2.59E−04 
                 179 
               
               
                 7981460 
                 PPP1R13B 
                 −0.25 
                 7.83 
                 8.04 
                 2.62E−04 
                 180 
               
               
                 8010454 
                 RNF213 
                 −0.36 
                 8.63 
                 9.01 
                 2.63E−04 
                 181 
               
               
                 8097903 
                 TLR2 
                 −0.37 
                 7.77 
                 8.26 
                 2.68E−04 
                 182 
               
               
                 8113369 
                 SLCO4C1 
                 −0.99 
                 7.24 
                 8.31 
                 2.73E−04 
                 183 
               
               
                 7950235 
                 STARD10 
                 −0.30 
                 7.13 
                 7.43 
                 2.79E−04 
                 184 
               
               
                 7910600 
                 KIAA1804 
                 −0.33 
                 6.00 
                 6.29 
                 2.79E−04 
                 185 
               
               
                 8117435 
                 BTN3A2 
                 −0.52 
                 9.06 
                 9.56 
                 2.79E−04 
                 186 
               
               
                 8143327 
                 PARP12 
                 −0.30 
                 7.96 
                 8.30 
                 2.80E−04 
                 187 
               
               
                 8087925 
                 TNNC1 
                 −0.90 
                 8.53 
                 9.30 
                 2.82E−04 
                 188 
               
               
                 8022045 
                 MYOM1 
                 0.42 
                 5.80 
                 5.42 
                 2.82E−04 
                 189 
               
               
                 8096070 
                 BMP3 
                 −0.60 
                 7.22 
                 7.81 
                 2.82E−04 
                 190 
               
               
                 8075709 
                 APOL4 
                 −0.39 
                 7.01 
                 7.41 
                 2.87E−04 
                 191 
               
               
                 7915500 
                 C1orf210 
                 −0.32 
                 7.17 
                 7.59 
                 2.91E−04 
                 192 
               
               
                 7920297 
                 S100A14 
                 −0.56 
                 8.42 
                 8.87 
                 2.94E−04 
                 193 
               
               
                 7983630 
                 FGF7 
                 0.67 
                 7.64 
                 6.98 
                 2.94E−04 
                 194 
               
               
                 8010287 
                 C1QTNF1 
                 0.35 
                 7.81 
                 7.49 
                 3.09E−04 
                 195 
               
               
                 8018966 
                 TIMP2 
                 0.18 
                 10.53 
                 10.34 
                 3.09E−04 
                 196 
                 Used 
               
               
                 7951593 
                 NA 
                 −0.51 
                 7.28 
                 7.84 
                 3.16E−04 
                 197 
               
               
                 8048541 
                 DES 
                 0.71 
                 8.81 
                 8.19 
                 3.20E−04 
                 198 
                 Used 
               
               
                 7975361 
                 KIAA0247 
                 −0.22 
                 8.17 
                 8.37 
                 3.20E−04 
                 199 
               
               
                 8170428 
                 MTM1 
                 −0.31 
                 7.23 
                 7.52 
                 3.22E−04 
                 200 
               
               
                   
               
               
                 Abbreviations: TCID = transcript-cluster identity; Symbol = gene symbol; logFC = log fold-change; MedExpr.UIP = median expression level across the UIP samples; MedExpr.NonUIP = median expression level across the UIP samples; FDR = false discovery rate; Used by classifier = indicator of whether the gene is used by the microarray classifier. 
               
            
           
         
       
     
     The number and location of the samplings (upper vs. lower and central vs. peripheral) are indicated in  FIG.  6    and IPF patient clinical characteristics in Table 4. To identify genes useful in measuring spatial heterogeneity, we looked for differential expression in normal versus IPF samples. This comparison produced ˜5,000 significantly differentially expressed RNA transcripts with FDR&lt;0·05 (data not shown). We selected the top 200 differentially expressed genes and measured pairwise correlation. The results for the three patients diagnosed with IPF are shown in  FIG.  1   . Although correlation across all IPF samples is high, three distinct patterns emerge in the correlation structure among IPF samples. One patient (P1) shows substantial differences in upper vs. lower lobe gene expression i.e. lower correlation in gene signals. One patient (P3) shows higher correlation between the upper and lower lobe samplings. The third patient (P2) shows an intermediate result between these two cases, with sometimes higher, and sometimes lower, correlation between samplings from the upper and lower lobes. These results, while on a small number of patients, suggest that samples with lobe-specific pathology may be more accurate during the training phase of classifier development. Based on this information we prepared a classifier using SLB tissues with truth labels assigned at the sample level, using lobe-derived pathology. Our results, which are presented in Example 7, demonstrate the presence of a molecular signature in SLB tissues that classifies UIP and non-UIP samples with high prospective accuracy. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Clinical characteristics of three IPF explant patients. 
               
            
           
           
               
               
               
               
               
            
               
                 Patient 
                 Gender 
                 Age 
                 Smoking Status 
                 Clinical Remarks 
               
               
                   
               
               
                 P1 
                 M 
                 49 
                 non-smoker 
                 Exertional dyspnea for ~2 years prior 
               
               
                   
                   
                   
                   
                 to initial evaluation. 
               
               
                   
                   
                   
                   
                 Pre-transplant SLB demonstrated 
               
               
                   
                   
                   
                   
                 clear UIP pattern, no granuloma or 
               
               
                   
                   
                   
                   
                 bronchiolocentricity. 
               
               
                   
                   
                   
                   
                 Diagnosis of IPF at transplant 
               
               
                   
                   
                   
                   
                 reported patchy subpleural and 
               
               
                   
                   
                   
                   
                 paraseptal interstitial fibrosis, dense 
               
               
                   
                   
                   
                   
                 scarring and honeycombing by 
               
               
                   
                   
                   
                   
                 surgical pathology. No evidence of 
               
               
                   
                   
                   
                   
                 granuloma or extensive 
               
               
                   
                   
                   
                   
                 inflammation. 
               
               
                 P2 
                 M 
                 68 
                 50 pack years 
                 Initial evaluation occurred almost 
               
               
                   
                   
                   
                   
                 immediately after first presentation of 
               
               
                   
                   
                   
                   
                 exertional dyspnea; progressive 
               
               
                   
                   
                   
                   
                 worsening over ~2.5 years. 
               
               
                   
                   
                   
                   
                 Pathology at transplant demonstrated 
               
               
                   
                   
                   
                   
                 end-stage lung disease, diffuse 
               
               
                   
                   
                   
                   
                 fibrosis, temporal heterogeneity and 
               
               
                   
                   
                   
                   
                 fibroblastic foci suggestive of UIP. 
               
               
                 P3 
                 F 
                 64 
                 24 pack years 
                 Exertional dyspnea for ~2 years prior 
               
               
                   
                   
                   
                   
                 to initial evaluation, worsening over 
               
               
                   
                   
                   
                   
                 the last year. Possible occupational 
               
               
                   
                   
                   
                   
                 exposure. 
               
               
                   
                   
                   
                   
                 Pre-transplant SLB demonstrated UIP 
               
               
                   
                   
                   
                   
                 pattern with fibroblastic foci 
               
               
                   
                   
                   
                   
                 consistent with IPF. Pathology at 
               
               
                   
                   
                   
                   
                 transplant showed interstitial fibrosis, 
               
               
                   
                   
                   
                   
                 giant cell reaction, reorganization, 
               
               
                   
                   
                   
                   
                 bronchiectasis and reactive lymph 
               
               
                   
                   
                   
                   
                 node. 
               
               
                   
               
            
           
         
       
     
     Example 7 
     Performance of Microarray Classifier on Surgical Lung Biopsies 
     Using sample-specific pathology labels on biopsies obtained during VATS, a microarray classifier was trained by logistic regression on the top 200 genes separating UIP and non-UIP samples (see Table 12). A final model was built with 22 genes (Table 5). 
     Expression data was normalized by Robust Multi-array Average (RMA). Feature selection and model estimation were performed by logistic regression with lasso penalty using glmnet3. Raw reads were aligned using TopHat. Gene counts were obtained using HTSeq and normalized using DESeq. The top features (N ranging from 10 to 200) were used to train a linear support vector machine (SVM) using the e1071 library. Confidence intervals were computed using the pROC package. 
     LOPO CV performance is summarized as a receiver operating characteristic (ROC) curve ( FIG.  2 A ). The AUC is 0·9 [CI 0·82-0·96], with 92% [CI 84%400%] specificity and 64% [CI 49%-79%] sensitivity. Individual LOPO CV classification scores are shown for all patients ( FIG.  2 B ). Among the three misclassified non-UIP samples, two have scores very close to the threshold (0·86 and 1·30), and one has a high score (4·21). The latter sample with the high score was diagnosed as an ‘unclassifiable fibrotic ILD’ at both the sample- and patient-level. Among the UIP samples, fifteen (36%) have a score below the threshold (false negatives) but none of those samples have a large negative score. Since LOPO CV in certain cases has the potential to overestimate performance, we also evaluated 10-fold patient-level CV (i.e., 10% of patients are left out in each loop) which gives very similar performance (the median AUC from five repeated 10-fold CVs is 0·88). 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Twenty two genes included in a preferred array classifier. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 SYMBOL 
                   
                   
                   
                   
               
               
                   
                 (SEQ ID 
                   
                   
                   
                   
               
               
                 TCID 
                 NO.) 
                 logFC 
                 MedExpr.UIP 
                 MedExpr.NonUIP 
                 FDR 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 8117760 
                 HLA-F 
                 −0.48 
                 9.02 
                 9.53 
                 2.35E−09 
               
               
                   
                 (1) 
                   
                   
                   
                   
               
               
                 8101031 
                 CDKL2 
                 −0.95 
                 7.31 
                 8.16 
                 1.29E−07 
               
               
                   
                 (2) 
                   
                   
                   
                   
               
               
                 8106827 
                 GPR98 
                 −0.77 
                 6.11 
                 6.74 
                 2.16E−07 
               
               
                   
                 (3) 
                   
                   
                   
                   
               
               
                 7931930 
                 PRKCQ 
                 −0.64 
                 6.78 
                 7.4 
                 1.81E−06 
               
               
                   
                 (4) 
                   
                   
                   
                   
               
               
                 8177725 
                 HLA-G 
                 −0.29 
                 10.67 
                 10.89 
                 2.37E−06 
               
               
                   
                 (5) 
                   
                   
                   
                   
               
               
                 7926037 
                 PFKFB3 
                 −0.45 
                 7.66 
                 8.1 
                 2.81E−06 
               
               
                   
                 (6) 
                   
                   
                   
                   
               
               
                 8037205 
                 CEACAM1 
                 −0.41 
                 6.47 
                 6.97 
                 3.04E−06 
               
               
                   
                 (7) 
                   
                   
                   
                   
               
               
                 7907492 
                 RABGAP1L 
                 −0.32 
                 8.01 
                 8.33 
                 3.88E−06 
               
               
                   
                 (8) 
                   
                   
                   
                   
               
               
                 8154233 
                 CD274 
                 −0.84 
                 6.35 
                 7.14 
                 4.54E−06 
               
               
                   
                 (9) 
                   
                   
                   
                   
               
               
                 8161865 
                 PRUNE2 
                 0.79 
                 7.44 
                 6.75 
                 7.05E−06 
               
               
                   
                 (10) 
                   
                   
                   
                   
               
               
                 8099760 
                 ARAP2 
                 −0.41 
                 7.55 
                 7.9 
                 1.06E−05 
               
               
                   
                 (11) 
                   
                   
                   
                   
               
               
                 7972336 
                 DZIP1 
                 0.33 
                 7.72 
                 7.47 
                 1.16E−05 
               
               
                   
                 (12) 
                   
                   
                   
                   
               
               
                 8056217 
                 MXRA7 
                 0.4 
                 8.58 
                 8.29 
                 1.21E−05 
               
               
                   
                 (13) 
                   
                   
                   
                   
               
               
                 8126853 
                 PTCHD4 
                 0.75 
                 7.02 
                 6.07 
                 4.27E−05 
               
               
                   
                 (14) 
                   
                   
                   
                   
               
               
                 8104022 
                 PDLIM3 
                 0.58 
                 8.33 
                 7.63 
                 5.03E−05 
               
               
                   
                 (15) 
                   
                   
                   
                   
               
               
                 8025918 
                 CNN1 
                 0.86 
                 8.39 
                 7.52 
                 5.43E−05 
               
               
                   
                 (16) 
                   
                   
                   
                   
               
               
                 8157027 
                 NIPSNAP3B 
                 0.29 
                 5.25 
                 4.98 
                 5.62E−05 
               
               
                   
                 (17) 
                   
                   
                   
                   
               
               
                 7913858 
                 PAQR7 
                 0.22 
                 6.58 
                 6.38 
                 1.46E−04 
               
               
                   
                 (18) 
                   
                   
                   
                   
               
               
                 8042788 
                 ACTG2 
                 0.98 
                 10.11 
                 9.21 
                 1.79E−04 
               
               
                   
                 (19) 
                   
                   
                   
                   
               
               
                 8173924 
                 NA 
                 −0.95 
                 5.22 
                 6.25 
                 2.03E−04 
               
               
                   
                 (20) 
                   
                   
                   
                   
               
               
                 8018966 
                 TIMP2 
                 0.18 
                 10.53 
                 10.34 
                 3.09E−04 
               
               
                   
                 (21) 
                   
                   
                   
                   
               
               
                 8048541 
                 DES 
                 0.71 
                 8.81 
                 8.19 
                 3.20E−04 
               
               
                   
                 (22) 
               
               
                   
               
               
                 Abbreviations: TCID = transcript-cluster identify; Symbol = gene symbol; logFC = log fold-change; MedExpr.UIP = median expression level across the UIP samples; MedExpr.NonUIP = median expression level across the UIP samples; FDR = false discovery rate. 
               
            
           
         
       
     
     Independent test set performance is shown in  FIG.  2 C  showing an AUC of 0·94 [CI 0·86-0·99], with 92% [CI 81%400%] specificity and 82% [CI 64%-95%] sensitivity. The individual classification score distribution shows good separation between UIP and non-UIP classes ( FIG.  2 D ). The two misclassified non-UIP samples have both patient- and sample-level expert diagnoses of ‘unclassifiable fibrotic ILD’ indicating uncertainty in the diagnosis. The score range observed in the test set ( FIG.  2 D ) is narrower than the range seen in LOPO CV scores ( FIG.  2 B ), likely due to the larger variability inherent in applying a series of sub-classifiers within each CV loop, compared to scores obtained by applying a single model. Classification performance including 95% confidence intervals are summarized in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Classifier performance summary, including 95% confidence intervals (CI). 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 RNASeqSet- 
               
               
                   
                 Array 
                 Array 
                 RNASeq 
                 matched array 
               
               
                   
                 classifier 
                 classifier 
                 classifier 
                 classifier 
               
               
                   
                 (LOPO CV) 
                 (Testing) 
                 (LOPO CV) 
                 (LOPO CV) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 AUC [95% CI] 
                 0.90 
                 [0.82-0.96] 
                 0.94 
                 [0.86-0.99] 
                 0.90 
                 [0.77-1.00] 
                 0.86 
                 [0.73-0.96] 
               
               
                 Specificity [95% 
                 92% 
                 [84%-100%] 
                 92% 
                 [81%-100%] 
                 95% 
                 [84%-100%] 
                 95% 
                 [84%-100%] 
               
               
                 CI] 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Sensitivity [95% 
                 64% 
                 [49%-79%] 
                 82% 
                 [64%-95%] 
                 59% 
                 [35%-82%] 
                 47% 
                 [24%-71%] 
               
               
                 CI] 
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Threshold 
                 0.72 
                 1.04 
                 0.64 
                 1 
               
               
                 False positive 
                 3 
                 2 
                 1 
                 1 
               
               
                 count 
                   
                   
                   
                   
               
               
                 True negative 
                 35 
                 24 
                 18 
                 18 
               
               
                 count 
                   
                   
                   
                   
               
               
                 False negative 
                 14 
                 4 
                 7 
                 9 
               
               
                 count 
                   
                   
                   
                   
               
               
                 True negative 
                 25 
                 18 
                 10 
                 8 
               
               
                 count 
                   
                   
                   
                   
               
               
                 Total 
                 77 
                 48 
                 36 
                 36 
               
               
                   
               
            
           
         
       
     
     Our approach offers significant advantages. Earlier gene-expression profiling studies focused on comparing IPF versus a few non-IPF ILD subtypes such as HP or NSIP, or against subjects without ILD 18,19,23,25 . The non-UIP cohort reported here represents a broad spectrum of pathology subtypes including HP, NSIP, sarcoidosis, RB, bronchiolitis, organizing pneumonia (OP), and others, thus approximating the diversity of ILDs encountered in clinical practice. In addition, the classifier was trained and tested using a combination of banked and prospectively collected SLBs to ensure robustness against potential differences in sample handling and collection. Finally, many earlier studies focused on differential gene expression analyses alone, without building a classification engine. In contrast, our approach is a rigorous method for the development of molecular tests which, when properly trained and validated, generalized well to independent data sets. 
     Example 8 
     Performance of RNASeq Classifier on Surgical Lung Biopsies 
     A subset of 36 samples with RNASeq data were used to train a linear SVM classifier and the performance evaluated by LOPO CV. AUCs are consistently above 0·80 for gene numbers spanning 10 to 200 (data not shown). We chose a model using 100 genes for further examination. The AUC is 0·9 [CI 0·77-1·00] (specificity=95% [CI 84%-100%], sensitivity=59% [CI 35%-82%]) ( FIG.  3 A ). Only a single non-UIP sample is misclassified ( FIG.  3 B ). The sample-level pathology for this sample is respiratory bronchiolitis (RB), and the patient-pathology is diffuse alveolar damage (DAD), two subtypes that may have been difficult to model because of their sparsity. We carried out a similar analysis using matching array data on the same set of samples; the array-based classifier achieves similar performance (AUC=0·86 [CI 0·73-0·96]) using 160 genes. Specificity is 95% [CI 84%400%] and sensitivity is 47% [CI 24%-71%] ( FIG.  3 C ). Interestingly, the same non-UIP sample that was misclassified as a UIP by the RNASeq classifier is also misclassified by the microarray classifier ( FIG.  3 D ). Overall, classification based on RNASeq achieves comparable performance to that of the array platform. 
     Example 9 
     Biological Pathways Associated with Genes Used by the Classifiers 
     To determine if there are common biological underpinnings across the genes selected by the machine learning process, we used over-representation analysis (ORA) to identify statistically significant participation of genes in selected pathways. Over/under-representation analyses (ORA) were performed using GeneTrail software (genetrail.bioinfuni-sb.de/) and the top 1,000 genes differentially expressed by limma between UIP and non-UIP samples (FDR&lt;0·013) in the microarray testing set (n=77) as the ORA test sets. The ORA reference set included all human genes (n=44,829) and annotation in the KEGG pathways and gene ontology (GO) databases. Significance was evaluated via Fisher&#39;s exact test with a corrected FDR threshold of p&lt;0·05. 
     In examining the top 1000 genes found in the UIP vs non-UIP comparison, distinct findings emerged (Table 2). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways and Gene 
               
               
                 Ontologies (GO) over-represented in UIP and non-UIP samples. 
               
               
                 Categories in each sample cohort are ranked by FDR p value. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 No. 
                 No. 
                 ORA 
                 FDR 
               
               
                 Source 
                 Category 
                 expected 
                 observed 
                 Proportion 
                 p value 
               
               
                   
               
            
           
           
               
            
               
                 Over-represented in UIP 
               
            
           
           
               
               
               
               
               
               
            
               
                 GO 
                 Extracellular matrix 
                 5 
                 31 
                 6.2 
                 1.46E−12 
               
               
                 GO 
                 Muscle system process 
                 5 
                 23 
                 4.6 
                 1.21E−07 
               
               
                 GO 
                 Cell migration/motility 
                 9 
                 27 
                 3.0 
                 7.31E−06 
               
               
                 KEGG 
                 Focal adhesion 
                 6 
                 21 
                 3.5 
                 1.20E−05 
               
               
                 GO 
                 Contractile fiber 
                 2 
                 12 
                 6.0 
                 1.73E−05 
               
               
                 KEGG 
                 Calcium signaling, pathway 
                 5 
                 18 
                 3.6 
                 5.38E−05 
               
               
                 KEGG 
                 Dilated cardiomyopathy 
                 3 
                 13 
                 4.3 
                 5.38E−05 
               
               
                 KEGG 
                 ECM-receptor interaction 
                 2 
                 12 
                 6.0 
                 5.95E−05 
               
               
                 KEGG 
                 Vascular Muscle contraction 
                 3 
                 14 
                 4.7 
                 5.95E−05 
               
               
                 KEGG 
                 Hypertropic cardiomyopathy (HCM) 
                 2 
                 11 
                 5.5 
                 2.90E−04 
               
               
                 KEGG 
                 Arrhythmogenic right ventricular 
                 2 
                 9 
                 4.5 
                 2.82E−03 
               
               
                   
                 cardiomyopathy (ARVC) 
                   
                   
                   
                   
               
               
                 KEGG 
                 Regulation of Actin cytoskeleton 
                 6 
                 16 
                 2.7 
                 3.39E−03 
               
               
                 KEGG 
                 Melanoma 
                 2 
                 8 
                 4.0 
                 6.26E−03 
               
               
                 KEGG 
                 Cardiac muscle contraction 
                 2 
                 7 
                 3.5 
                 4.53E−02 
               
               
                 KEGG 
                 MAPK signaling pathway 
                 8 
                 15 
                 1.9 
                 4.76E−02 
               
            
           
           
               
            
               
                 Over-represented in non-UIP 
               
            
           
           
               
               
               
               
               
               
            
               
                 KEGG 
                 Allograft rejection 
                 1 
                 15 
                 15.0 
                 9.25E−12 
               
               
                 KEGG 
                 Cell adhesion molecules 
                 4 
                 25 
                 6.3 
                 9.25E−12 
               
               
                 KEGG 
                 Antigen processing and presentation 
                 2 
                 19 
                 9.5 
                 3.40E−11 
               
               
                 KEGG 
                 Type I diabetes mellitus 
                 1 
                 14 
                 14.0 
                 5.95E−10 
               
               
                 GO 
                 Immune response 
                 13 
                 42 
                 3.2 
                 6.52E−09 
               
               
                 KEGG 
                 Autoimmune thyroid disorder 
                 2 
                 14 
                 7.0 
                 6.72E−09 
               
               
                 KEGG 
                 Viral myocarditis 
                 2 
                 16 
                 8.0 
                 6.72E−09 
               
               
                 KEGG 
                 Phagosome 
                 5 
                 20 
                 4.0 
                 7.01E−07 
               
               
                 GO 
                 MHC class I receptor activity 
                 1 
                 7 
                 7.0 
                 2.66E−05 
               
               
                 KEGG 
                 Systemic lupus erythematosus 
                 4 
                 16 
                 4.0 
                 6.11E−05 
               
               
                 KEGG 
                 Leishmaniasis 
                 2 
                 11 
                 5.5 
                 1.14E−04 
               
               
                 GO 
                 Innate immune response 
                 3 
                 14 
                 4.7 
                 2.34E−04 
               
               
                 KEGG 
                 Asthma 
                 1 
                 7 
                 7.0 
                 2.83E−04 
               
               
                 GO 
                 Signal transducer activity 
                 24 
                 48 
                 2 
                 3.44E−04 
               
               
                 GO 
                 Antigen processing and 
                 1 
                 4 
                 4 
                 7.50E−04 
               
               
                   
                 presentation of endogenous 
                   
                   
                   
                   
               
               
                   
                 antigen 
                   
                   
                   
                   
               
               
                 KEGG 
                 Intestinal immune network for 
                 2 
                 8 
                 4.0 
                 8.40E−04 
               
               
                   
                 IgA production 
                   
                   
                   
                   
               
               
                 KEGG 
                 Malaria 
                 2 
                 8 
                 4.0 
                 1.04E−03 
               
               
                 GO 
                 T cell activation 
                 3 
                 12 
                 4.0 
                 1.58E−03 
               
               
                 KEGG 
                 Natural killer cell mediated 
                 4 
                 13 
                 3.3 
                 1.91E−03 
               
               
                   
                 cytotoxicity 
                   
                   
                   
                   
               
               
                 KEGG 
                 Endocytosis 
                 6 
                 16 
                 2.7 
                 3.42E−03 
               
               
                 KEGG 
                 Steroid biosynthesis 
                 1 
                 4 
                 4.0 
                 8.78E−03 
               
               
                 KEGG 
                 Tight junction 
                 4 
                 11 
                 2.8 
                 1.50E−02 
               
               
                 KEGG 
                 Proteasome 
                 1 
                 6 
                 6.0 
                 1.71E−02 
               
               
                 KEGG 
                 Primary immunodeficiency 
                 1 
                 5 
                 5.0 
                 1.89E−02 
               
               
                 KEGG 
                 Toll-like receptor signaling 
                 3 
                 9 
                 3.0 
                 1.89E−02 
               
               
                   
               
               
                 Abbreviations: FDR = false discovery rate; GO = Gene Ontology; KEGG = Kyoto Encyclopedia of Genes and Genomes; ORA = over-representation analysis. 
               
            
           
         
       
     
     In UIP, genes involved in cell adhesion, muscle disease, cell migration and motility predominate. These results are consistent with previous reports of pathways differentially regulated in IPF 18,19,22,23 . In contrast, other non-UIP subtypes overexpress genes involved in immune processes, including both the adaptive and innate systems. This enrichment could be due to the RB and HP subtypes present in the non-UIP cohort; diseases known to exhibit immune components 24 . Genes over-represented in KEGG pathways and Gene Ontology groups are summarized in Tables 7 and 8. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Genes over-represented in KEGG pathways and Gene Ontology groups of UIP samples. 
               
               
                 OVER-REPRESENTED IN UIP 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 No. 
                   
               
               
                 Source 
                 Category 
                 observed 
                 Genes Observed 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 GO 
                 Extracellular matrix 
                 31 
                 ABI3BP, ADAMTS3, AEBP1, CLU, 
               
               
                   
                   
                   
                 COL14A1, COL15A1, COL1A2, COL21A1, 
               
               
                   
                   
                   
                 COL6A1, COL6A2, CPXM2, DST, FBLN1, 
               
               
                   
                   
                   
                 FBN1, FGF10, FMOD, HTRA1, LAMA4, 
               
               
                   
                   
                   
                 LAMB2, LAMC1, LTBP1, MGP, NID1, 
               
               
                   
                   
                   
                 PLAT, POSTN, SERPINF1, SFRP2, SNCA, 
               
               
                   
                   
                   
                 SPON1, TNC, VCAN 
               
               
                 GO 
                 Muscle system process 
                 23 
                 ACTA2, ACTG2, AGT, ATP1A2, BDKRB2, 
               
               
                   
                   
                   
                 CALD1, CNN1, CRYAB, DES, DTNA, IGF1, 
               
               
                   
                   
                   
                 LMOD1, MYH11, MYL9, MYLK, MYOCD, 
               
               
                   
                   
                   
                 SLC6A8, SSPN, TNNI2, TNNT3, TPM1, 
               
               
                   
                   
                   
                 TPM2, TPM4 
               
               
                 GO 
                 Cell 
                 27 
                 ADRA2A, AGT, ANGPT2, CCL24, CXCL12, 
               
               
                   
                 migration/motility 
                   
                 ENPP2, F10, FGF10, FGF7, IGF1, IGFBP5, 
               
               
                   
                   
                   
                 ITGB3, KRT2, LAMC1, NEXN, NR2F2, 
               
               
                   
                   
                   
                 PDGFRB, PODN, PPAP2A, ROR2, S100A2, 
               
               
                   
                   
                   
                 SCG2, SFRP2, SLIT3, THY1, TPM1, VCAN 
               
               
                 KEGG 
                 Focal adhesion 
                 21 
                 ACTN1, COLIA2, COL6A1, COL6A2, FLNC, 
               
               
                   
                   
                   
                 HGF, IGF1, ITGA7, ITGB3, ITGB4, LAMA4, 
               
               
                   
                   
                   
                 LAMB2, LAMC1, MYL9, MYLK, PARVA, 
               
               
                   
                   
                   
                 PDGFD, PDGFRB, SHC4, SPP1, TNC 
               
               
                 GO 
                 Contractile fiber 
                 12 
                 DES, MYH11, MYL9, MYOM1, NEXN, 
               
               
                   
                   
                   
                 PGM5, SVIL, TNNI2, TNNT3, TPM1, TPM2, 
               
               
                   
                   
                   
                 TPM4 
               
               
                 KEGG 
                 Calcium signaling, 
                 18 
                 ADCY3, AVPR1A, BDKRB2, CACNA1C, 
               
               
                   
                 pathway 
                   
                 GNAL, GRIN2A, HRH1, HTR2A, MYLK, 
               
               
                   
                   
                   
                 P2RX1, PDE1A, PDGFRB, PLCB1, PLN, 
               
               
                   
                   
                   
                 PTGER3, RYR3, TACR1, TRPC1 
               
               
                 KEGG 
                 Dilated 
                 13 
                 ADCY3, ADCY5, CACNA1C, CACNA2D1, 
               
               
                   
                 cardiomyopathy 
                   
                 DES, IGF1, ITGA7, ITGB3, ITGB4, PLN, 
               
               
                   
                   
                   
                 TPM1, TPM2, TPM4 
               
               
                 KEGG 
                 ECM-receptor 
                 12 
                 COL1A2, COL6A1, COL6A2, ITGA7, ITGB3, 
               
               
                   
                 interaction 
                   
                 ITGB4, LAMA4, LAMB2, LAMC1, SPP1, 
               
               
                   
                   
                   
                 SV2A, TNC 
               
               
                 KEGG 
                 Vascular Muscle 
                 14 
                 ACTA2, ACTG2, ADCY3, ADCY5, AVPR1A, 
               
               
                   
                 contraction 
                   
                 CACNA1C, CALD1, KCNMB1, MRVI1, 
               
               
                   
                   
                   
                 MYH11, MYL9, MYLK, PLA2G2A, PLCB1, 
               
               
                 KEGG 
                 Hypertropic 
                 11 
                 CACNA1C, CACNA2D1, DES, IGF1, ITGA7, 
               
               
                   
                 cardiomyopathy 
                   
                 ITGB3, ITGB4, PRKAA2, TPM1, TPM2, 
               
               
                   
                 (HCM) 
                   
                 TPM4 
               
               
                 KEGG 
                 Arrhythmogenic right 
                 9 
                 ACTN1, CACNA1C, CACNA2D1, CDH2, 
               
               
                   
                 ventricular 
                   
                 DES, ITGA7, ITGB3, ITGB4, PKP2 
               
               
                   
                 cardiomyopathy 
                   
                   
               
               
                   
                 (ARVC) 
                   
                   
               
               
                 KEGG 
                 Regulation of Actin 
                 16 
                 ACTN1, BDKRB2, ENAH, FGF10, FGF14, 
               
               
                   
                 cytoskeleton 
                   
                 FGF7, FGFR1, GNG12, ITGA7, ITGB3, 
               
               
                   
                   
                   
                 ITGB4, MRAS, MYL9, MYLK, PDGFD, 
               
               
                   
                   
                   
                 PDGFRB 
               
               
                 KEGG 
                 Melanoma 
                 8 
                 FGF10, FGF14, FGF7, FGFR1, HGF, IGF1, 
               
               
                   
                   
                   
                 PDGFD, PDGFRB 
               
               
                 KEGG 
                 Cardiac muscle 
                 7 
                 ATP1A2, ATP1B2, CACNA1C, CACNA2D1, 
               
               
                   
                 contraction 
                   
                 TPM1, TPM2, TPM4 
               
               
                 KEGG 
                 MAPK signaling 
                 15 
                 CACNA1C, CACNA2D1, FGF10, FGF14, 
               
               
                   
                 pathway 
                   
                 FGF7, FGFR1, FLNC, GNG12, HSPA2, 
               
               
                   
                   
                   
                 MAP4K4, MRAS, NFATC4, PDGFRB, 
               
               
                   
                   
                   
                 PLA2G2A, ZAK 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Genes over-represented in KEGG pathways and Gene Ontology groups of non-UIP samples, 
               
               
                 OVER-REPRESENTED IN non-UIP 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 No, 
                   
               
               
                 Source 
                 Category 
                 observed 
                 Genes Observed 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 KEGG 
                 Allograft rejection 
                 15 
                 CD40, FASLG, HLA-A, HLA-B, HLA-C, HLA- 
               
               
                   
                   
                   
                 DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, 
               
               
                   
                   
                   
                 HLA-DQA1, HLA-DRA, HLA-E, HLA-F, 
               
               
                   
                   
                   
                 HLA-G, IFNG 
               
               
                 KEGG 
                 Cell adhesion 
                 25 
                 CADM1, CD2, CD274, CD40, CD8A, 
               
               
                   
                 molecules 
                   
                 CLDN18, CLDN4, F11R, HLA-A, HLA-B, 
               
               
                   
                   
                   
                 HLA-C, HLA-, DMA, HLA-DOA, HLA-DPA1, 
               
               
                   
                   
                   
                 HLA-DPB1, HLA-DQA1, HLA-DRA, HLA-E, 
               
               
                   
                   
                   
                 HLA-F, HLA-G, ICAM1, ICOS, ITGAL, 
               
               
                   
                   
                   
                 OCLN, SDC4 
               
               
                 KEGG 
                 Antigen processing 
                 19 
                 CD74, CD8A, HLA-A, HLA-B, HLA-C, HLA- 
               
               
                   
                 and presentation 
                   
                 DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, 
               
               
                   
                   
                   
                 HLA-, DQA1, HLA-DRA, HLA-E, HLA-F, 
               
               
                   
                   
                   
                 HLA-G, IFNG, PSME1, PSME2, TAP1, TAP2 
               
               
                 KEGG 
                 Type I diabetes 
                 14 
                 FASLG, HLA-A, HLA-B, HLA-C, HLA-DMA, 
               
               
                   
                 mellitus 
                   
                 HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-, 
               
               
                   
                   
                   
                 DQA1, HLA-DRA, HLA-E, HLA-F, HLA-G, 
               
               
                   
                   
                   
                 IFNG 
               
               
                 GO 
                 Immune response 
                 42 
                 APOBEC3G, AQP4, BST2, C2, CADM1, 
               
               
                   
                   
                   
                 CCR5, CD274, CD74, CD8A, CRTAM, CTSC, 
               
               
                   
                   
                   
                 CTSW, CXCL16, ERAP1, FCGR1A, FCGR1B, 
               
               
                   
                   
                   
                 FCGR3A, GBP2, GCH1, GZMA, HLA-A, 
               
               
                   
                   
                   
                 HLA-B, HLA-C, HLA-DPA1, HLA-DQA1, 
               
               
                   
                   
                   
                 HLA-DRA, HLA-H, ICAM1, ICOS, IL32, 
               
               
                   
                   
                   
                 ITGAL, MICB, NUB1, PLA2G1B, PSMB10, 
               
               
                   
                   
                   
                 S100A14, SFTPD, SKAP1, THEMIS, TLR2, 
               
               
                   
                   
                   
                 TLR3, UBD 
               
               
                 KEGG 
                 Autoimmune thyroid 
                 14 
                 CD40, FASLG, HLA-A, HLA-B, HLA-C, HLA- 
               
               
                   
                 disorder 
                   
                 DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, 
               
               
                   
                   
                   
                 HLADQA1, HLA-DRA, HLA-E, HLA-F, 
               
               
                   
                   
                   
                 HLA-G 
               
               
                 KEGG 
                 Viral myocarditis 
                 16 
                 CD40, HLA-A, HLA-B, HLA-C, HLA-DMA, 
               
               
                   
                   
                   
                 HLA-DOA, HLA-DPA1, HLA-DPB1, HLA- 
               
               
                   
                   
                   
                 DQA1, HLA-DRA, HLA-E, HLA-F, HLA-G, 
               
               
                   
                   
                   
                 ICAM1, ITGAL, MYH14 
               
               
                 KEGG 
                 Phagosome 
                 20 
                 ATP6V0D1, FCGR1A, FCGR3A, HLA-A, 
               
               
                   
                   
                   
                 HLA-B, HLA-C, HLA-DMA, HLA-DOA, 
               
               
                   
                   
                   
                 HLA-, DPA1, HLA-DPB1, HLA-DQA1, HLA- 
               
               
                   
                   
                   
                 DRA, HLA-E, HLA-F, HLA-G, SFTPA1, 
               
               
                   
                   
                   
                 SFTPD, TAP1, TAP2, TLR2 
               
               
                 GO 
                 MHC class I receptor 
                 7 
                 HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, 
               
               
                   
                 activity 
                   
                 HLA-G, HLA-H 
               
               
                 KEGG 
                 Systemic lupus 
                 16 
                 C2, CD40, FCGR1A, FCGR3A, HIST1H2BJ, 
               
               
                   
                 erythematosus 
                   
                 HIST1H3F, HIST1H4E, HIST2H2BE, HLA-, 
               
               
                   
                   
                   
                 DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, 
               
               
                   
                   
                   
                 HLA-DQA1, HLA-DRA, IFNG, TRIM21 
               
               
                 KEGG 
                 Leishmaniasis 
                 11 
                 FCGR1A, FCGR3A, HLA-DMA, HLA-DOA, 
               
               
                   
                   
                   
                 HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-, 
               
               
                   
                   
                   
                 DRA, IFNG, STAT1, TLR2 
               
               
                 GO 
                 Innate immune 
                 14 
                 APOBEC3G, AQP4, C2, CADM1, CRTAM, 
               
               
                   
                 response 
                   
                 CXCL16, ERAP1, GCH1, NUB1, S100A14, 
               
               
                   
                   
                   
                 SFTPD, TLR2, TLR3, UBD 
               
               
                 KEGG 
                 Asthma 
                 7 
                 CD40, HLA-DMA, HLA-DOA, HLA-DPA1, 
               
               
                   
                   
                   
                 HLA-DPB1, HLA-DQA1, HLA-DRA 
               
               
                 GO 
                 Signal transducer 
                 48 
                 AGER, BST2, CCL4, CCL5, CCR5, CD2, 
               
               
                   
                 activity 
                   
                 CD40, CD47, CD74, CD8A, CLDN4, CXCL16, 
               
               
                   
                   
                   
                 CXCR6, EBP, ERBB3, FCGR1A, FCGR1B, 
               
               
                   
                   
                   
                 FGFR2, FLRT3, FZD5, GPR98, HLA-A, HLA- 
               
               
                   
                   
                   
                 B, HLA-C, HLA-DOA, HLA-DPA1, HLA- 
               
               
                   
                   
                   
                 DQA1, HLA-DRA, HLA-E, HLA-F, HLA-G, 
               
               
                   
                   
                   
                 HLA-H, ICAM1, IL2RB, KLRB1, LDLR, 
               
               
                   
                   
                   
                 MAP3K13, PTPRJ, SCTR, SDC4, SH2D1A, 
               
               
                   
                   
                   
                 SKAP1, STAT1, TAPT1, TLR2, TLR3, 
               
               
                   
                   
                   
                 TP53BP2, UNC13B 
               
               
                 GO 
                 Antigen processing 
                 4 
                 CD74, ERAP1, TAP1, TAP2 
               
               
                   
                 and presentation of 
                   
                   
               
               
                   
                 endogenous antigen 
                   
                   
               
               
                 KEGG 
                 Intestinal immune 
                 8 
                 CD40, HLA-DMA, HLA-DOA, HLA-DPA1, 
               
               
                   
                 network for IgA 
                   
                 HLA-DPB1, HLA-DQA1, HLA-DRA, ICOS 
               
               
                   
                 production 
                   
                   
               
               
                 KEGG 
                 Malaria 
                 8 
                 CD40, ICAM1, IFNG, ITGAL, KLRB1, 
               
               
                   
                   
                   
                 KLRK1, SDC4, TLR2 
               
               
                 GO 
                 T cell activation 
                 12 
                 CADM1, CD2, CD47, CD74, CD8A, CRTAM, 
               
               
                   
                   
                   
                 ICAM1, ITGAL, KLRK1, MICB, SFTPD, 
               
               
                   
                   
                   
                 THEMIS 
               
               
                 KEGG 
                 Natural killer cell 
                 13 
                 FASLG, FCGR3A, HLA-A, HLA-B, HLA-C, 
               
               
                   
                 mediated cytotoxicity 
                   
                 HLA-E, HLA-G, ICAM1, IFNG, ITGAL, 
               
               
                   
                   
                   
                 KLRK1, MICB, SH2D1A 
               
               
                 KEGG 
                 Endocytosis 
                 16 
                 ARAP2, CCR5, DNM2, ERBB3, FGFR2, HLA- 
               
               
                   
                   
                   
                 A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, 
               
               
                   
                   
                   
                 IL2RB, LDLR, NEDD4L, PARD6B, PRKCZ 
               
               
                 KEGG 
                 Steroid biosynthesis 
                 4 
                 DHCR24, EBP, FDFT1, SQLE 
               
               
                 KEGG 
                 Tight junction 
                 11 
                 CLDN18, CLDN4, F11R, INADL, LLGL2, 
               
               
                   
                   
                   
                 MAGI3, MYH14, OCLN, PARD6B, PRKCQ, 
               
               
                   
                   
                   
                 PRKCZ 
               
               
                 KEGG 
                 Proteasome 
                 6 
                 IFNG, PSMB10, PSMB8, PSMB9, PSME1, 
               
               
                   
                   
                   
                 PSME2 
               
               
                 KEGG 
                 Primary 
                 5 
                 CD40, CD8A, ICOS, TAP1, TAP2 
               
               
                   
                 immunodeficiency 
                   
                   
               
               
                 KEGG 
                 Toll-like receptor 
                 9 
                 CCL4, CCL5, CD40, CXCL10, CXCL11, 
               
               
                   
                 signaling 
                   
                 CXCL9, STAT1, TLR2, TLR3 
               
               
                   
               
            
           
         
       
     
     Example 10 
     Mislabeling Simulation Study 
     A simulation study swapping binary classification labels (UIP or non-UIP) was performed on the microarray training set. Samples were selected at random for label permutation, at total proportions per simulation set ranging from 1% to 40%. The level of agreement in the blinded review of the three expert pathology diagnoses is 3/3 (n=44), 2/2 (n=8), 2/3 (n=24), and 1/3 (n=1). Sample labels were changed to the other class with a weight proportional to the probability accounting for the disagreement level in the blinded review of the three expert pathologists: 5% for 3/3 or 2/2 agreement, 50% for 2/3 agreement, and 90% for 1/3 agreement. Simulations were repeated 100 times at each proportion. 
     The LOPO CV performance (AUC) was evaluated over 100 repeated simulations across a range of proportion of swapped labels ( FIG.  4   ). When there is no label swap, the median performance is very close to the array classifier performance shown in  FIG.  2 A  (AUC=0·9). (Using the same set of samples and labels, model estimation can have slight variability). As the swap rate increases, the performance decreases monotonically. When 40% of the labels are swapped, the median performance approaches 0·5, indicating classification is no better than random chance. 
     Example 11 
     Magnitude and direction of UIP/Non-UIP differential gene expression differs in smoker vs. non-smoker test subjects. 
     Interstitial lung diseases are more prevalent in persons that smoke, or have had a long history of smoking prior to quitting, than in persons who never smoked. We compared differential gene expression profiles of samples derived from smoker and non-smoker UIP or non-UIP subjects to determine if smoking status affects performance of UIP diagnostic classifiers. 
     Transbronchial biopsy samples were prepared [according to the methods described in Examples 1 and 2, and RNA sequencing analysis was performed according to the method described in Example 3]. RNASeq data was generated for a subset of 24 samples (9 UIP and 15 non-UIP), and differential gene expression was analyzed according to three binary comparisons: (i) UIP vs. non-UIP, n=9 and 15 samples, respectively; (ii) Non-smoker UIP vs. Non-smoker non-UIP, n=3 and 5 samples, respectively; and (iii) Smoker UIP vs. Smoker non-UIP, n=12 and 4 samples, respectively. 
     The results of the expression analysis for groups (i) to (iii) are shown in Tables 9 to 11, respectively, and are summarized in  FIGS.  8 - 10   . The number of genes differentially expressed between UIP and Non UIP samples differs drastically between smokers and non-smokers (64 differentially expressed in samples from smokers, 671 differentially expressed in samples from non-smokers) ( FIG.  8   ). Moreover, certain genes that were differentially upregulated in non-smokers were downregulated on not differentially expressed in smokers ( FIGS.  9  and  10   ). These data demonstrate that certain genes that are useful in UIP classification of samples from non-smokers are not informative, or can be contradictory in the diagnosis of the same disease, in smokers. Smoker-status differences in gene expression can reduce the performance of gene expression classifier predictions generated using traditional 2-class machine learning methods. We overcome this problem using three different techniques that are optionally combined or used individually in combination with the UIP vs. Non-UIP classifiers and methods of diagnosis UIP vs. Non-UIP via the diagnostic methods disclosed herein. 
     In a first approach, smoking status (smoker vs. non-smoker) is used as a covariate in the model during training. This simple approach boosts signal-to-noise ratio, particularly in data derived from smokers (were noise is higher) and allows data derived from smokers and non-smokers to be combined and used simultaneously. 
     In a second approach, genes that are susceptible to smoker-status bias are identified and excluded, or optionally weighted differently than genes that are not susceptible to such bias, during classifier training. This method enriches the feature space used for training with genes that are not confounded or affected by smoking status. 
     In a third approach, a tiered classification effort is utilized in which an initial classifier is trained to recognize gene signatures that distinguish smokers from non-smokers. Once patient samples are pre-classified as “smoker” or “non-smoker”, distinct classifiers that were each trained to distinguish UIP vs. Non UIP in smokers or non-smokers, respectively, are implemented. Such smoker or non-smoker-specific classifiers provide improved diagnostic performance. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Differentially expressed genes in UIP vs. Non-UIP samples, irrespective of smoker status. 
               
               
                 Table 9. All samples 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 log2 Fold 
                   
                   
               
               
                   
                   
                   
                 Change 
                   
                 FDR 
               
               
                 Ensembl ID 
                 Entrez ID 
                 Gene symbol 
                 (UIP/NonUIP) 
                 p value 
                 p value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 ENSG00000204256 
                 6046 
                 BRD2 
                 −0.30 
                 4.03E−11 
                 6.40E−07 
               
               
                 ENSG00000129204 
                 9098 
                 USP6 
                 1.88 
                 2.57E−10 
                 2.04E−06 
               
               
                 ENSG00000148357 
                 256158 
                 HMCN2 
                 1.71 
                 1.62E−08 
                 8.58E−05 
               
               
                 ENSG00000178031 
                 92949 
                 ADAMTSL1 
                 1.69 
                 1.23E−07 
                 4.83E−04 
               
               
                 ENSG00000112130 
                 9025 
                 RNF8 
                 −0.40 
                 1.52E−07 
                 4.83E−04 
               
               
                 ENSG00000197705 
                 57565 
                 KLHL14 
                 1.58 
                 1.97E−07 
                 5.21E−04 
               
               
                 ENSG00000204632 
                 3135 
                 HLA-G 
                 −1.65 
                 4.51E−07 
                 1.02E−03 
               
               
                 ENSG00000157064 
                 23057 
                 NMNAT2 
                 1.47 
                 6.62E−07 
                 1.31E−03 
               
               
                 ENSG00000112245 
                 7803 
                 PTP4A1 
                 −0.59 
                 1.38E−06 
                 2.43E−03 
               
               
                 ENSG00000114115 
                 5947 
                 RBP1 
                 0.95 
                 1.69E−06 
                 2.68E−03 
               
               
                 ENSG00000152413 
                 9456 
                 HOMER1 
                 −0.48 
                 2.30E−06 
                 3.32E−03 
               
               
                 ENSG00000143603 
                 3782 
                 KCNN3 
                 0.81 
                 2.85E−06 
                 3.54E−03 
               
               
                 ENSG00000198074 
                 57016 
                 AKR1B10 
                 −1.48 
                 2.90E−06 
                 3.54E−03 
               
               
                 ENSG00000160007 
                 2909 
                 ARHGAP35 
                 −0.28 
                 4.24E−06 
                 4.49E−03 
               
               
                 ENSG00000076053 
                 10179 
                 RBM7 
                 −0.30 
                 4.23E−06 
                 4.49E−03 
               
               
                 ENSG00000085563 
                 5243 
                 ABCB1 
                 1.40 
                 5.90E−06 
                 5.55E−03 
               
               
                 ENSG00000047365 
                 116984 
                 ARAP2 
                 −0.60 
                 5.95E−06 
                 5.55E−03 
               
               
                 ENSG00000130600 
                 283120 
                 H19 
                 1.45 
                 7.10E−06 
                 5.68E−03 
               
               
                 ENSG00000131355 
                 84658 
                 ADGRE3 
                 1.43 
                 7.22E−06 
                 5.68E−03 
               
               
                 ENSG00000135837 
                 9857 
                 CEP350 
                 −0.23 
                 6.63E−06 
                 5.68E−03 
               
               
                 ENSG00000102221 
                 9767 
                 JADE3 
                 −0.42 
                 7.52E−06 
                 5.68E−03 
               
               
                 ENSG00000105784 
                 154661 
                 RUNDC3B 
                 1.31 
                 1.02E−05 
                 6.94E−03 
               
               
                 ENSG00000198734 
                 2153 
                 F5 
                 0.96 
                 1.05E−05 
                 6.94E−03 
               
               
                 ENSG00000124226 
                 55905 
                 RNF114 
                 −0.39 
                 1.04E−05 
                 6.94E−03 
               
               
                 ENSG00000106852 
                 26468 
                 LHX6 
                 1.16 
                 1.12E−05 
                 7.10E−03 
               
               
                 ENSG00000183454 
                 2903 
                 GRIN2A 
                 1.41 
                 1.47E−05 
                 8.93E−03 
               
               
                 ENSG00000170153 
                 57484 
                 RNF150 
                 1.04 
                 1.54E−05 
                 8.93E−03 
               
               
                 ENSG00000187527 
                 344905 
                 ATP13A5 
                 −1.39 
                 1.58E−05 
                 8.93E−03 
               
               
                 ENSG00000244734 
                 3043 
                 HBB 
                 1.40 
                 1.71E−05 
                 9.05E−03 
               
               
                 ENSG00000204936 
                 57126 
                 CD177 
                 1.40 
                 1.67E−05 
                 9.05E−03 
               
               
                 ENSG00000136560 
                 10010 
                 TANK 
                 −0.37 
                 2.26E−05 
                 1.16E−02 
               
               
                 ENSG00000196562 
                 55959 
                 SULF2 
                 0.98 
                 2.87E−05 
                 1.42E−02 
               
               
                 ENSG00000151789 
                 79750 
                 ZNF385D 
                 1.36 
                 3.17E−05 
                 1.44E−02 
               
               
                 ENSG00000145808 
                 171019 
                 ADAMTS19 
                 1.07 
                 3.14E−05 
                 1.44E−02 
               
               
                 ENSG00000177666 
                 57104 
                 PNPLA2 
                 −0.53 
                 3.00E−05 
                 1.44E−02 
               
               
                 ENSG00000007312 
                 974 
                 CD79B 
                 1.31 
                 3.51E−05 
                 1.47E−02 
               
               
                 ENSG00000104213 
                 5157 
                 PDGFRL 
                 1.24 
                 3.53E−05 
                 1.47E−02 
               
               
                 ENSG00000023171 
                 57476 
                 GRAMD1B 
                 −0.86 
                 3.41E−05 
                 1.47E−02 
               
               
                 ENSG00000117322 
                 1380 
                 CR2 
                 1.31 
                 4.37E−05 
                 1.78E−02 
               
               
                 ENSG00000171724 
                 57687 
                 VAT1L 
                 1.33 
                 4.51E−05 
                 1.79E−02 
               
               
                 ENSG00000108852 
                 4355 
                 MPP2 
                 1.21 
                 4.84E−05 
                 1.87E−02 
               
               
                 ENSG00000136098 
                 4752 
                 NEK3 
                 0.51 
                 5.00E−05 
                 1.89E−02 
               
               
                 ENSG00000189056 
                 5649 
                 RELN 
                 1.29 
                 5.13E−05 
                 1.89E−02 
               
               
                 ENSG00000054938 
                 25884 
                 CHRDL2 
                 1.30 
                 6.70E−05 
                 2.36E−02 
               
               
                 ENSG00000132704 
                 79368 
                 FCRL2 
                 1.30 
                 6.62E−05 
                 2.36E−02 
               
               
                 ENSG00000196628 
                 6925 
                 TCF4 
                 0.50 
                 7.00E−05 
                 2.41E−02 
               
               
                 ENSG00000142856 
                 23421 
                 ITGB3BP 
                 0.55 
                 7.32E−05 
                 2.47E−02 
               
               
                 ENSG00000136153 
                 4008 
                 LMO7 
                 −0.80 
                 8.61E−05 
                 2.85E−02 
               
               
                 ENSG00000203867 
                 282996 
                 RBM20 
                 1.20 
                 9.01E−05 
                 2.92E−02 
               
               
                 ENSG00000171049 
                 2358 
                 FPR2 
                 1.26 
                 9.26E−05 
                 2.94E−02 
               
               
                 ENSG00000152953 
                 55351 
                 STK32B 
                 1.23 
                 9.47E−05 
                 2.95E−02 
               
               
                 ENSG00000099968 
                 23786 
                 BCL2L13 
                 −0.37 
                 9.73E−05 
                 2.97E−02 
               
               
                 ENSG00000188536 
                 3040 
                 HBA2 
                 1.26 
                 1.03E−04 
                 3.00E−02 
               
               
                 ENSG00000198569 
                 142680 
                 SLC34A3 
                 0.94 
                 1.04E−04 
                 3.00E−02 
               
               
                 ENSG00000163701 
                 132014 
                 IL17RE 
                 −0.60 
                 1.02E−04 
                 3.00E−02 
               
               
                 ENSG00000197614 
                 8076 
                 MFAP5 
                 1.25 
                 1.10E−04 
                 3.12E−02 
               
               
                 ENSG00000146021 
                 26249 
                 KLHL3 
                 0.84 
                 1.15E−04 
                 3.19E−02 
               
               
                 ENSG00000156103 
                 4325 
                 MMP16 
                 1.25 
                 1.21E−04 
                 3.24E−02 
               
               
                 ENSG00000185022 
                 23764 
                 MAFF 
                 −1.05 
                 1.20E−04 
                 3.24E−02 
               
               
                 ENSG00000088882 
                 56265 
                 CPXM1 
                 1.22 
                 1.32E−04 
                 3.49E−02 
               
               
                 ENSG00000163032 
                 7447 
                 VSNL1 
                 0.78 
                 1.38E−04 
                 3.58E−02 
               
               
                 ENSG00000186184 
                 51082 
                 POLR1D 
                 −0.47 
                 1.40E−04 
                 3.58E−02 
               
               
                 ENSG00000177106 
                 64787 
                 EPS8L2 
                 −0.52 
                 1.42E−04 
                 3.58E−02 
               
               
                 ENSG00000214711 
                 440854 
                 CAPN14 
                 1.23 
                 1.44E−04 
                 3.58E−02 
               
               
                 ENSG00000113212 
                 56129 
                 PCDHB7 
                 1.04 
                 1.51E−04 
                 3.64E−02 
               
               
                 ENSG00000001629 
                 54467 
                 ANKIB1 
                 −0.22 
                 1.52E−04 
                 3.64E−02 
               
               
                 ENSG00000180871 
                 3579 
                 CXCR2 
                 1.20 
                 1.79E−04 
                 4.17E−02 
               
               
                 ENSG00000065618 
                 1308 
                 COL17A1 
                 1.04 
                 1.79E−04 
                 4.17E−02 
               
               
                 ENSG00000008394 
                 4257 
                 MGST1 
                 −0.59 
                 1.81E−04 
                 4.17E−02 
               
               
                 ENSG00000185046 
                 56899 
                 ANKS1B 
                 1.01 
                 2.16E−04 
                 4.82E−02 
               
               
                 ENSG00000165949 
                 3429 
                 IFI27 
                 −1.05 
                 2.14E−04 
                 4.82E−02 
               
               
                 ENSG00000186847 
                 3861 
                 KRT14 
                 1.20 
                 2.30E−04 
                 5.04E−02 
               
               
                 ENSG00000136929 
                 55363 
                 HEMGN 
                 1.19 
                 2.35E−04 
                 5.04E−02 
               
               
                 ENSG00000167107 
                 80221 
                 ACSF2 
                 −0.55 
                 2.35E−04 
                 5.04E−02 
               
               
                 ENSG00000169129 
                 84632 
                 AFAP1L2 
                 0.87 
                 2.45E−04 
                 5.19E−02 
               
               
                 ENSG00000134762 
                 1825 
                 DSC3 
                 1.10 
                 2.86E−04 
                 5.88E−02 
               
               
                 ENSG00000212743 
                 NA 
                   
                 0.96 
                 2.85E−04 
                 5.88E−02 
               
               
                 ENSG00000149575 
                 6327 
                 SCN2B 
                 1.13 
                 3.00E−04 
                 6.10E−02 
               
               
                 ENSG00000188257 
                 5320 
                 PLA2G2A 
                 1.16 
                 3.22E−04 
                 6.15E−02 
               
               
                 ENSG00000102935 
                 23090 
                 ZNF423 
                 1.02 
                 3.15E−04 
                 6.15E−02 
               
               
                 ENSG00000143320 
                 1382 
                 CRABP2 
                 0.99 
                 3.22E−04 
                 6.15E−02 
               
               
                 ENSG00000138660 
                 55435 
                 AP1AR 
                 −0.49 
                 3.07E−04 
                 6.15E−02 
               
               
                 ENSG00000157601 
                 4599 
                 MX1 
                 −0.88 
                 3.15E−04 
                 6.15E−02 
               
               
                 ENSG00000171847 
                 55138 
                 FAM90A1 
                 0.80 
                 3.36E−04 
                 6.22E−02 
               
               
                 ENSG00000115461 
                 3488 
                 IGFBP5 
                 0.71 
                 3.37E−04 
                 6.22E−02 
               
               
                 ENSG00000151632 
                 1646 
                 AKR1C2 
                 −1.17 
                 3.36E−04 
                 6.22E−02 
               
               
                 ENSG00000189306 
                 27341 
                 RRP7A 
                 0.44 
                 3.42E−04 
                 6.24E−02 
               
               
                 ENSG00000148541 
                 220965 
                 FAM13C 
                 0.72 
                 3.60E−04 
                 6.49E−02 
               
               
                 ENSG00000111725 
                 5564 
                 PRKAB1 
                 −0.49 
                 3.65E−04 
                 6.50E−02 
               
               
                 ENSG00000182885 
                 222487 
                 ADGRG3 
                 1.15 
                 3.74E−04 
                 6.54E−02 
               
               
                 ENSG00000206172 
                 3039 
                 HBA1 
                 1.15 
                 3.80E−04 
                 6.54E−02 
               
               
                 ENSG00000157502 
                 139221 
                 MUM1L1 
                 1.09 
                 3.77E−04 
                 6.54E−02 
               
               
                 ENSG00000169891 
                 9185 
                 REPS2 
                 −0.46 
                 3.88E−04 
                 6.54E−02 
               
               
                 ENSG00000129437 
                 43847 
                 KLK14 
                 −1.09 
                 3.85E−04 
                 6.54E−02 
               
               
                 ENSG00000211956 
                 NA 
                 IGHV4-34 
                 1.15 
                 3.93E−04 
                 6.57E−02 
               
               
                 ENSG00000106483 
                 6424 
                 SFRP4 
                 1.15 
                 4.19E−04 
                 6.75E−02 
               
               
                 ENSG00000175879 
                 3234 
                 HOXD8 
                 1.13 
                 4.36E−04 
                 6.75E−02 
               
               
                 ENSG00000166947 
                 2038 
                 EPB42 
                 1.04 
                 4.35E−04 
                 6.75E−02 
               
               
                 ENSG00000028310 
                 65980 
                 BRD9 
                 0.17 
                 4.15E−04 
                 6.75E−02 
               
               
                 ENSG00000134046 
                 8932 
                 MBD2 
                 −0.18 
                 4.39E−04 
                 6.75E−02 
               
               
                 ENSG00000011007 
                 6924 
                 TCEB3 
                 −0.29 
                 4.10E−04 
                 6.75E−02 
               
               
                 ENSG00000198722 
                 10497 
                 UNC13B 
                 −0.46 
                 4.24E−04 
                 6.75E−02 
               
               
                 ENSG00000182795 
                 79098 
                 C1orf116 
                 −0.80 
                 4.33E−04 
                 6.75E−02 
               
               
                 ENSG00000110042 
                 23220 
                 DTX4 
                 −0.40 
                 4.44E−04 
                 6.78E−02 
               
               
                 ENSG00000169612 
                 83640 
                 FAM103A1 
                 −0.67 
                 4.56E−04 
                 6.88E−02 
               
               
                 ENSG00000139517 
                 222484 
                 LNX2 
                 −0.38 
                 4.66E−04 
                 6.98E−02 
               
               
                 ENSG00000165966 
                 29951 
                 PDZRN4 
                 1.14 
                 4.80E−04 
                 7.01E−02 
               
               
                 ENSG00000196109 
                 163223 
                 ZNF676 
                 1.12 
                 4.81E−04 
                 7.01E−02 
               
               
                 ENSG00000188517 
                 84570 
                 COL25A1 
                 1.12 
                 4.86E−04 
                 7.01E−02 
               
               
                 ENSG00000121898 
                 119587 
                 CPXM2 
                 1.07 
                 4.83E−04 
                 7.01E−02 
               
               
                 ENSG00000185739 
                 6345 
                 SRL 
                 1.13 
                 5.01E−04 
                 7.10E−02 
               
               
                 ENSG00000166033 
                 5654 
                 HTRA1 
                 0.82 
                 4.98E−04 
                 7.10E−02 
               
               
                 ENSG00000179772 
                 2307 
                 FOXS1 
                 1.13 
                 5.20E−04 
                 7.17E−02 
               
               
                 ENSG00000172137 
                 794 
                 CALB2 
                 1.13 
                 5.19E−04 
                 7.17E−02 
               
               
                 ENSG00000086544 
                 80271 
                 ITPKC 
                 −0.42 
                 5.15E−04 
                 7.17E−02 
               
               
                 ENSG00000130513 
                 9518 
                 GDF15 
                 −1.04 
                 5.29E−04 
                 7.17E−02 
               
               
                 ENSG00000129451 
                 5655 
                 KLK10 
                 −1.05 
                 5.26E−04 
                 7.17E−02 
               
               
                 ENSG00000109472 
                 1363 
                 CPE 
                 1.03 
                 5.40E−04 
                 7.20E−02 
               
               
                 ENSG00000171206 
                 81603 
                 TRIM8 
                 −0.30 
                 5.38E−04 
                 7.20E−02 
               
               
                 ENSG00000128285 
                 2847 
                 MCHR1 
                 1.09 
                 5.60E−04 
                 7.40E−02 
               
               
                 ENSG00000197993 
                 3792 
                 KEL 
                 1.08 
                 5.68E−04 
                 7.45E−02 
               
               
                 ENSG00000138642 
                 55008 
                 HERC6 
                 −0.82 
                 5.78E−04 
                 7.51E−02 
               
               
                 ENSG00000162729 
                 93185 
                 IGSF8 
                 0.32 
                 5.93E−04 
                 7.65E−02 
               
               
                 ENSG00000105369 
                 973 
                 CD79A 
                 1.11 
                 6.54E−04 
                 7.67E−02 
               
               
                 ENSG00000146374 
                 84870 
                 RSPO3 
                 1.11 
                 6.56E−04 
                 7.67E−02 
               
               
                 ENSG00000167483 
                 199786 
                 FAM129C 
                 1.11 
                 6.75E−04 
                 7.67E−02 
               
               
                 ENSG00000205038 
                 93035 
                 PKHD1L1 
                 1.07 
                 6.67E−04 
                 7.67E−02 
               
               
                 ENSG00000158560 
                 1780 
                 DYNC1I1 
                 1.07 
                 6.63E−04 
                 7.67E−02 
               
               
                 ENSG00000101000 
                 10544 
                 PROCR 
                 1.04 
                 6.65E−04 
                 7.67E−02 
               
               
                 ENSG00000197410 
                 54798 
                 DCHS2 
                 1.03 
                 6.66E−04 
                 7.67E−02 
               
               
                 ENSG00000137573 
                 23213 
                 SULF1 
                 1.02 
                 6.74E−04 
                 7.67E−02 
               
               
                 ENSG00000091972 
                 4345 
                 CD200 
                 1.01 
                 6.81E−04 
                 7.67E−02 
               
               
                 ENSG00000161381 
                 57125 
                 PLXDC1 
                 0.97 
                 6.23E−04 
                 7.67E−02 
               
               
                 ENSG00000067840 
                 57595 
                 PDZD4 
                 0.94 
                 6.64E−04 
                 7.67E−02 
               
               
                 ENSG00000244363 
                 NA 
                 RPL7P23 
                 0.77 
                 6.71E−04 
                 7.67E−02 
               
               
                 ENSG00000141698 
                 115024 
                 NT5C3B 
                 0.41 
                 6.51E−04 
                 7.67E−02 
               
               
                 ENSG00000184056 
                 26276 
                 VPS33B 
                 0.24 
                 6.73E−04 
                 7.67E−02 
               
               
                 ENSG00000226742 
                 440498 
                 HSBP1L1 
                 −0.37 
                 6.66E−04 
                 7.67E−02 
               
               
                 ENSG00000064666 
                 1265 
                 CNN2 
                 −0.38 
                 6.73E−04 
                 7.67E−02 
               
               
                 ENSG00000198142 
                 65124 
                 SOWAHC 
                 −0.53 
                 6.36E−04 
                 7.67E−02 
               
               
                 ENSG00000198183 
                 51297 
                 BPIFA1 
                 −1.09 
                 6.79E−04 
                 7.67E−02 
               
               
                 ENSG00000185271 
                 123103 
                 KLHL33 
                 1.10 
                 7.36E−04 
                 7.96E−02 
               
               
                 ENSG00000143248 
                 8490 
                 RGS5 
                 1.10 
                 7.26E−04 
                 7.96E−02 
               
               
                 ENSG00000106018 
                 7434 
                 VIPR2 
                 1.10 
                 7.45E−04 
                 7.96E−02 
               
               
                 ENSG00000168542 
                 1281 
                 COL3A1 
                 1.10 
                 7.33E−04 
                 7.96E−02 
               
               
                 ENSG00000186105 
                 100130733 
                 LRRC70 
                 0.93 
                 7.44E−04 
                 7.96E−02 
               
               
                 ENSG00000265150 
                 NA 
                 NA 
                 0.87 
                 7.23E−04 
                 7.96E−02 
               
               
                 ENSG00000172840 
                 57546 
                 PDP2 
                 −0.34 
                 7.47E−04 
                 7.96E−02 
               
               
                 ENSG00000156675 
                 80223 
                 RAB11FIP1 
                 −0.61 
                 7.27E−04 
                 7.96E−02 
               
               
                 ENSG00000108001 
                 253738 
                 EBF3 
                 1.10 
                 7.84E−04 
                 8.11E−02 
               
               
                 ENSG00000114948 
                 8745 
                 ADAM23 
                 1.08 
                 7.82E−04 
                 8.11E−02 
               
               
                 ENSG00000106404 
                 24146 
                 CLDN15 
                 1.08 
                 7.73E−04 
                 8.11E−02 
               
               
                 ENSG00000139910 
                 4857 
                 NOVA1 
                 1.07 
                 7.92E−04 
                 8.11E−02 
               
               
                 ENSG00000146802 
                 64418 
                 TMEM168 
                 0.33 
                 7.92E−04 
                 8.11E−02 
               
               
                 ENSG00000183486 
                 4600 
                 MX2 
                 −0.91 
                 7.89E−04 
                 8.11E−02 
               
               
                 ENSG00000157766 
                 176 
                 ACAN 
                 1.08 
                 8.06E−04 
                 8.16E−02 
               
               
                 ENSG00000214174 
                 201283 
                 AMZ2P1 
                 −0.54 
                 8.08E−04 
                 8.16E−02 
               
               
                 ENSG00000185305 
                 54622 
                 ARL15 
                 0.67 
                 8.21E−04 
                 8.19E−02 
               
               
                 ENSG00000137709 
                 25833 
                 POU2F3 
                 −0.67 
                 8.17E−04 
                 8.19E−02 
               
               
                 ENSG00000117707 
                 5629 
                 PROX1 
                 0.99 
                 8.39E−04 
                 8.31E−02 
               
               
                 ENSG00000144619 
                 152330 
                 CNTN4 
                 0.77 
                 8.54E−04 
                 8.41E−02 
               
               
                 ENSG00000158578 
                 212 
                 ALAS2 
                 1.08 
                 8.94E−04 
                 8.58E−02 
               
               
                 ENSG00000228570 
                 NA 
                 NUTM2E 
                 1.08 
                 9.23E−04 
                 8.58E−02 
               
               
                 ENSG00000163735 
                 6374 
                 CXCL5 
                 1.08 
                 9.30E−04 
                 8.58E−02 
               
               
                 ENSG00000167476 
                 126306 
                 JSRP1 
                 1.07 
                 9.11E−04 
                 8.58E−02 
               
               
                 ENSG00000116833 
                 2494 
                 NR5A2 
                 1.06 
                 8.81E−04 
                 8.58E−02 
               
               
                 ENSG00000120322 
                 56128 
                 PCDHB8 
                 1.05 
                 9.31E−04 
                 8.58E−02 
               
               
                 ENSG00000238741 
                 677767 
                 SCARNA7 
                 0.37 
                 9.26E−04 
                 8.58E−02 
               
               
                 ENSG00000169093 
                 8623 
                 ASMTL 
                 0.23 
                 9.12E−04 
                 8.58E−02 
               
               
                 ENSG00000081026 
                 260425 
                 MAGI3 
                 −0.61 
                 9.06E−04 
                 8.58E−02 
               
               
                 ENSG00000103528 
                 51760 
                 SYT17 
                 −0.62 
                 9.00E−04 
                 8.58E−02 
               
               
                 ENSG00000100033 
                 5625 
                 PRODH 
                 −0.81 
                 9.09E−04 
                 8.58E−02 
               
               
                 ENSG00000165868 
                 259217 
                 HSPA12A 
                 0.86 
                 9.54E−04 
                 8.75E−02 
               
               
                 ENSG00000163251 
                 7855 
                 FZD5 
                 −0.74 
                 9.87E−04 
                 9.00E−02 
               
               
                 ENSG00000122140 
                 51116 
                 MRPS2 
                 −0.38 
                 9.93E−04 
                 9.00E−02 
               
               
                 ENSG00000171792 
                 83695 
                 RHNO1 
                 −0.48 
                 1.00E−03 
                 9.02E−02 
               
               
                 ENSG00000104369 
                 56704 
                 JPH1 
                 −0.58 
                 1.03E−03 
                 9.20E−02 
               
               
                 ENSG00000168079 
                 286133 
                 SCARA5 
                 1.07 
                 1.03E−03 
                 9.21E−02 
               
               
                 ENSG00000092295 
                 7051 
                 TGM1 
                 1.00 
                 1.04E−03 
                 9.22E−02 
               
               
                 ENSG00000106809 
                 4969 
                 OGN 
                 1.07 
                 1.06E−03 
                 9.35E−02 
               
               
                 ENSG00000163534 
                 115350 
                 FCRL1 
                 1.06 
                 1.11E−03 
                 9.44E−02 
               
               
                 ENSG00000091137 
                 5172 
                 SLC26A4 
                 1.00 
                 1.10E−03 
                 9.44E−02 
               
               
                 ENSG00000099958 
                 91319 
                 DERL3 
                 0.89 
                 1.15E−03 
                 9.44E−02 
               
               
                 ENSG00000153253 
                 6328 
                 SCN3A 
                 0.82 
                 1.16E−03 
                 9.44E−02 
               
               
                 ENSG00000251402 
                 NA 
                 FAM90A25P 
                 0.74 
                 1.12E−03 
                 9.44E−02 
               
               
                 ENSG00000120327 
                 56122 
                 PCDHB14 
                 0.72 
                 1.09E−03 
                 9.44E−02 
               
               
                 ENSG00000138795 
                 51176 
                 LEF1 
                 0.64 
                 1.13E−03 
                 9.44E−02 
               
               
                 ENSG00000144040 
                 94097 
                 SFXN5 
                 0.44 
                 1.12E−03 
                 9.44E−02 
               
               
                 ENSG00000155463 
                 5018 
                 OXA1L 
                 −0.20 
                 1.15E−03 
                 9.44E−02 
               
               
                 ENSG00000136830 
                 64855 
                 FAM129B 
                 −0.24 
                 1.15E−03 
                 9.44E−02 
               
               
                 ENSG00000141452 
                 29919 
                 C18orf8 
                 −0.30 
                 1.15E−03 
                 9.44E−02 
               
               
                 ENSG00000148730 
                 1979 
                 EIF4EBP2 
                 −0.33 
                 1.12E−03 
                 9.44E−02 
               
               
                 ENSG00000115415 
                 6772 
                 STAT1 
                 −0.86 
                 1.10E−03 
                 9.44E−02 
               
               
                 ENSG00000126709 
                 2537 
                 IFI6 
                 −1.03 
                 1.15E−03 
                 9.44E−02 
               
               
                 ENSG00000095951 
                 3096 
                 HIVEP1 
                 −0.24 
                 1.20E−03 
                 9.76E−02 
               
               
                 ENSG00000187942 
                 401944 
                 LDLRAD2 
                 0.97 
                 1.21E−03 
                 9.80E−02 
               
               
                 ENSG00000105928 
                 1687 
                 DFNA5 
                 0.83 
                 1.22E−03 
                 9.81E−02 
               
               
                 ENSG00000224397 
                 NA 
                 LINC01272 
                 1.02 
                 1.23E−03 
                 9.83E−02 
               
               
                 ENSG00000170011 
                 25924 
                 MYRIP 
                 0.86 
                 1.32E−03 
                 1.00E−01 
               
               
                 ENSG00000120784 
                 22835 
                 ZFP30 
                 0.37 
                 1.30E−03 
                 1.00E−01 
               
               
                 ENSG00000170185 
                 84640 
                 USP38 
                 −0.26 
                 1.31E−03 
                 1.00E−01 
               
               
                 ENSG00000076513 
                 88455 
                 ANKRD13A 
                 −0.31 
                 1.26E−03 
                 1.00E−01 
               
               
                 ENSG00000135148 
                 10906 
                 TRAFD1 
                 −0.32 
                 1.28E−03 
                 1.00E−01 
               
               
                 ENSG00000170085 
                 375484 
                 SIMC1 
                 −0.43 
                 1.32E−03 
                 1.00E−01 
               
               
                 ENSG00000175324 
                 27257 
                 LSM1 
                 −0.45 
                 1.30E−03 
                 1.00E−01 
               
               
                 ENSG00000141738 
                 2886 
                 GRB7 
                 −0.54 
                 1.28E−03 
                 1.00E−01 
               
               
                 ENSG00000088002 
                 6820 
                 SULT2B1 
                 −0.75 
                 1.28E−03 
                 1.00E−01 
               
               
                 ENSG00000010030 
                 51513 
                 ETV7 
                 −0.86 
                 1.29E−03 
                 1.00E−01 
               
               
                 ENSG00000137959 
                 10964 
                 IFI44L 
                 −1.01 
                 1.27E−03 
                 1.00E−01 
               
               
                   
               
               
                 UIP (n = 9 samples); Non UIP (n = 15 samples). Positive log2 fold change value indicates over- expression in UIP relative to Non UIP; negative log2 value indicates under-expression in UIP relative to Non UIP. In this analysis the smoking history status of the patients involved was not evaluated, and the cohort harbored both smokers and non-smokers. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Differentially expressed genes in non-smoker UIP vs. non-smoker Non-UIP samples. 
               
               
                 Table 10. Non-smokers 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Log2 Fold 
                   
                   
               
               
                   
                   
                   
                 Change 
               
               
                 Ensembl ID 
                 Entrez ID 
                 Gene symbol 
                 (UIP/NonUIP) 
                 P value 
                 FDR P value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 ENSG00000133687 
                 83857 
                 TMTC1 
                 1.72 
                 4.52E−21 
                 6.68E−17 
               
               
                 ENSG00000169129 
                 84632 
                 AFAP1L2 
                 1.63 
                 1.62E−19 
                 1.19E−15 
               
               
                 ENSG00000180229 
                 283755 
                 HERC2P3 
                 2.52 
                 9.77E−15 
                 4.81E−11 
               
               
                 ENSG00000107518 
                 26033 
                 ATRNL1 
                 3.00 
                 2.49E−14 
                 9.21E−11 
               
               
                 ENSG00000198380 
                 2673 
                 GFPT1 
                 −0.62 
                 9.55E−14 
                 2.35E−10 
               
               
                 ENSG00000211976 
                 NA 
                 IGHV3-73 
                 2.21 
                 9.47E−14 
                 2.35E−10 
               
               
                 ENSG00000114902 
                 28972 
                 SPCS1 
                 −0.64 
                 1.99E−12 
                 4.20E−09 
               
               
                 ENSG00000108001 
                 253738 
                 EBF3 
                 2.77 
                 3.39E−12 
                 6.27E−09 
               
               
                 ENSG00000154122 
                 56172 
                 ANKH 
                 1.02 
                 4.17E−12 
                 6.85E−09 
               
               
                 ENSG00000012660 
                 60481 
                 ELOVL5 
                 −0.66 
                 6.94E−12 
                 1.03E−08 
               
               
                 ENSG00000119888 
                 4072 
                 EPCAM 
                 −1.04 
                 8.67E−12 
                 1.16E−08 
               
               
                 ENSG00000147676 
                 114569 
                 MAL2 
                 −1.08 
                 1.83E−11 
                 1.94E−08 
               
               
                 ENSG00000148357 
                 256158 
                 HMCN2 
                 1.99 
                 1.62E−11 
                 1.94E−08 
               
               
                 ENSG00000185499 
                 4582 
                 MUC1 
                 −1.09 
                 1.84E−11 
                 1.94E−08 
               
               
                 ENSG00000157557 
                 2114 
                 ETS2 
                 0.73 
                 8.18E−11 
                 8.06E−08 
               
               
                 ENSG00000151789 
                 79750 
                 ZNF385D 
                 2.73 
                 1.04E−10 
                 9.62E−08 
               
               
                 ENSG00000213088 
                 2532 
                 ACKR1 
                 2.18 
                 3.53E−10 
                 3.06E−07 
               
               
                 ENSG00000038210 
                 55300 
                 PI4K2B 
                 −0.77 
                 4.14E−10 
                 3.40E−07 
               
               
                 ENSG00000105426 
                 5802 
                 PTPRS 
                 0.80 
                 9.94E−10 
                 7.73E−07 
               
               
                 ENSG00000100034 
                 9647 
                 PPM1F 
                 1.27 
                 1.17E−09 
                 8.14E−07 
               
               
                 ENSG00000112562 
                 64094 
                 SMOC2 
                 1.70 
                 1.21E−09 
                 8.14E−07 
               
               
                 ENSG00000139211 
                 347902 
                 AMIGO2 
                 0.93 
                 1.15E−09 
                 8.14E−07 
               
               
                 ENSG00000130158 
                 57572 
                 DOCK6 
                 0.75 
                 1.42E−09 
                 9.10E−07 
               
               
                 ENSG00000124145 
                 6385 
                 SDC4 
                 −0.67 
                 2.44E−09 
                 1.44E−06 
               
               
                 ENSG00000129255 
                 9526 
                 MPDU1 
                 −0.54 
                 2.44E−09 
                 1.44E−06 
               
               
                 ENSG00000100219 
                 7494 
                 XBP1 
                 −1.02 
                 2.76E−09 
                 1.48E−06 
               
               
                 ENSG00000120318 
                 64411 
                 ARAP3 
                 0.93 
                 2.80E−09 
                 1.48E−06 
               
               
                 ENSG00000144136 
                 6574 
                 SLC20A1 
                 −0.65 
                 2.63E−09 
                 1.48E−06 
               
               
                 ENSG00000140873 
                 170692 
                 ADAMTS18 
                 2.27 
                 3.32E−09 
                 1.69E−06 
               
               
                 ENSG00000120693 
                 4093 
                 SMAD9 
                 1.43 
                 4.04E−09 
                 1.99E−06 
               
               
                 ENSG00000080007 
                 55510 
                 DDX43 
                 −2.11 
                 6.55E−09 
                 3.12E−06 
               
               
                 ENSG00000105737 
                 2901 
                 GRIK5 
                 2.34 
                 8.09E−09 
                 3.54E−06 
               
               
                 ENSG00000157064 
                 23057 
                 NMNAT2 
                 2.14 
                 8.14E−09 
                 3.54E−06 
               
               
                 ENSG00000161381 
                 57125 
                 PLXDC1 
                 1.21 
                 7.73E−09 
                 3.54E−06 
               
               
                 ENSG00000154736 
                 11096 
                 ADAMTS5 
                 1.92 
                 1.01E−08 
                 4.13E−06 
               
               
                 ENSG00000185046 
                 56899 
                 ANKS1B 
                 1.51 
                 9.78E−09 
                 4.13E−06 
               
               
                 ENSG00000104213 
                 5157 
                 PDGFRL 
                 2.09 
                 1.19E−08 
                 4.52E−06 
               
               
                 ENSG00000166398 
                 9710 
                 KIAA0355 
                 0.82 
                 1.19E−08 
                 4.52E−06 
               
               
                 ENSG00000189058 
                 347 
                 APOD 
                 1.55 
                 1.14E−08 
                 4.52E−06 
               
               
                 ENSG00000102935 
                 23090 
                 ZNF423 
                 1.47 
                 1.34E−08 
                 4.86E−06 
               
               
                 ENSG00000111145 
                 2004 
                 ELK3 
                 0.89 
                 1.35E−08 
                 4.86E−06 
               
               
                 ENSG00000138160 
                 3832 
                 KIF11 
                 −1.35 
                 1.44E−08 
                 5.06E−06 
               
               
                 ENSG00000197147 
                 23507 
                 LRRC8B 
                 −0.89 
                 1.80E−08 
                 6.19E−06 
               
               
                 ENSG00000131386 
                 117248 
                 GALNT15 
                 2.41 
                 1.95E−08 
                 6.39E−06 
               
               
                 ENSG00000177839 
                 56127 
                 PCDHB9 
                 1.87 
                 1.91E−08 
                 6.39E−06 
               
               
                 ENSG00000114446 
                 55081 
                 IFT57 
                 −0.65 
                 2.20E−08 
                 7.06E−06 
               
               
                 ENSG00000198932 
                 9737 
                 GPRASP1 
                 0.90 
                 2.34E−08 
                 7.36E−06 
               
               
                 ENSG00000178031 
                 92949 
                 ADAMTSL1 
                 2.30 
                 2.50E−08 
                 7.70E−06 
               
               
                 ENSG00000230989 
                 3281 
                 HSBP1 
                 −0.74 
                 2.59E−08 
                 7.80E−06 
               
               
                 ENSG00000100065 
                 29775 
                 CARD10 
                 1.69 
                 2.91E−08 
                 8.60E−06 
               
               
                 ENSG00000142798 
                 3339 
                 HSPG2 
                 1.20 
                 3.13E−08 
                 9.06E−06 
               
               
                 ENSG00000134533 
                 85004 
                 RERG 
                 1.68 
                 3.70E−08 
                 1.05E−05 
               
               
                 ENSG00000105784 
                 154661 
                 RUNDC3B 
                 2.28 
                 3.87E−08 
                 1.08E−05 
               
               
                 ENSG00000039068 
                 999 
                 CDH1 
                 −0.87 
                 6.14E−08 
                 1.55E−05 
               
               
                 ENSG00000104549 
                 6713 
                 SQLE 
                 −1.38 
                 6.10E−08 
                 1.55E−05 
               
               
                 ENSG00000105996 
                 3199 
                 HOXA2 
                 1.60 
                 5.72E−08 
                 1.55E−05 
               
               
                 ENSG00000130234 
                 59272 
                 ACE2 
                 −1.52 
                 6.19E−08 
                 1.55E−05 
               
               
                 ENSG00000162881 
                 165140 
                 OXER1 
                 1.30 
                 5.81E−08 
                 1.55E−05 
               
               
                 ENSG00000177098 
                 6330 
                 SCN4B 
                 1.12 
                 6.10E−08 
                 1.55E−05 
               
               
                 ENSG00000007312 
                 974 
                 CD79B 
                 2.13 
                 6.62E−08 
                 1.58E−05 
               
               
                 ENSG00000163898 
                 200879 
                 LIPH 
                 −0.91 
                 6.52E−08 
                 1.58E−05 
               
               
                 ENSG00000189377 
                 284340 
                 CXCL17 
                 −1.17 
                 6.53E−08 
                 1.58E−05 
               
               
                 ENSG00000198814 
                 2710 
                 GK 
                 −0.83 
                 6.79E−08 
                 1.59E−05 
               
               
                 ENSG00000076944 
                 6813 
                 STXBP2 
                 −0.56 
                 7.52E−08 
                 1.71E−05 
               
               
                 ENSG00000153902 
                 163175 
                 LGI4 
                 1.74 
                 7.53E−08 
                 1.71E−05 
               
               
                 ENSG00000117448 
                 10327 
                 AKR1A1 
                 −0.63 
                 7.74E−08 
                 1.73E−05 
               
               
                 ENSG00000164530 
                 221476 
                 PI16 
                 2.17 
                 8.33E−08 
                 1.84E−05 
               
               
                 ENSG00000233297 
                 NA 
                 RASA4DP 
                 2.29 
                 9.09E−08 
                 1.97E−05 
               
               
                 ENSG00000182718 
                 302 
                 ANXA2 
                 −0.62 
                 9.95E−08 
                 2.13E−05 
               
               
                 ENSG00000110455 
                 84680 
                 ACCS 
                 0.98 
                 1.03E−07 
                 2.17E−05 
               
               
                 ENSG00000197253 
                 64499 
                 TPSB2 
                 2.07 
                 1.10E−07 
                 2.29E−05 
               
               
                 ENSG00000125999 
                 92747 
                 BPIFB1 
                 −1.76 
                 1.15E−07 
                 2.37E−05 
               
               
                 ENSG00000211936 
                 NA 
                 NA 
                 2.23 
                 1.22E−07 
                 2.47E−05 
               
               
                 ENSG00000108852 
                 4355 
                 MPP2 
                 1.68 
                 1.28E−07 
                 2.55E−05 
               
               
                 ENSG00000119514 
                 79695 
                 GALNT12 
                 −0.60 
                 1.64E−07 
                 3.18E−05 
               
               
                 ENSG00000146021 
                 26249 
                 KLHL3 
                 1.36 
                 1.63E−07 
                 3.18E−05 
               
               
                 ENSG00000173702 
                 56667 
                 MUC13 
                 −2.33 
                 1.78E−07 
                 3.41E−05 
               
               
                 ENSG00000116748 
                 270 
                 AMPD1 
                 1.80 
                 1.85E−07 
                 3.50E−05 
               
               
                 ENSG00000196411 
                 2050 
                 EPHB4 
                 0.86 
                 2.09E−07 
                 3.91E−05 
               
               
                 ENSG00000086061 
                 3301 
                 DNAJA1 
                 −0.73 
                 2.20E−07 
                 4.07E−05 
               
               
                 ENSG00000074181 
                 4854 
                 NOTCH3 
                 0.92 
                 2.24E−07 
                 4.07E−05 
               
               
                 ENSG00000181234 
                 92293 
                 TMEM132C 
                 2.08 
                 2.26E−07 
                 4.07E−05 
               
               
                 ENSG00000074590 
                 9891 
                 NUAK1 
                 1.27 
                 2.47E−07 
                 4.39E−05 
               
               
                 ENSG00000154263 
                 10349 
                 ABCA10 
                 1.44 
                 2.92E−07 
                 5.14E−05 
               
               
                 ENSG00000186322 
                 NA 
                 NA 
                 1.99 
                 3.30E−07 
                 5.74E−05 
               
               
                 ENSG00000130164 
                 3949 
                 LDLR 
                 −1.00 
                 3.36E−07 
                 5.77E−05 
               
               
                 ENSG00000133935 
                 11161 
                 C14orf1 
                 −0.76 
                 3.54E−07 
                 5.99E−05 
               
               
                 ENSG00000151892 
                 2674 
                 GFRA1 
                 1.96 
                 3.57E−07 
                 5.99E−05 
               
               
                 ENSG00000196628 
                 6925 
                 TCF4 
                 0.93 
                 3.65E−07 
                 6.06E−05 
               
               
                 ENSG00000106070 
                 2887 
                 GRB10 
                 1.22 
                 3.94E−07 
                 6.46E−05 
               
               
                 ENSG00000076555 
                 32 
                 ACACB 
                 1.06 
                 4.48E−07 
                 7.27E−05 
               
               
                 ENSG00000173947 
                 128344 
                 PIFO 
                 −1.26 
                 4.74E−07 
                 7.61E−05 
               
               
                 ENSG00000004468 
                 952 
                 CD38 
                 −1.40 
                 5.09E−07 
                 8.08E−05 
               
               
                 ENSG00000154330 
                 5239 
                 PGM5 
                 1.72 
                 5.62E−07 
                 8.83E−05 
               
               
                 ENSG00000085185 
                 63035 
                 BCORL1 
                 0.61 
                 5.71E−07 
                 8.88E−05 
               
               
                 ENSG00000157933 
                 6497 
                 SKI 
                 0.57 
                 5.77E−07 
                 8.89E−05 
               
               
                 ENSG00000080854 
                 22997 
                 IGSF9B 
                 1.56 
                 6.01E−07 
                 9.16E−05 
               
               
                 ENSG00000244734 
                 3043 
                 HBB 
                 2.28 
                 6.25E−07 
                 9.42E−05 
               
               
                 ENSG00000080572 
                 139212 
                 PIH1D3 
                 −1.44 
                 6.80E−07 
                 1.02E−04 
               
               
                 ENSG00000154529 
                 728577 
                 CNTNAP3B 
                 1.83 
                 7.23E−07 
                 1.07E−04 
               
               
                 ENSG00000142731 
                 10733 
                 PLK4 
                 −1.30 
                 9.19E−07 
                 1.34E−04 
               
               
                 ENSG00000146425 
                 6993 
                 DYNLT1 
                 −1.05 
                 9.34E−07 
                 1.35E−04 
               
               
                 ENSG00000109861 
                 1075 
                 CTSC 
                 −0.92 
                 9.89E−07 
                 1.42E−04 
               
               
                 ENSG00000118640 
                 8673 
                 VAMP8 
                 −0.83 
                 1.00E−06 
                 1.43E−04 
               
               
                 ENSG00000091262 
                 368 
                 ABCC6 
                 −0.97 
                 1.05E−06 
                 1.48E−04 
               
               
                 ENSG00000012124 
                 933 
                 CD22 
                 1.94 
                 1.08E−06 
                 1.48E−04 
               
               
                 ENSG00000079337 
                 10411 
                 RAPGEF3 
                 1.63 
                 1.09E−06 
                 1.48E−04 
               
               
                 ENSG00000113161 
                 3156 
                 HMGCR 
                 −1.13 
                 1.09E−06 
                 1.48E−04 
               
               
                 ENSG00000183346 
                 219621 
                 C10orf107 
                 −1.22 
                 1.07E−06 
                 1.48E−04 
               
               
                 ENSG00000197705 
                 57565 
                 KLHL14 
                 2.01 
                 1.11E−06 
                 1.49E−04 
               
               
                 ENSG00000215217 
                 134121 
                 C5orf49 
                 −1.20 
                 1.14E−06 
                 1.52E−04 
               
               
                 ENSG00000070190 
                 27071 
                 DAPP1 
                 −1.19 
                 1.19E−06 
                 1.55E−04 
               
               
                 ENSG00000165434 
                 283209 
                 PGM2L1 
                 −0.92 
                 1.18E−06 
                 1.55E−04 
               
               
                 ENSG00000102738 
                 10240 
                 MRPS31 
                 −0.97 
                 1.22E−06 
                 1.56E−04 
               
               
                 ENSG00000132698 
                 57111 
                 RAB25 
                 −0.79 
                 1.22E−06 
                 1.56E−04 
               
               
                 ENSG00000186105 
                 100130733 
                 LRRC70 
                 1.77 
                 1.24E−06 
                 1.58E−04 
               
               
                 ENSG00000123983 
                 2181 
                 ACSL3 
                 −0.87 
                 1.38E−06 
                 1.72E−04 
               
               
                 ENSG00000188010 
                 729967 
                 MORN2 
                 −1.27 
                 1.37E−06 
                 1.72E−04 
               
               
                 ENSG00000138670 
                 153020 
                 RASGEF1B 
                 −0.83 
                 1.56E−06 
                 1.94E−04 
               
               
                 ENSG00000152104 
                 5784 
                 PTPN14 
                 0.94 
                 1.62E−06 
                 1.98E−04 
               
               
                 ENSG00000165995 
                 783 
                 CACNB2 
                 1.24 
                 1.62E−06 
                 1.98E−04 
               
               
                 ENSG00000109586 
                 51809 
                 GALNT7 
                 −0.94 
                 1.73E−06 
                 2.10E−04 
               
               
                 ENSG00000129946 
                 25759 
                 SHC2 
                 1.66 
                 1.82E−06 
                 2.18E−04 
               
               
                 ENSG00000139910 
                 4857 
                 NOVA1 
                 2.15 
                 1.99E−06 
                 2.37E−04 
               
               
                 ENSG00000188175 
                 253012 
                 HEPACAM2 
                 −1.75 
                 2.01E−06 
                 2.37E−04 
               
               
                 ENSG00000174405 
                 3981 
                 LIG4 
                 −0.58 
                 2.04E−06 
                 2.37E−04 
               
               
                 ENSG00000181885 
                 1366 
                 CLDN7 
                 −1.13 
                 2.03E−06 
                 2.37E−04 
               
               
                 ENSG00000187134 
                 1645 
                 AKR1C1 
                 −0.86 
                 2.07E−06 
                 2.39E−04 
               
               
                 ENSG00000253731 
                 56109 
                 PCDHGA6 
                 1.19 
                 2.09E−06 
                 2.39E−04 
               
               
                 ENSG00000090006 
                 8425 
                 LTBP4 
                 1.38 
                 2.13E−06 
                 2.42E−04 
               
               
                 ENSG00000176438 
                 161176 
                 SYNE3 
                 0.98 
                 2.18E−06 
                 2.44E−04 
               
               
                 ENSG00000188536 
                 3040 
                 HBA2 
                 2.17 
                 2.17E−06 
                 2.44E−04 
               
               
                 ENSG00000141198 
                 10040 
                 TOM1L1 
                 −0.57 
                 2.27E−06 
                 2.50E−04 
               
               
                 ENSG00000164124 
                 55314 
                 TMEM144 
                 −0.88 
                 2.26E−06 
                 2.50E−04 
               
               
                 ENSG00000068912 
                 27248 
                 ERLEC1 
                 −0.48 
                 2.33E−06 
                 2.55E−04 
               
               
                 ENSG00000167779 
                 3489 
                 IGFBP6 
                 1.85 
                 2.44E−06 
                 2.65E−04 
               
               
                 ENSG00000159212 
                 54102 
                 CLIC6 
                 −0.90 
                 2.50E−06 
                 2.70E−04 
               
               
                 ENSG00000116833 
                 2494 
                 NR5A2 
                 1.94 
                 2.54E−06 
                 2.72E−04 
               
               
                 ENSG00000197614 
                 8076 
                 MFAP5 
                 2.15 
                 2.70E−06 
                 2.87E−04 
               
               
                 ENSG00000152518 
                 678 
                 ZFP36L2 
                 0.79 
                 2.81E−06 
                 2.96E−04 
               
               
                 ENSG00000177156 
                 6888 
                 TALDO1 
                 −0.45 
                 2.83E−06 
                 2.96E−04 
               
               
                 ENSG00000144619 
                 152330 
                 CNTN4 
                 0.79 
                 2.89E−06 
                 3.01E−04 
               
               
                 ENSG00000124772 
                 57699 
                 CPNE5 
                 1.80 
                 2.99E−06 
                 3.04E−04 
               
               
                 ENSG00000166908 
                 79837 
                 PIP4K2C 
                 −0.49 
                 2.99E−06 
                 3.04E−04 
               
               
                 ENSG00000168765 
                 2948 
                 GSTM4 
                 0.72 
                 2.95E−06 
                 3.04E−04 
               
               
                 ENSG00000105928 
                 1687 
                 DFNA5 
                 1.47 
                 3.02E−06 
                 3.05E−04 
               
               
                 ENSG00000186471 
                 158798 
                 AKAP14 
                 −1.21 
                 3.04E−06 
                 3.05E−04 
               
               
                 ENSG00000183604 
                 NA 
                 SMG1P5 
                 1.68 
                 3.12E−06 
                 3.11E−04 
               
               
                 ENSG00000182272 
                 338707 
                 B4GALNT4 
                 1.65 
                 3.32E−06 
                 3.29E−04 
               
               
                 ENSG00000170017 
                 214 
                 ALCAM 
                 −1.08 
                 3.37E−06 
                 3.32E−04 
               
               
                 ENSG00000163191 
                 6282 
                 S100A11 
                 −0.92 
                 3.77E−06 
                 3.69E−04 
               
               
                 ENSG00000100243 
                 1727 
                 CYB5R3 
                 0.31 
                 3.83E−06 
                 3.70E−04 
               
               
                 ENSG00000119616 
                 51077 
                 FCF1 
                 −0.57 
                 3.81E−06 
                 3.70E−04 
               
               
                 ENSG00000106852 
                 26468 
                 LHX6 
                 1.71 
                 3.86E−06 
                 3.70E−04 
               
               
                 ENSG00000164056 
                 10252 
                 SPRY1 
                 1.10 
                 4.26E−06 
                 4.06E−04 
               
               
                 ENSG00000256870 
                 160728 
                 SLC5A8 
                 −1.68 
                 4.31E−06 
                 4.08E−04 
               
               
                 ENSG00000112110 
                 29074 
                 MRPL18 
                 −0.74 
                 4.36E−06 
                 4.10E−04 
               
               
                 ENSG00000243716 
                 440345 
                 NPIPB5 
                 0.46 
                 4.42E−06 
                 4.13E−04 
               
               
                 ENSG00000182093 
                 7485 
                 WRB 
                 −0.58 
                 4.63E−06 
                 4.30E−04 
               
               
                 ENSG00000213398 
                 3931 
                 LCAT 
                 0.87 
                 4.66E−06 
                 4.31E−04 
               
               
                 ENSG00000079459 
                 2222 
                 FDFT1 
                 −0.89 
                 4.75E−06 
                 4.36E−04 
               
               
                 ENSG00000163082 
                 130367 
                 SGPP2 
                 −0.75 
                 4.82E−06 
                 4.40E−04 
               
               
                 ENSG00000181722 
                 26137 
                 ZBTB20 
                 0.71 
                 4.96E−06 
                 4.50E−04 
               
               
                 ENSG00000152953 
                 55351 
                 STK32B 
                 2.03 
                 5.05E−06 
                 4.55E−04 
               
               
                 ENSG00000070193 
                 2255 
                 FGF10 
                 1.89 
                 5.24E−06 
                 4.67E−04 
               
               
                 ENSG00000106404 
                 24146 
                 CLDN15 
                 2.03 
                 5.27E−06 
                 4.67E−04 
               
               
                 ENSG00000107281 
                 56654 
                 NPDC1 
                 1.21 
                 5.22E−06 
                 4.67E−04 
               
               
                 ENSG00000107949 
                 56647 
                 BCCIP 
                 −0.61 
                 5.32E−06 
                 4.68E−04 
               
               
                 ENSG00000161055 
                 92304 
                 SCGB3A1 
                 −1.74 
                 6.01E−06 
                 5.25E−04 
               
               
                 ENSG00000087916 
                 NA 
                 NA 
                 −1.75 
                 6.14E−06 
                 5.34E−04 
               
               
                 ENSG00000119139 
                 9414 
                 TJP2 
                 −0.47 
                 6.21E−06 
                 5.36E−04 
               
               
                 ENSG00000151468 
                 83643 
                 CCDC3 
                 1.74 
                 6.27E−06 
                 5.39E−04 
               
               
                 ENSG00000205809 
                 3822 
                 KLRC2 
                 −1.67 
                 6.68E−06 
                 5.70E−04 
               
               
                 ENSG00000131374 
                 9779 
                 TBC1D5 
                 0.35 
                 6.76E−06 
                 5.71E−04 
               
               
                 ENSG00000178741 
                 9377 
                 COX5A 
                 −0.63 
                 6.73E−06 
                 5.71E−04 
               
               
                 ENSG00000075142 
                 6717 
                 SRI 
                 −0.78 
                 6.86E−06 
                 5.73E−04 
               
               
                 ENSG00000141720 
                 NA 
                 NA 
                 0.40 
                 6.87E−06 
                 5.73E−04 
               
               
                 ENSG00000159167 
                 6781 
                 STC1 
                 1.91 
                 6.99E−06 
                 5.80E−04 
               
               
                 ENSG00000081818 
                 56131 
                 PCDHB4 
                 1.46 
                 7.29E−06 
                 5.95E−04 
               
               
                 ENSG00000135773 
                 10753 
                 CAPN9 
                 −0.90 
                 7.27E−06 
                 5.95E−04 
               
               
                 ENSG00000165300 
                 26050 
                 SLITRK5 
                 1.88 
                 7.26E−06 
                 5.95E−04 
               
               
                 ENSG00000133321 
                 5920 
                 RARRES3 
                 −1.58 
                 7.92E−06 
                 6.43E−04 
               
               
                 ENSG00000160447 
                 29941 
                 PKN3 
                 1.30 
                 8.24E−06 
                 6.66E−04 
               
               
                 ENSG00000136859 
                 23452 
                 ANGPTL2 
                 1.38 
                 8.33E−06 
                 6.69E−04 
               
               
                 ENSG00000222009 
                 149478 
                 BTBD19 
                 1.14 
                 8.54E−06 
                 6.82E−04 
               
               
                 ENSG00000185250 
                 285755 
                 PPIL6 
                 −1.17 
                 8.59E−06 
                 6.83E−04 
               
               
                 ENSG00000164330 
                 1879 
                 EBF1 
                 1.73 
                 8.71E−06 
                 6.86E−04 
               
               
                 ENSG00000182771 
                 2894 
                 GRID1 
                 1.81 
                 8.73E−06 
                 6.86E−04 
               
               
                 ENSG00000137842 
                 80021 
                 TMEM62 
                 −0.91 
                 8.80E−06 
                 6.88E−04 
               
               
                 ENSG00000088538 
                 1795 
                 DOCK3 
                 1.25 
                 8.88E−06 
                 6.91E−04 
               
               
                 ENSG00000178966 
                 80010 
                 RMI1 
                 −0.93 
                 9.01E−06 
                 6.97E−04 
               
               
                 ENSG00000133665 
                 84332 
                 DYDC2 
                 −1.18 
                 9.18E−06 
                 7.06E−04 
               
               
                 ENSG00000117322 
                 1380 
                 CR2 
                 2.00 
                 9.44E−06 
                 7.23E−04 
               
               
                 ENSG00000100170 
                 6523 
                 SLC5A1 
                 −1.54 
                 1.00E−05 
                 7.61E−04 
               
               
                 ENSG00000101384 
                 182 
                 JAG1 
                 0.73 
                 1.00E−05 
                 7.61E−04 
               
               
                 ENSG00000120756 
                 5357 
                 PLS1 
                 −1.01 
                 1.10E−05 
                 8.29E−04 
               
               
                 ENSG00000102098 
                 10389 
                 SCML2 
                 1.41 
                 1.12E−05 
                 8.41E−04 
               
               
                 ENSG00000114200 
                 590 
                 BCHE 
                 1.93 
                 1.13E−05 
                 8.41E−04 
               
               
                 ENSG00000013275 
                 5704 
                 PSMC4 
                 −0.67 
                 1.15E−05 
                 8.50E−04 
               
               
                 ENSG00000108953 
                 7531 
                 YWHAE 
                 −0.48 
                 1.15E−05 
                 8.50E−04 
               
               
                 ENSG00000140181 
                 NA 
                 NA 
                 1.02 
                 1.17E−05 
                 8.53E−04 
               
               
                 ENSG00000152939 
                 153562 
                 MARVELD2 
                 −0.86 
                 1.16E−05 
                 8.53E−04 
               
               
                 ENSG00000162882 
                 23498 
                 HAAO 
                 1.22 
                 1.28E−05 
                 9.29E−04 
               
               
                 ENSG00000088448 
                 55608 
                 ANKRD10 
                 0.59 
                 1.31E−05 
                 9.49E−04 
               
               
                 ENSG00000272636 
                 8447 
                 DOC2B 
                 1.36 
                 1.34E−05 
                 9.64E−04 
               
               
                 ENSG00000052802 
                 6307 
                 MSMO1 
                 −1.29 
                 1.36E−05 
                 9.70E−04 
               
               
                 ENSG00000077063 
                 83992 
                 CTTNBP2 
                 1.25 
                 1.37E−05 
                 9.70E−04 
               
               
                 ENSG00000112972 
                 3157 
                 HMGCS1 
                 −1.11 
                 1.36E−05 
                 9.70E−04 
               
               
                 ENSG00000133019 
                 1131 
                 CHRM3 
                 1.44 
                 1.37E−05 
                 9.70E−04 
               
               
                 ENSG00000069329 
                 55737 
                 VPS35 
                 −0.48 
                 1.40E−05 
                 9.88E−04 
               
               
                 ENSG00000166265 
                 116159 
                 CYYR1 
                 1.63 
                 1.42E−05 
                 9.94E−04 
               
               
                 ENSG00000159399 
                 3099 
                 HK2 
                 −1.04 
                 1.44E−05 
                 1.00E−03 
               
               
                 ENSG00000257057 
                 NA 
                 C11orf97 
                 −1.40 
                 1.47E−05 
                 1.02E−03 
               
               
                 ENSG00000065618 
                 1308 
                 COL17A1 
                 1.62 
                 1.52E−05 
                 1.05E−03 
               
               
                 ENSG00000163624 
                 1040 
                 CDS1 
                 −1.01 
                 1.67E−05 
                 1.14E−03 
               
               
                 ENSG00000164764 
                 157869 
                 SBSPON 
                 1.82 
                 1.67E−05 
                 1.14E−03 
               
               
                 ENSG00000171444 
                 4163 
                 MCC 
                 0.99 
                 1.67E−05 
                 1.14E−03 
               
               
                 ENSG00000183323 
                 202243 
                 CCDC125 
                 −1.05 
                 1.66E−05 
                 1.14E−03 
               
               
                 ENSG00000152332 
                 127933 
                 UHMK1 
                 −0.55 
                 1.71E−05 
                 1.16E−03 
               
               
                 ENSG00000205277 
                 10071 
                 MUC12 
                 1.47 
                 1.75E−05 
                 1.18E−03 
               
               
                 ENSG00000091592 
                 22861 
                 NLRP1 
                 0.94 
                 1.77E−05 
                 1.18E−03 
               
               
                 ENSG00000101230 
                 140862 
                 ISM1 
                 1.31 
                 1.77E−05 
                 1.18E−03 
               
               
                 ENSG00000112981 
                 8382 
                 NME5 
                 −1.10 
                 1.79E−05 
                 1.18E−03 
               
               
                 ENSG00000196263 
                 57573 
                 ZNF471 
                 0.81 
                 1.79E−05 
                 1.18E−03 
               
               
                 ENSG00000149809 
                 7108 
                 TM7SF2 
                 −0.74 
                 1.81E−05 
                 1.19E−03 
               
               
                 ENSG00000139644 
                 7009 
                 TMBIM6 
                 −0.60 
                 1.83E−05 
                 1.20E−03 
               
               
                 ENSG00000116138 
                 23341 
                 DNAJC16 
                 −0.51 
                 1.88E−05 
                 1.21E−03 
               
               
                 ENSG00000143248 
                 8490 
                 RGS5 
                 1.70 
                 1.88E−05 
                 1.21E−03 
               
               
                 ENSG00000183644 
                 399949 
                 C11orf88 
                 −1.23 
                 1.88E−05 
                 1.21E−03 
               
               
                 ENSG00000109814 
                 7358 
                 UGDH 
                 −0.76 
                 1.89E−05 
                 1.22E−03 
               
               
                 ENSG00000131475 
                 84313 
                 VPS25 
                 −0.57 
                 1.94E−05 
                 1.24E−03 
               
               
                 ENSG00000183454 
                 2903 
                 GRIN2A 
                 1.94 
                 1.98E−05 
                 1.26E−03 
               
               
                 ENSG00000057252 
                 6646 
                 SOAT1 
                 −0.77 
                 2.07E−05 
                 1.31E−03 
               
               
                 ENSG00000106123 
                 2051 
                 EPHB6 
                 1.12 
                 2.11E−05 
                 1.31E−03 
               
               
                 ENSG00000133067 
                 59352 
                 LGR6 
                 1.51 
                 2.11E−05 
                 1.31E−03 
               
               
                 ENSG00000138356 
                 316 
                 AOX1 
                 1.79 
                 2.09E−05 
                 1.31E−03 
               
               
                 ENSG00000173269 
                 79812 
                 MMRN2 
                 1.69 
                 2.09E−05 
                 1.31E−03 
               
               
                 ENSG00000186642 
                 5138 
                 PDE2A 
                 1.94 
                 2.12E−05 
                 1.31E−03 
               
               
                 ENSG00000178053 
                 4291 
                 MLF1 
                 −1.06 
                 2.15E−05 
                 1.33E−03 
               
               
                 ENSG00000087995 
                 339175 
                 METTL2A 
                 −0.57 
                 2.18E−05 
                 1.34E−03 
               
               
                 ENSG00000130600 
                 283120 
                 H19 
                 1.87 
                 2.18E−05 
                 1.34E−03 
               
               
                 ENSG00000114573 
                 523 
                 ATP6V1A 
                 −0.62 
                 2.24E−05 
                 1.35E−03 
               
               
                 ENSG00000131203 
                 3620 
                 IDO1 
                 −1.91 
                 2.23E−05 
                 1.35E−03 
               
               
                 ENSG00000143036 
                 126969 
                 SLC44A3 
                 −0.74 
                 2.21E−05 
                 1.35E−03 
               
               
                 ENSG00000262209 
                 56102 
                 PCDHGB3 
                 1.37 
                 2.22E−05 
                 1.35E−03 
               
               
                 ENSG00000168079 
                 286133 
                 SCARA5 
                 1.77 
                 2.29E−05 
                 1.37E−03 
               
               
                 ENSG00000163534 
                 115350 
                 FCRL1 
                 1.93 
                 2.35E−05 
                 1.40E−03 
               
               
                 ENSG00000165304 
                 9833 
                 MELK 
                 −1.58 
                 2.36E−05 
                 1.40E−03 
               
               
                 ENSG00000101421 
                 128866 
                 CHMP4B 
                 −0.48 
                 2.37E−05 
                 1.41E−03 
               
               
                 ENSG00000162961 
                 84661 
                 DPY30 
                 −0.75 
                 2.53E−05 
                 1.49E−03 
               
               
                 ENSG00000188931 
                 257177 
                 CFAP126 
                 −1.15 
                 2.53E−05 
                 1.49E−03 
               
               
                 ENSG00000129467 
                 196883 
                 ADCY4 
                 1.60 
                 2.55E−05 
                 1.49E−03 
               
               
                 ENSG00000173530 
                 8793 
                 TNFRSF10D 
                 0.83 
                 2.54E−05 
                 1.49E−03 
               
               
                 ENSG00000158683 
                 168507 
                 PKD1L1 
                 1.68 
                 2.68E−05 
                 1.56E−03 
               
               
                 ENSG00000000003 
                 7105 
                 TSPAN6 
                 −1.01 
                 2.70E−05 
                 1.56E−03 
               
               
                 ENSG00000135679 
                 4193 
                 MDM2 
                 −0.59 
                 2.70E−05 
                 1.56E−03 
               
               
                 ENSG00000241244 
                 NA 
                 IGKV1D-16 
                 1.79 
                 2.76E−05 
                 1.58E−03 
               
               
                 ENSG00000086548 
                 4680 
                 CEACAM6 
                 −1.11 
                 2.86E−05 
                 1.64E−03 
               
               
                 ENSG00000005108 
                 221981 
                 THSD7A 
                 1.06 
                 2.87E−05 
                 1.64E−03 
               
               
                 ENSG00000163001 
                 112942 
                 CFAP36 
                 −0.57 
                 2.91E−05 
                 1.65E−03 
               
               
                 ENSG00000178445 
                 2731 
                 GLDC 
                 1.32 
                 2.92E−05 
                 1.65E−03 
               
               
                 ENSG00000196586 
                 4646 
                 MYO6 
                 −0.56 
                 2.94E−05 
                 1.66E−03 
               
               
                 ENSG00000130300 
                 83483 
                 PLVAP 
                 1.89 
                 2.97E−05 
                 1.66E−03 
               
               
                 ENSG00000173068 
                 54796 
                 BNC2 
                 1.44 
                 2.98E−05 
                 1.66E−03 
               
               
                 ENSG00000211972 
                 NA 
                 IGHV3-66 
                 1.82 
                 2.98E−05 
                 1.66E−03 
               
               
                 ENSG00000163531 
                 23114 
                 NFASC 
                 0.75 
                 3.10E−05 
                 1.72E−03 
               
               
                 ENSG00000145287 
                 51316 
                 PLAC8 
                 −1.30 
                 3.13E−05 
                 1.72E−03 
               
               
                 ENSG00000157764 
                 673 
                 BRAF 
                 0.36 
                 3.14E−05 
                 1.72E−03 
               
               
                 ENSG00000197959 
                 26052 
                 DNM3 
                 1.09 
                 3.12E−05 
                 1.72E−03 
               
               
                 ENSG00000119138 
                 687 
                 KLF9 
                 1.20 
                 3.18E−05 
                 1.74E−03 
               
               
                 ENSG00000185760 
                 56479 
                 KCNQ5 
                 1.62 
                 3.26E−05 
                 1.78E−03 
               
               
                 ENSG00000066382 
                 744 
                 MPPED2 
                 1.28 
                 3.35E−05 
                 1.80E−03 
               
               
                 ENSG00000088986 
                 8655 
                 DYNLL1 
                 −0.77 
                 3.32E−05 
                 1.80E−03 
               
               
                 ENSG00000104413 
                 54845 
                 ESRP1 
                 −0.77 
                 3.35E−05 
                 1.80E−03 
               
               
                 ENSG00000116906 
                 8443 
                 GNPAT 
                 −0.33 
                 3.32E−05 
                 1.80E−03 
               
               
                 ENSG00000165716 
                 138311 
                 FAM69B 
                 1.58 
                 3.34E−05 
                 1.80E−03 
               
               
                 ENSG00000163263 
                 388701 
                 C1orf189 
                 −1.27 
                 3.44E−05 
                 1.83E−03 
               
               
                 ENSG00000163993 
                 6286 
                 S100P 
                 −1.73 
                 3.46E−05 
                 1.84E−03 
               
               
                 ENSG00000102287 
                 2564 
                 GABRE 
                 1.02 
                 3.59E−05 
                 1.90E−03 
               
               
                 ENSG00000011523 
                 23177 
                 CEP68 
                 0.74 
                 3.67E−05 
                 1.94E−03 
               
               
                 ENSG00000149212 
                 143686 
                 SESN3 
                 0.83 
                 3.74E−05 
                 1.96E−03 
               
               
                 ENSG00000174059 
                 947 
                 CD34 
                 1.78 
                 3.73E−05 
                 1.96E−03 
               
               
                 ENSG00000178125 
                 286187 
                 PPP1R42 
                 −1.05 
                 3.74E−05 
                 1.96E−03 
               
               
                 ENSG00000145494 
                 4726 
                 NDUFS6 
                 −0.39 
                 3.84E−05 
                 2.00E−03 
               
               
                 ENSG00000166562 
                 90701 
                 SEC11C 
                 −0.65 
                 3.97E−05 
                 2.06E−03 
               
               
                 ENSG00000261934 
                 56107 
                 PCDHGA9 
                 0.90 
                 3.99E−05 
                 2.06E−03 
               
               
                 ENSG00000126895 
                 554 
                 AVPR2 
                 1.24 
                 4.01E−05 
                 2.06E−03 
               
               
                 ENSG00000131844 
                 64087 
                 MCCC2 
                 −0.44 
                 4.04E−05 
                 2.07E−03 
               
               
                 ENSG00000166813 
                 374654 
                 KIF7 
                 1.34 
                 4.12E−05 
                 2.11E−03 
               
               
                 ENSG00000185245 
                 2811 
                 GP1BA 
                 1.18 
                 4.22E−05 
                 2.15E−03 
               
               
                 ENSG00000057704 
                 57458 
                 TMCC3 
                 1.54 
                 4.29E−05 
                 2.18E−03 
               
               
                 ENSG00000148541 
                 220965 
                 FAM13C 
                 1.17 
                 4.38E−05 
                 2.21E−03 
               
               
                 ENSG00000224114 
                 NA 
                   
                 −1.66 
                 4.44E−05 
                 2.24E−03 
               
               
                 ENSG00000068796 
                 3796 
                 KIF2A 
                 −0.75 
                 4.51E−05 
                 2.26E−03 
               
               
                 ENSG00000254986 
                 10072 
                 DPP3 
                 −0.57 
                 4.52E−05 
                 2.26E−03 
               
               
                 ENSG00000266714 
                 NA 
                 MYO15B 
                 0.93 
                 4.52E−05 
                 2.26E−03 
               
               
                 ENSG00000145824 
                 9547 
                 CXCL14 
                 1.80 
                 4.67E−05 
                 2.32E−03 
               
               
                 ENSG00000262576 
                 56111 
                 PCDHGA4 
                 1.35 
                 4.70E−05 
                 2.33E−03 
               
               
                 ENSG00000204604 
                 90333 
                 ZNF468 
                 −0.74 
                 4.96E−05 
                 2.45E−03 
               
               
                 ENSG00000111834 
                 345895 
                 RSPH4A 
                 −1.07 
                 5.07E−05 
                 2.46E−03 
               
               
                 ENSG00000134202 
                 2947 
                 GSTM3 
                 1.58 
                 4.99E−05 
                 2.46E−03 
               
               
                 ENSG00000139193 
                 939 
                 CD27 
                 1.61 
                 5.06E−05 
                 2.46E−03 
               
               
                 ENSG00000142687 
                 79932 
                 KIAA0319L 
                 −0.66 
                 5.07E−05 
                 2.46E−03 
               
               
                 ENSG00000143653 
                 51097 
                 SCCPDH 
                 −0.61 
                 5.05E−05 
                 2.46E−03 
               
               
                 ENSG00000187244 
                 4059 
                 BCAM 
                 0.98 
                 5.00E−05 
                 2.46E−03 
               
               
                 ENSG00000225698 
                 NA 
                 IGHV3-72 
                 1.84 
                 5.26E−05 
                 2.54E−03 
               
               
                 ENSG00000162896 
                 5284 
                 PIGR 
                 −1.10 
                 5.29E−05 
                 2.54E−03 
               
               
                 ENSG00000253485 
                 56110 
                 PCDHGA5 
                 1.40 
                 5.32E−05 
                 2.55E−03 
               
               
                 ENSG00000103184 
                 9717 
                 SEC14L5 
                 −1.57 
                 5.39E−05 
                 2.57E−03 
               
               
                 ENSG00000117399 
                 991 
                 CDC20 
                 −1.23 
                 5.38E−05 
                 2.57E−03 
               
               
                 ENSG00000128591 
                 2318 
                 FLNC 
                 1.71 
                 5.43E−05 
                 2.57E−03 
               
               
                 ENSG00000153291 
                 9481 
                 SLC25A27 
                 0.80 
                 5.42E−05 
                 2.57E−03 
               
               
                 ENSG00000143153 
                 481 
                 ATP1B1 
                 −0.71 
                 5.54E−05 
                 2.62E−03 
               
               
                 ENSG00000161798 
                 362 
                 AQP5 
                 −1.15 
                 5.59E−05 
                 2.63E−03 
               
               
                 ENSG00000138413 
                 3417 
                 IDH1 
                 −0.56 
                 5.62E−05 
                 2.64E−03 
               
               
                 ENSG00000070182 
                 6710 
                 SPTB 
                 1.24 
                 5.67E−05 
                 2.65E−03 
               
               
                 ENSG00000165325 
                 159989 
                 CCDC67 
                 −1.20 
                 5.68E−05 
                 2.65E−03 
               
               
                 ENSG00000073060 
                 949 
                 SCARB1 
                 1.42 
                 5.92E−05 
                 2.75E−03 
               
               
                 ENSG00000120437 
                 39 
                 ACAT2 
                 −1.08 
                 5.99E−05 
                 2.77E−03 
               
               
                 ENSG00000181789 
                 22820 
                 COPG1 
                 −0.45 
                 6.01E−05 
                 2.77E−03 
               
               
                 ENSG00000265150 
                 NA 
                 NA 
                 1.14 
                 6.00E−05 
                 2.77E−03 
               
               
                 ENSG00000211934 
                 NA 
                 IGHV1-2 
                 1.76 
                 6.10E−05 
                 2.80E−03 
               
               
                 ENSG00000143772 
                 3707 
                 ITPKB 
                 0.62 
                 6.17E−05 
                 2.82E−03 
               
               
                 ENSG00000109846 
                 1410 
                 CRYAB 
                 1.44 
                 6.45E−05 
                 2.93E−03 
               
               
                 ENSG00000138031 
                 109 
                 ADCY3 
                 1.04 
                 6.49E−05 
                 2.93E−03 
               
               
                 ENSG00000148180 
                 2934 
                 GSN 
                 0.67 
                 6.48E−05 
                 2.93E−03 
               
               
                 ENSG00000253910 
                 56103 
                 PCDHGB2 
                 1.36 
                 6.45E−05 
                 2.93E−03 
               
               
                 ENSG00000156966 
                 93010 
                 B3GNT7 
                 −0.86 
                 6.54E−05 
                 2.94E−03 
               
               
                 ENSG00000130770 
                 93974 
                 ATPIF1 
                 −0.63 
                 6.74E−05 
                 3.02E−03 
               
               
                 ENSG00000170312 
                 983 
                 CDK1 
                 −1.01 
                 6.74E−05 
                 3.02E−03 
               
               
                 ENSG00000140263 
                 6652 
                 SORD 
                 −1.46 
                 6.79E−05 
                 3.03E−03 
               
               
                 ENSG00000139625 
                 7786 
                 MAP3K12 
                 0.86 
                 7.13E−05 
                 3.17E−03 
               
               
                 ENSG00000089356 
                 5349 
                 FXYD3 
                 −1.11 
                 7.18E−05 
                 3.19E−03 
               
               
                 ENSG00000172349 
                 3603 
                 IL16 
                 0.87 
                 7.60E−05 
                 3.36E−03 
               
               
                 ENSG00000103534 
                 79838 
                 TMC5 
                 −1.14 
                 7.68E−05 
                 3.39E−03 
               
               
                 ENSG00000138175 
                 403 
                 ARL3 
                 −0.75 
                 7.75E−05 
                 3.40E−03 
               
               
                 ENSG00000204632 
                 3135 
                 HLA-G 
                 −1.80 
                 7.73E−05 
                 3.40E−03 
               
               
                 ENSG00000156675 
                 80223 
                 RAB11FIP1 
                 −0.72 
                 7.88E−05 
                 3.44E−03 
               
               
                 ENSG00000081870 
                 51668 
                 HSPB11 
                 −0.85 
                 7.95E−05 
                 3.45E−03 
               
               
                 ENSG00000133056 
                 5287 
                 PIK3C2B 
                 0.47 
                 7.94E−05 
                 3.45E−03 
               
               
                 ENSG00000133313 
                 55748 
                 CNDP2 
                 −0.77 
                 7.98E−05 
                 3.46E−03 
               
               
                 ENSG00000184903 
                 83943 
                 IMMP2L 
                 0.82 
                 8.32E−05 
                 3.60E−03 
               
               
                 ENSG00000068976 
                 5837 
                 PYGM 
                 1.50 
                 8.37E−05 
                 3.60E−03 
               
               
                 ENSG00000037042 
                 27175 
                 TUBG2 
                 0.71 
                 8.40E−05 
                 3.61E−03 
               
               
                 ENSG00000168056 
                 4054 
                 LTBP3 
                 0.85 
                 8.45E−05 
                 3.61E−03 
               
               
                 ENSG00000168067 
                 5871 
                 MAP4K2 
                 0.60 
                 8.44E−05 
                 3.61E−03 
               
               
                 ENSG00000119630 
                 5228 
                 PGF 
                 1.77 
                 8.51E−05 
                 3.62E−03 
               
               
                 ENSG00000116678 
                 3953 
                 LEPR 
                 1.54 
                 8.58E−05 
                 3.64E−03 
               
               
                 ENSG00000166226 
                 10576 
                 CCT2 
                 −0.59 
                 8.78E−05 
                 3.72E−03 
               
               
                 ENSG00000167088 
                 6632 
                 SNRPD1 
                 −0.54 
                 8.80E−05 
                 3.72E−03 
               
               
                 ENSG00000105696 
                 25789 
                 TMEM59L 
                 1.67 
                 8.95E−05 
                 3.73E−03 
               
               
                 ENSG00000105711 
                 6324 
                 SCN1B 
                 1.26 
                 8.96E−05 
                 3.73E−03 
               
               
                 ENSG00000134339 
                 6289 
                 SAA2 
                 −1.78 
                 8.97E−05 
                 3.73E−03 
               
               
                 ENSG00000139631 
                 51380 
                 CSAD 
                 0.90 
                 8.88E−05 
                 3.73E−03 
               
               
                 ENSG00000162928 
                 5194 
                 PEX13 
                 −0.59 
                 8.91E−05 
                 3.73E−03 
               
               
                 ENSG00000005189 
                 81691 
                   
                 −0.88 
                 9.05E−05 
                 3.74E−03 
               
               
                 ENSG00000137947 
                 2959 
                 GTF2B 
                 −0.53 
                 9.01E−05 
                 3.74E−03 
               
               
                 ENSG00000166793 
                 219539 
                 YPEL4 
                 1.34 
                 9.06E−05 
                 3.74E−03 
               
               
                 ENSG00000156299 
                 7074 
                 TIAM1 
                 0.90 
                 9.12E−05 
                 3.75E−03 
               
               
                 ENSG00000138385 
                 6741 
                 SSB 
                 −0.66 
                 9.17E−05 
                 3.77E−03 
               
               
                 ENSG00000231259 
                 NA 
                   
                 0.99 
                 9.22E−05 
                 3.77E−03 
               
               
                 ENSG00000150773 
                 120379 
                 PIH1D2 
                 −1.07 
                 9.31E−05 
                 3.80E−03 
               
               
                 ENSG00000172586 
                 118487 
                 CHCHD1 
                 −0.80 
                 9.32E−05 
                 3.80E−03 
               
               
                 ENSG00000134058 
                 1022 
                 CDK7 
                 −0.78 
                 9.49E−05 
                 3.84E−03 
               
               
                 ENSG00000196636 
                 57001 
                 SDHAF3 
                 −0.92 
                 9.47E−05 
                 3.84E−03 
               
               
                 ENSG00000116288 
                 11315 
                 PARK7 
                 −0.33 
                 9.92E−05 
                 4.00E−03 
               
               
                 ENSG00000078596 
                 9452 
                 ITM2A 
                 1.13 
                 1.01E−04 
                 4.05E−03 
               
               
                 ENSG00000092096 
                 51310 
                 SLC22A17 
                 1.07 
                 1.01E−04 
                 4.05E−03 
               
               
                 ENSG00000233974 
                 NA 
                   
                 1.28 
                 1.01E−04 
                 4.05E−03 
               
               
                 ENSG00000104419 
                 10397 
                 NDRG1 
                 1.20 
                 1.02E−04 
                 4.07E−03 
               
               
                 ENSG00000197993 
                 3792 
                 KEL 
                 1.38 
                 1.02E−04 
                 4.08E−03 
               
               
                 ENSG00000000419 
                 8813 
                 DPM1 
                 −0.56 
                 1.03E−04 
                 4.08E−03 
               
               
                 ENSG00000075089 
                 64431 
                 ACTR6 
                 −0.66 
                 1.04E−04 
                 4.08E−03 
               
               
                 ENSG00000101443 
                 10406 
                 WFDC2 
                 −1.35 
                 1.04E−04 
                 4.08E−03 
               
               
                 ENSG00000140526 
                 11057 
                 ABHD2 
                 −0.77 
                 1.03E−04 
                 4.08E−03 
               
               
                 ENSG00000198087 
                 23607 
                 CD2AP 
                 −0.57 
                 1.04E−04 
                 4.08E−03 
               
               
                 ENSG00000149150 
                 8501 
                 SLC43A1 
                 0.96 
                 1.05E−04 
                 4.11E−03 
               
               
                 ENSG00000251039 
                 NA 
                 IGKV2D-40 
                 1.53 
                 1.05E−04 
                 4.11E−03 
               
               
                 ENSG00000172935 
                 116535 
                 MRGPRF 
                 1.56 
                 1.06E−04 
                 4.13E−03 
               
               
                 ENSG00000221716 
                 677799 
                 SNORA11 
                 1.44 
                 1.06E−04 
                 4.14E−03 
               
               
                 ENSG00000148400 
                 4851 
                 NOTCH1 
                 0.61 
                 1.08E−04 
                 4.16E−03 
               
               
                 ENSG00000224411 
                 NA 
                 HSP90AA2P 
                 −0.80 
                 1.07E−04 
                 4.16E−03 
               
               
                 ENSG00000103168 
                 9013 
                 TAF1C 
                 0.98 
                 1.11E−04 
                 4.28E−03 
               
               
                 ENSG00000032742 
                 8100 
                 IFT88 
                 −0.68 
                 1.13E−04 
                 4.34E−03 
               
               
                 ENSG00000112297 
                 202 
                 AIM1 
                 −0.48 
                 1.15E−04 
                 4.42E−03 
               
               
                 ENSG00000172037 
                 3913 
                 LAMB2 
                 0.72 
                 1.15E−04 
                 4.42E−03 
               
               
                 ENSG00000119328 
                 54942 
                 FAM206A 
                 −0.63 
                 1.17E−04 
                 4.45E−03 
               
               
                 ENSG00000164114 
                 79884 
                 MAP9 
                 −0.78 
                 1.17E−04 
                 4.45E−03 
               
               
                 ENSG00000100591 
                 10598 
                 AHSA1 
                 −0.74 
                 1.22E−04 
                 4.62E−03 
               
               
                 ENSG00000127884 
                 1892 
                 ECHS1 
                 −0.42 
                 1.24E−04 
                 4.62E−03 
               
               
                 ENSG00000134709 
                 51361 
                 HOOK1 
                 −0.81 
                 1.23E−04 
                 4.62E−03 
               
               
                 ENSG00000153904 
                 23576 
                 DDAH1 
                 −0.53 
                 1.22E−04 
                 4.62E−03 
               
               
                 ENSG00000165929 
                 123036 
                 TC2N 
                 −0.81 
                 1.24E−04 
                 4.62E−03 
               
               
                 ENSG00000169550 
                 143662 
                 MUC15 
                 −1.09 
                 1.23E−04 
                 4.62E−03 
               
               
                 ENSG00000214776 
                 NA 
                   
                 1.28 
                 1.23E−04 
                 4.62E−03 
               
               
                 ENSG00000163406 
                 6565 
                 SLC15A2 
                 −0.97 
                 1.24E−04 
                 4.63E−03 
               
               
                 ENSG00000177054 
                 54503 
                 ZDHHC13 
                 −0.84 
                 1.24E−04 
                 4.63E−03 
               
               
                 ENSG00000100626 
                 57452 
                 GALNT16 
                 1.34 
                 1.27E−04 
                 4.70E−03 
               
               
                 ENSG00000129055 
                 25847 
                 ANAPC13 
                 −0.81 
                 1.27E−04 
                 4.70E−03 
               
               
                 ENSG00000080824 
                 3320 
                 HSP90AA1 
                 −0.67 
                 1.28E−04 
                 4.72E−03 
               
               
                 ENSG00000119912 
                 3416 
                 IDE 
                 −0.54 
                 1.31E−04 
                 4.81E−03 
               
               
                 ENSG00000148346 
                 3934 
                 LCN2 
                 −1.55 
                 1.31E−04 
                 4.82E−03 
               
               
                 ENSG00000211459 
                 NA 
                 MT-RNR1 
                 0.83 
                 1.32E−04 
                 4.85E−03 
               
               
                 ENSG00000175309 
                 85007 
                 PHYKPL 
                 0.77 
                 1.33E−04 
                 4.87E−03 
               
               
                 ENSG00000178460 
                 157777 
                 MCMDC2 
                 −1.36 
                 1.33E−04 
                 4.87E−03 
               
               
                 ENSG00000159079 
                 56683 
                 C21orf59 
                 −1.02 
                 1.37E−04 
                 4.99E−03 
               
               
                 ENSG00000137691 
                 85016 
                 C11orf70 
                 −1.02 
                 1.38E−04 
                 5.02E−03 
               
               
                 ENSG00000185585 
                 169611 
                 OLFML2A 
                 1.02 
                 1.39E−04 
                 5.02E−03 
               
               
                 ENSG00000127838 
                 25953 
                 PNKD 
                 −0.49 
                 1.40E−04 
                 5.06E−03 
               
               
                 ENSG00000143387 
                 1513 
                 CTSK 
                 1.44 
                 1.40E−04 
                 5.06E−03 
               
               
                 ENSG00000142733 
                 9064 
                 MAP3K6 
                 0.60 
                 1.42E−04 
                 5.11E−03 
               
               
                 ENSG00000147862 
                 4781 
                 NFIB 
                 0.61 
                 1.46E−04 
                 5.22E−03 
               
               
                 ENSG00000115339 
                 2591 
                 GALNT3 
                 −0.90 
                 1.46E−04 
                 5.23E−03 
               
               
                 ENSG00000073969 
                 4905 
                 NSF 
                 −0.51 
                 1.48E−04 
                 5.28E−03 
               
               
                 ENSG00000109971 
                 3312 
                 HSPA8 
                 −0.53 
                 1.49E−04 
                 5.29E−03 
               
               
                 ENSG00000116299 
                 57535 
                 KIAA1324 
                 −0.76 
                 1.51E−04 
                 5.35E−03 
               
               
                 ENSG00000092421 
                 57556 
                 SEMA6A 
                 1.00 
                 1.52E−04 
                 5.36E−03 
               
               
                 ENSG00000129493 
                 25938 
                 HEATR5A 
                 −0.39 
                 1.52E−04 
                 5.36E−03 
               
               
                 ENSG00000197279 
                 7718 
                 ZNF165 
                 −0.98 
                 1.51E−04 
                 5.36E−03 
               
               
                 ENSG00000161544 
                 114757 
                 CYGB 
                 0.93 
                 1.54E−04 
                 5.41E−03 
               
               
                 ENSG00000211890 
                 NA 
                 IGHA2 
                 1.70 
                 1.54E−04 
                 5.42E−03 
               
               
                 ENSG00000133063 
                 1118 
                 CHIT1 
                 1.69 
                 1.57E−04 
                 5.50E−03 
               
               
                 ENSG00000160469 
                 84446 
                 BRSK1 
                 1.36 
                 1.62E−04 
                 5.63E−03 
               
               
                 ENSG00000185681 
                 254956 
                 MORN5 
                 −1.16 
                 1.61E−04 
                 5.63E−03 
               
               
                 ENSG00000122420 
                 5737 
                 PTGFR 
                 −1.33 
                 1.63E−04 
                 5.66E−03 
               
               
                 ENSG00000130066 
                 6303 
                 SAT1 
                 −0.63 
                 1.63E−04 
                 5.66E−03 
               
               
                 ENSG00000179222 
                 9500 
                 MAGED1 
                 −0.58 
                 1.65E−04 
                 5.72E−03 
               
               
                 ENSG00000095380 
                 54187 
                 NANS 
                 −0.75 
                 1.68E−04 
                 5.79E−03 
               
               
                 ENSG00000089127 
                 4938 
                 OAS1 
                 −1.31 
                 1.69E−04 
                 5.83E−03 
               
               
                 ENSG00000066185 
                 84217 
                 ZMYND12 
                 −1.04 
                 1.70E−04 
                 5.83E−03 
               
               
                 ENSG00000234745 
                 3106 
                 HLA-B 
                 −0.84 
                 1.71E−04 
                 5.85E−03 
               
               
                 ENSG00000175792 
                 8607 
                 RUVBL1 
                 −0.80 
                 1.72E−04 
                 5.88E−03 
               
               
                 ENSG00000101846 
                 412 
                 STS 
                 −0.54 
                 1.75E−04 
                 5.97E−03 
               
               
                 ENSG00000206149 
                 440248 
                 HERC2P9 
                 0.90 
                 1.78E−04 
                 6.06E−03 
               
               
                 ENSG00000076685 
                 22978 
                 NT5C2 
                 −0.42 
                 1.79E−04 
                 6.09E−03 
               
               
                 ENSG00000069702 
                 7049 
                 TGFBR3 
                 0.94 
                 1.80E−04 
                 6.10E−03 
               
               
                 ENSG00000153292 
                 266977 
                 ADGRF1 
                 −1.45 
                 1.81E−04 
                 6.11E−03 
               
               
                 ENSG00000059145 
                 64718 
                 UNKL 
                 0.91 
                 1.83E−04 
                 6.14E−03 
               
               
                 ENSG00000113212 
                 56129 
                 PCDHB7 
                 1.36 
                 1.83E−04 
                 6.14E−03 
               
               
                 ENSG00000177455 
                 930 
                 CD19 
                 1.71 
                 1.82E−04 
                 6.14E−03 
               
               
                 ENSG00000106483 
                 6424 
                 SFRP4 
                 1.62 
                 1.83E−04 
                 6.14E−03 
               
               
                 ENSG00000013016 
                 30845 
                 EHD3 
                 1.11 
                 1.85E−04 
                 6.18E−03 
               
               
                 ENSG00000168961 
                 3965 
                 LGALS9 
                 −0.70 
                 1.85E−04 
                 6.18E−03 
               
               
                 ENSG00000163131 
                 1520 
                 CTSS 
                 −0.77 
                 1.87E−04 
                 6.24E−03 
               
               
                 ENSG00000147041 
                 94122 
                 SYTL5 
                 −1.12 
                 1.89E−04 
                 6.25E−03 
               
               
                 ENSG00000214517 
                 51400 
                 PPME1 
                 −0.60 
                 1.89E−04 
                 6.25E−03 
               
               
                 ENSG00000211956 
                 NA 
                 IGHV4-34 
                 1.68 
                 1.89E−04 
                 6.26E−03 
               
               
                 ENSG00000110675 
                 55531 
                 ELMOD1 
                 1.58 
                 1.91E−04 
                 6.29E−03 
               
               
                 ENSG00000128039 
                 79644 
                 SRD5A3 
                 −0.97 
                 1.93E−04 
                 6.35E−03 
               
               
                 ENSG00000185813 
                 5833 
                 PCYT2 
                 −0.92 
                 1.95E−04 
                 6.40E−03 
               
               
                 ENSG00000184254 
                 220 
                 ALDH1A3 
                 −0.68 
                 2.01E−04 
                 6.58E−03 
               
               
                 ENSG00000084207 
                 2950 
                 GSTP1 
                 −0.85 
                 2.03E−04 
                 6.59E−03 
               
               
                 ENSG00000123243 
                 80760 
                 ITIH5 
                 1.40 
                 2.03E−04 
                 6.59E−03 
               
               
                 ENSG00000143106 
                 5686 
                 PSMA5 
                 −0.56 
                 2.02E−04 
                 6.59E−03 
               
               
                 ENSG00000167775 
                 51293 
                 CD320 
                 0.85 
                 2.03E−04 
                 6.59E−03 
               
               
                 ENSG00000187391 
                 9863 
                 MAGI2 
                 0.92 
                 2.03E−04 
                 6.59E−03 
               
               
                 ENSG00000168477 
                 7148 
                 TNXB 
                 1.50 
                 2.08E−04 
                 6.74E−03 
               
               
                 ENSG00000241755 
                 NA 
                 IGKV1-9 
                 1.66 
                 2.11E−04 
                 6.81E−03 
               
               
                 ENSG00000136810 
                 7295 
                 TXN 
                 −0.77 
                 2.13E−04 
                 6.87E−03 
               
               
                 ENSG00000104332 
                 6422 
                 SFRP1 
                 1.68 
                 2.14E−04 
                 6.87E−03 
               
               
                 ENSG00000184076 
                 29796 
                 UQCR10 
                 −0.78 
                 2.14E−04 
                 6.87E−03 
               
               
                 ENSG00000106537 
                 27075 
                 TSPAN13 
                 −0.82 
                 2.15E−04 
                 6.88E−03 
               
               
                 ENSG00000127362 
                 50831 
                 TAS2R3 
                 1.02 
                 2.16E−04 
                 6.91E−03 
               
               
                 ENSG00000160213 
                 1476 
                 CSTB 
                 −0.51 
                 2.17E−04 
                 6.91E−03 
               
               
                 ENSG00000067064 
                 3422 
                 IDI1 
                 −0.95 
                 2.19E−04 
                 6.95E−03 
               
               
                 ENSG00000143196 
                 1805 
                 DPT 
                 1.57 
                 2.21E−04 
                 7.00E−03 
               
               
                 ENSG00000105929 
                 50617 
                 ATP6V0A4 
                 −1.54 
                 2.24E−04 
                 7.09E−03 
               
               
                 ENSG00000145391 
                 80854 
                 SETD7 
                 0.69 
                 2.27E−04 
                 7.16E−03 
               
               
                 ENSG00000066735 
                 26153 
                 KIF26A 
                 1.55 
                 2.28E−04 
                 7.19E−03 
               
               
                 ENSG00000108179 
                 10105 
                 PPIF 
                 −0.65 
                 2.30E−04 
                 7.22E−03 
               
               
                 ENSG00000124107 
                 6590 
                 SLPI 
                 −1.05 
                 2.30E−04 
                 7.22E−03 
               
               
                 ENSG00000163902 
                 6184 
                 RPN1 
                 −0.42 
                 2.31E−04 
                 7.22E−03 
               
               
                 ENSG00000198919 
                 9666 
                 DZIP3 
                 −0.79 
                 2.31E−04 
                 7.22E−03 
               
               
                 ENSG00000134363 
                 10468 
                 FST 
                 1.30 
                 2.32E−04 
                 7.24E−03 
               
               
                 ENSG00000133328 
                 54979 
                 HRASLS2 
                 −1.41 
                 2.35E−04 
                 7.32E−03 
               
               
                 ENSG00000100968 
                 4776 
                 NFATC4 
                 1.14 
                 2.36E−04 
                 7.33E−03 
               
               
                 ENSG00000097007 
                 25 
                 ABL1 
                 0.38 
                 2.41E−04 
                 7.46E−03 
               
               
                 ENSG00000147155 
                 10682 
                 EBP 
                 −0.75 
                 2.41E−04 
                 7.46E−03 
               
               
                 ENSG00000184432 
                 9276 
                 COPB2 
                 −0.48 
                 2.43E−04 
                 7.50E−03 
               
               
                 ENSG00000135387 
                 4076 
                 CAPRIN1 
                 −0.38 
                 2.44E−04 
                 7.52E−03 
               
               
                 ENSG00000177169 
                 8408 
                 ULK1 
                 0.49 
                 2.47E−04 
                 7.58E−03 
               
               
                 ENSG00000086232 
                 27102 
                 EIF2AK1 
                 −0.46 
                 2.49E−04 
                 7.63E−03 
               
               
                 ENSG00000132141 
                 10693 
                 CCT6B 
                 −0.92 
                 2.50E−04 
                 7.66E−03 
               
               
                 ENSG00000102900 
                 9688 
                 NUP93 
                 −0.43 
                 2.51E−04 
                 7.66E−03 
               
               
                 ENSG00000117528 
                 5825 
                 ABCD3 
                 −0.57 
                 2.52E−04 
                 7.67E−03 
               
               
                 ENSG00000167523 
                 124045 
                 SPATA33 
                 −0.90 
                 2.54E−04 
                 7.74E−03 
               
               
                 ENSG00000203734 
                 345930 
                 ECT2L 
                 −0.91 
                 2.60E−04 
                 7.88E−03 
               
               
                 ENSG00000044115 
                 1495 
                 CTNNA1 
                 −0.40 
                 2.65E−04 
                 8.04E−03 
               
               
                 ENSG00000065361 
                 2065 
                 ERBB3 
                 −0.86 
                 2.67E−04 
                 8.06E−03 
               
               
                 ENSG00000138294 
                 NA 
                 NA 
                 −1.54 
                 2.67E−04 
                 8.06E−03 
               
               
                 ENSG00000197697 
                 NA 
                 NA 
                 −0.77 
                 2.68E−04 
                 8.07E−03 
               
               
                 ENSG00000184983 
                 4700 
                 NDUFA6 
                 −0.52 
                 2.69E−04 
                 8.07E−03 
               
               
                 ENSG00000155254 
                 83742 
                 MARVELD1 
                 1.25 
                 2.73E−04 
                 8.17E−03 
               
               
                 ENSG00000081760 
                 65985 
                 AACS 
                 −0.64 
                 2.74E−04 
                 8.17E−03 
               
               
                 ENSG00000132746 
                 222 
                 ALDH3B2 
                 −1.46 
                 2.74E−04 
                 8.17E−03 
               
               
                 ENSG00000151364 
                 65987 
                 KCTD14 
                 −1.25 
                 2.73E−04 
                 8.17E−03 
               
               
                 ENSG00000164347 
                 84340 
                 GFM2 
                 −0.86 
                 2.75E−04 
                 8.17E−03 
               
               
                 ENSG00000105875 
                 29062 
                 WDR91 
                 0.65 
                 2.77E−04 
                 8.21E−03 
               
               
                 ENSG00000136153 
                 4008 
                 LMO7 
                 −0.80 
                 2.81E−04 
                 8.31E−03 
               
               
                 ENSG00000116133 
                 1718 
                 DHCR24 
                 −0.76 
                 2.83E−04 
                 8.35E−03 
               
               
                 ENSG00000124201 
                 57169 
                 ZNFX1 
                 −0.52 
                 2.84E−04 
                 8.37E−03 
               
               
                 ENSG00000158234 
                 55179 
                 FAIM 
                 −0.82 
                 2.85E−04 
                 8.38E−03 
               
               
                 ENSG00000144834 
                 29114 
                 TAGLN3 
                 −1.37 
                 2.86E−04 
                 8.41E−03 
               
               
                 ENSG00000099290 
                 387680 
                 FAM21A 
                 −1.43 
                 2.87E−04 
                 8.42E−03 
               
               
                 ENSG00000149021 
                 7356 
                 SCGB1A1 
                 −1.45 
                 2.90E−04 
                 8.49E−03 
               
               
                 ENSG00000135378 
                 79056 
                 PRRG4 
                 −0.92 
                 2.92E−04 
                 8.54E−03 
               
               
                 ENSG00000134744 
                 23318 
                 ZCCHC11 
                 0.50 
                 2.99E−04 
                 8.71E−03 
               
               
                 ENSG00000005175 
                 79657 
                 RPAP3 
                 −0.38 
                 3.01E−04 
                 8.77E−03 
               
               
                 ENSG00000173467 
                 155465 
                 AGR3 
                 −0.78 
                 3.04E−04 
                 8.81E−03 
               
               
                 ENSG00000164251 
                 2150 
                 F2RL1 
                 −0.87 
                 3.12E−04 
                 9.03E−03 
               
               
                 ENSG00000253250 
                 100127983 
                 C8orf88 
                 1.46 
                 3.14E−04 
                 9.09E−03 
               
               
                 ENSG00000090061 
                 8812 
                 CCNK 
                 −0.34 
                 3.23E−04 
                 9.32E−03 
               
               
                 ENSG00000101204 
                 1137 
                 CHRNA4 
                 1.64 
                 3.23E−04 
                 9.32E−03 
               
               
                 ENSG00000143127 
                 8515 
                 ITGA10 
                 1.00 
                 3.26E−04 
                 9.36E−03 
               
               
                 ENSG00000187800 
                 375033 
                 PEAR1 
                 1.54 
                 3.29E−04 
                 9.45E−03 
               
               
                 ENSG00000162909 
                 824 
                 CAPN2 
                 −0.49 
                 3.32E−04 
                 9.51E−03 
               
               
                 ENSG00000103316 
                 1428 
                 CRYM 
                 −1.06 
                 3.34E−04 
                 9.55E−03 
               
               
                 ENSG00000069869 
                 4734 
                 NEDD4 
                 0.92 
                 3.37E−04 
                 9.58E−03 
               
               
                 ENSG00000162407 
                 8613 
                 PPAP2B 
                 1.12 
                 3.37E−04 
                 9.58E−03 
               
               
                 ENSG00000143933 
                 805 
                 CALM2 
                 −0.58 
                 3.40E−04 
                 9.66E−03 
               
               
                 ENSG00000125827 
                 56255 
                 TMX4 
                 0.60 
                 3.41E−04 
                 9.67E−03 
               
               
                 ENSG00000185055 
                 NA 
                 EFCAB10 
                 −1.13 
                 3.47E−04 
                 9.82E−03 
               
               
                 ENSG00000029993 
                 3149 
                 HMGB3 
                 −0.96 
                 3.54E−04 
                 9.94E−03 
               
               
                 ENSG00000135424 
                 3679 
                 ITGA7 
                 1.29 
                 3.53E−04 
                 9.94E−03 
               
               
                 ENSG00000158373 
                 3017 
                 HIST1H2BD 
                 −0.54 
                 3.52E−04 
                 9.94E−03 
               
               
                 ENSG00000165097 
                 221656 
                 KDM1B 
                 −0.71 
                 3.53E−04 
                 9.94E−03 
               
               
                 ENSG00000173432 
                 6288 
                 SAA1 
                 −1.61 
                 3.55E−04 
                 9.95E−03 
               
               
                   
               
               
                 UIP (n = 3 samples); Non-UIP (n = 5 samples). Positive log2 fold change value indicates over-expression in UIP relative to Non UIP; negative log2 value indicates under-expression in UIP relative to Non UIP. In this analysis only patients without any smoking history were evaluated, hence this subset harbored only non-smokers. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Differentially expressed genes in UIP samples 
               
               
                 from smokers vs. Non-UIP samples from smokers. 
               
               
                 Table 11. Smokers 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Log2 Fold 
                   
                   
               
               
                   
                   
                   
                 Change 
               
               
                 Ensembl ID 
                 Entrez ID 
                 Gene symbol 
                 (UIP/NonUIP) 
                 p value 
                 FDR P value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 ENSG00000137968 
                 204962 
                 SLC44A5 
                 3.58 
                 2.38E−20 
                 3.68E−16 
               
               
                 ENSG00000099968 
                 23786 
                 BCL2L13 
                 −0.68 
                 3.12E−18 
                 2.41E−14 
               
               
                 ENSG00000168329 
                 1524 
                 CX3CR1 
                 2.27 
                 8.45E−14 
                 4.35E−10 
               
               
                 ENSG00000088882 
                 56265 
                 CPXM1 
                 2.72 
                 1.16E−11 
                 4.49E−08 
               
               
                 ENSG00000152672 
                 165530 
                 CLEC4F 
                 2.63 
                 1.78E−11 
                 5.49E−08 
               
               
                 ENSG00000129204 
                 9098 
                 USP6 
                 2.74 
                 5.40E−11 
                 1.39E−07 
               
               
                 ENSG00000132823 
                 51526 
                 OSER1 
                 −0.56 
                 3.27E−10 
                 7.21E−07 
               
               
                 ENSG00000177666 
                 57104 
                 PNPLA2 
                 −0.84 
                 9.60E−10 
                 1.85E−06 
               
               
                 ENSG00000125730 
                 718 
                 C3 
                 1.60 
                 1.11E−09 
                 1.90E−06 
               
               
                 ENSG00000198074 
                 57016 
                 AKR1B10 
                 −2.89 
                 1.97E−09 
                 3.04E−06 
               
               
                 ENSG00000198142 
                 65124 
                 SOWAHC 
                 −1.00 
                 3.09E−09 
                 4.34E−06 
               
               
                 ENSG00000112130 
                 9025 
                 RNF8 
                 −0.56 
                 4.53E−09 
                 5.83E−06 
               
               
                 ENSG00000255112 
                 57132 
                 CHMP1B 
                 −0.86 
                 1.94E−08 
                 2.31E−05 
               
               
                 ENSG00000145888 
                 2741 
                 GLRA1 
                 2.19 
                 2.15E−08 
                 2.37E−05 
               
               
                 ENSG00000151632 
                 1646 
                 AKR1C2 
                 −2.37 
                 2.60E−08 
                 2.68E−05 
               
               
                 ENSG00000238741 
                 677767 
                 SCARNA7 
                 0.58 
                 2.90E−08 
                 2.80E−05 
               
               
                 ENSG00000148948 
                 57689 
                 LRRC4C 
                 2.14 
                 3.13E−08 
                 2.84E−05 
               
               
                 ENSG00000179344 
                 3119 
                 HLA-DQB1 
                 2.30 
                 2.89E−07 
                 2.35E−04 
               
               
                 ENSG00000211789 
                 NA 
                 TRAV12-2 
                 2.44 
                 2.75E−07 
                 2.35E−04 
               
               
                 ENSG00000106565 
                 28959 
                 TMEM176B 
                 1.55 
                 3.23E−07 
                 2.44E−04 
               
               
                 ENSG00000204338 
                 NA 
                 CYP21A1P 
                 2.23 
                 3.32E−07 
                 2.44E−04 
               
               
                 ENSG00000010932 
                 2326 
                 FMO1 
                 2.17 
                 4.30E−07 
                 3.01E−04 
               
               
                 ENSG00000103742 
                 57722 
                 IGDCC4 
                 2.37 
                 4.82E−07 
                 3.24E−04 
               
               
                 ENSG00000162692 
                 7412 
                 VCAM1 
                 2.12 
                 5.91E−07 
                 3.80E−04 
               
               
                 ENSG00000158481 
                 911 
                 CD1C 
                 1.96 
                 6.26E−07 
                 3.87E−04 
               
               
                 ENSG00000136098 
                 4752 
                 NEK3 
                 0.67 
                 6.66E−07 
                 3.95E−04 
               
               
                 ENSG00000134375 
                 10440 
                 TIMM17A 
                 −0.48 
                 7.00E−07 
                 4.00E−04 
               
               
                 ENSG00000127951 
                 10875 
                 FGL2 
                 1.23 
                 1.18E−06 
                 6.49E−04 
               
               
                 ENSG00000185022 
                 23764 
                 MAFF 
                 −1.68 
                 1.22E−06 
                 6.49E−04 
               
               
                 ENSG00000100079 
                 3957 
                 LGALS2 
                 1.93 
                 1.51E−06 
                 7.56E−04 
               
               
                 ENSG00000151572 
                 121601 
                 ANO4 
                 2.28 
                 1.57E−06 
                 7.56E−04 
               
               
                 ENSG00000238460 
                 NA 
                   
                 1.65 
                 1.52E−06 
                 7.56E−04 
               
               
                 ENSG00000187527 
                 344905 
                 ATP13A5 
                 −2.18 
                 1.99E−06 
                 9.29E−04 
               
               
                 ENSG00000176153 
                 2877 
                 GPX2 
                 −2.11 
                 2.29E−06 
                 1.04E−03 
               
               
                 ENSG00000105559 
                 57664 
                 PLEKHA4 
                 1.30 
                 2.99E−06 
                 1.32E−03 
               
               
                 ENSG00000178115 
                 NA 
                 GOLGA8Q 
                 2.05 
                 3.27E−06 
                 1.40E−03 
               
               
                 ENSG00000137033 
                 90865 
                 IL33 
                 1.41 
                 4.10E−06 
                 1.68E−03 
               
               
                 ENSG00000196735 
                 3117 
                 HLA-DQA1 
                 2.10 
                 4.14E−06 
                 1.68E−03 
               
               
                 ENSG00000007944 
                 29116 
                 MYLIP 
                 −0.46 
                 4.53E−06 
                 1.79E−03 
               
               
                 ENSG00000130695 
                 64793 
                 CEP85 
                 −0.76 
                 4.86E−06 
                 1.88E−03 
               
               
                 ENSG00000262539 
                 NA 
                   
                 −2.01 
                 5.01E−06 
                 1.89E−03 
               
               
                 ENSG00000174194 
                 NA 
                 NA 
                 1.27 
                 5.42E−06 
                 1.99E−03 
               
               
                 ENSG00000178187 
                 285676 
                 ZNF454 
                 1.08 
                 6.40E−06 
                 2.25E−03 
               
               
                 ENSG00000204256 
                 6046 
                 BRD2 
                 −0.33 
                 6.28E−06 
                 2.25E−03 
               
               
                 ENSG00000002933 
                 55365 
                 TMEM176A 
                 1.30 
                 6.91E−06 
                 2.36E−03 
               
               
                 ENSG00000196139 
                 8644 
                 AKR1C3 
                 −1.45 
                 7.02E−06 
                 2.36E−03 
               
               
                 ENSG00000186529 
                 4051 
                 CYP4F3 
                 −1.80 
                 8.32E−06 
                 2.66E−03 
               
               
                 ENSG00000227097 
                 NA 
                 RPS28P7 
                 1.59 
                 8.45E−06 
                 2.66E−03 
               
               
                 ENSG00000244486 
                 91179 
                 SCARF2 
                 1.00 
                 8.18E−06 
                 2.66E−03 
               
               
                 ENSG00000172985 
                 344558 
                 SH3RF3 
                 0.84 
                 9.51E−06 
                 2.94E−03 
               
               
                 ENSG00000023171 
                 57476 
                 GRAMD1B 
                 −1.22 
                 1.13E−05 
                 3.21E−03 
               
               
                 ENSG00000065613 
                 9748 
                 SLK 
                 −0.49 
                 1.09E−05 
                 3.21E−03 
               
               
                 ENSG00000143603 
                 3782 
                 KCNN3 
                 1.09 
                 1.07E−05 
                 3.21E−03 
               
               
                 ENSG00000154096 
                 7070 
                 THY1 
                 2.05 
                 1.14E−05 
                 3.21E−03 
               
               
                 ENSG00000178562 
                 940 
                 CD28 
                 2.08 
                 1.11E−05 
                 3.21E−03 
               
               
                 ENSG00000196839 
                 100 
                 ADA 
                 1.10 
                 1.16E−05 
                 3.21E−03 
               
               
                 ENSG00000159618 
                 221188 
                 ADGRG5 
                 1.59 
                 1.21E−05 
                 3.27E−03 
               
               
                 ENSG00000128309 
                 4357 
                 MPST 
                 −0.73 
                 1.36E−05 
                 3.61E−03 
               
               
                 ENSG00000168229 
                 5729 
                 PTGDR 
                 1.61 
                 1.39E−05 
                 3.62E−03 
               
               
                 ENSG00000125510 
                 4987 
                 OPRL1 
                 1.56 
                 1.45E−05 
                 3.73E−03 
               
               
                 ENSG00000017427 
                 3479 
                 IGF1 
                 1.86 
                 1.54E−05 
                 3.83E−03 
               
               
                 ENSG00000159228 
                 873 
                 CBR1 
                 −1.00 
                 1.53E−05 
                 3.83E−03 
               
               
                 ENSG00000136490 
                 80774 
                 LIMD2 
                 1.68 
                 1.76E−05 
                 4.19E−03 
               
               
                 ENSG00000177156 
                 6888 
                 TALDO1 
                 −0.78 
                 1.76E−05 
                 4.19E−03 
               
               
                 ENSG00000225614 
                 84627 
                 ZNF469 
                 0.98 
                 1.72E−05 
                 4.19E−03 
               
               
                 ENSG00000218336 
                 55714 
                 TENM3 
                 1.69 
                 1.88E−05 
                 4.40E−03 
               
               
                 ENSG00000151693 
                 8853 
                 ASAP2 
                 −0.60 
                 1.97E−05 
                 4.54E−03 
               
               
                 ENSG00000211941 
                 NA 
                 IGHV3-11 
                 2.04 
                 2.00E−05 
                 4.54E−03 
               
               
                 ENSG00000140961 
                 29948 
                 OSGIN1 
                 −1.25 
                 2.11E−05 
                 4.73E−03 
               
               
                 ENSG00000124782 
                 6239 
                 RREB1 
                 −0.41 
                 2.30E−05 
                 5.08E−03 
               
               
                 ENSG00000103222 
                 4363 
                 ABCC1 
                 −0.81 
                 2.55E−05 
                 5.47E−03 
               
               
                 ENSG00000196664 
                 51284 
                 TLR7 
                 1.53 
                 2.54E−05 
                 5.47E−03 
               
               
                 ENSG00000148357 
                 256158 
                 HMCN2 
                 1.92 
                 2.61E−05 
                 5.53E−03 
               
               
                 ENSG00000124151 
                 8202 
                 NCOA3 
                 −0.39 
                 2.87E−05 
                 6.00E−03 
               
               
                 ENSG00000211653 
                 NA 
                 IGLV1-40 
                 1.99 
                 2.98E−05 
                 6.06E−03 
               
               
                 ENSG00000230006 
                 645784 
                 ANKRD36BP2 
                 1.82 
                 2.97E−05 
                 6.06E−03 
               
               
                 ENSG00000106809 
                 4969 
                 OGN 
                 1.85 
                 3.11E−05 
                 6.23E−03 
               
               
                 ENSG00000162877 
                 148811 
                 PM20D1 
                 1.70 
                 3.17E−05 
                 6.28E−03 
               
               
                 ENSG00000128016 
                 7538 
                 ZFP36 
                 −1.41 
                 3.51E−05 
                 6.77E−03 
               
               
                 ENSG00000196345 
                 55888 
                 ZKSCAN7 
                 0.83 
                 3.49E−05 
                 6.77E−03 
               
               
                 ENSG00000108821 
                 1277 
                 COL1A1 
                 1.88 
                 3.56E−05 
                 6.78E−03 
               
               
                 ENSG00000137573 
                 23213 
                 SULF1 
                 1.63 
                 3.68E−05 
                 6.93E−03 
               
               
                 ENSG00000197993 
                 3792 
                 KEL 
                 1.86 
                 3.93E−05 
                 7.32E−03 
               
               
                 ENSG00000170153 
                 57484 
                 RNF150 
                 1.44 
                 4.36E−05 
                 8.00E−03 
               
               
                 ENSG00000130513 
                 9518 
                 GDF15 
                 −1.73 
                 4.55E−05 
                 8.20E−03 
               
               
                 ENSG00000174123 
                 81793 
                 TLR10 
                 1.81 
                 4.57E−05 
                 8.20E−03 
               
               
                 ENSG00000110076 
                 9379 
                 NRXN2 
                 1.95 
                 4.68E−05 
                 8.30E−03 
               
               
                 ENSG00000182551 
                 55256 
                 ADI1 
                 −0.52 
                 5.20E−05 
                 9.08E−03 
               
               
                 ENSG00000182557 
                 201305 
                 SPNS3 
                 1.65 
                 5.23E−05 
                 9.08E−03 
               
               
                 ENSG00000117215 
                 26279 
                 PLA2G2D 
                 1.94 
                 5.54E−05 
                 9.50E−03 
               
               
                 ENSG00000128285 
                 2847 
                 MCHR1 
                 1.85 
                 5.80E−05 
                 9.83E−03 
               
               
                 ENSG00000183813 
                 1233 
                 CCR4 
                 1.90 
                 6.00E−05 
                 1.01E−02 
               
               
                 ENSG00000007312 
                 974 
                 CD79B 
                 1.81 
                 6.30E−05 
                 1.04E−02 
               
               
                 ENSG00000163817 
                 54716 
                 SLC6A20 
                 1.85 
                 6.43E−05 
                 1.06E−02 
               
               
                 ENSG00000102802 
                 84935 
                 MEDAG 
                 1.85 
                 6.69E−05 
                 1.09E−02 
               
               
                 ENSG00000101134 
                 55816 
                 DOK5 
                 1.90 
                 7.00E−05 
                 1.10E−02 
               
               
                 ENSG00000102362 
                 94121 
                 SYTL4 
                 −0.80 
                 6.89E−05 
                 1.10E−02 
               
               
                 ENSG00000128000 
                 163131 
                 ZNF780B 
                 0.66 
                 7.03E−05 
                 1.10E−02 
               
               
                 ENSG00000256229 
                 90649 
                 ZNF486 
                 1.00 
                 7.04E−05 
                 1.10E−02 
               
               
                 ENSG00000086102 
                 4799 
                 NFX1 
                 −0.36 
                 7.46E−05 
                 1.14E−02 
               
               
                 ENSG00000099875 
                 2872 
                 MKNK2 
                 −0.58 
                 7.58E−05 
                 1.14E−02 
               
               
                 ENSG00000171502 
                 255631 
                 COL24A1 
                 1.24 
                 7.69E−05 
                 1.14E−02 
               
               
                 ENSG00000211637 
                 NA 
                 IGLV4-69 
                 1.91 
                 7.66E−05 
                 1.14E−02 
               
               
                 ENSG00000244731 
                 720 
                 C4A 
                 1.50 
                 7.70E−05 
                 1.14E−02 
               
               
                 ENSG00000082641 
                 4779 
                 NFE2L1 
                 −0.32 
                 7.79E−05 
                 1.14E−02 
               
               
                 ENSG00000136802 
                 56262 
                 LRRC8A 
                 −0.91 
                 8.12E−05 
                 1.18E−02 
               
               
                 ENSG00000225784 
                 NA 
                 NA 
                 1.81 
                 8.26E−05 
                 1.19E−02 
               
               
                 ENSG00000181631 
                 53829 
                 P2RY13 
                 1.57 
                 8.40E−05 
                 1.20E−02 
               
               
                 ENSG00000116031 
                 50489 
                 CD207 
                 1.47 
                 8.80E−05 
                 1.25E−02 
               
               
                 ENSG00000108106 
                 27338 
                 UBE2S 
                 −0.71 
                 9.40E−05 
                 1.32E−02 
               
               
                 ENSG00000105639 
                 3718 
                 JAK3 
                 1.60 
                 1.06E−04 
                 1.43E−02 
               
               
                 ENSG00000125804 
                 284800 
                 FAM182A 
                 1.82 
                 1.07E−04 
                 1.43E−02 
               
               
                 ENSG00000139722 
                 79720 
                 VPS37B 
                 −0.67 
                 1.07E−04 
                 1.43E−02 
               
               
                 ENSG00000157557 
                 2114 
                 ETS2 
                 −0.85 
                 1.03E−04 
                 1.43E−02 
               
               
                 ENSG00000165841 
                 1557 
                 CYP2C19 
                 −1.37 
                 1.07E−04 
                 1.43E−02 
               
               
                 ENSG00000182487 
                 654816 
                 NCF1B 
                 1.59 
                 1.05E−04 
                 1.43E−02 
               
               
                 ENSG00000171847 
                 55138 
                 FAM90A1 
                 1.18 
                 1.08E−04 
                 1.43E−02 
               
               
                 ENSG00000162804 
                 25992 
                 SNED1 
                 0.71 
                 1.09E−04 
                 1.43E−02 
               
               
                 ENSG00000186184 
                 51082 
                 POLR1D 
                 −0.67 
                 1.11E−04 
                 1.43E−02 
               
               
                 ENSG00000172493 
                 4299 
                 AFF1 
                 −0.34 
                 1.14E−04 
                 1.47E−02 
               
               
                 ENSG00000179954 
                 284297 
                 SSC5D 
                 1.43 
                 1.15E−04 
                 1.47E−02 
               
               
                 ENSG00000244682 
                 NA 
                 FCGR2C 
                 1.54 
                 1.17E−04 
                 1.48E−02 
               
               
                 ENSG00000081148 
                 50939 
                 IMPG2 
                 0.85 
                 1.23E−04 
                 1.54E−02 
               
               
                 ENSG00000126353 
                 1236 
                 CCR7 
                 1.51 
                 1.26E−04 
                 1.57E−02 
               
               
                 ENSG00000197705 
                 57565 
                 KLHL14 
                 1.75 
                 1.27E−04 
                 1.57E−02 
               
               
                 ENSG00000232268 
                 390037 
                 OR52I1 
                 1.53 
                 1.30E−04 
                 1.59E−02 
               
               
                 ENSG00000099204 
                 3983 
                 ABLIM1 
                 −0.69 
                 1.32E−04 
                 1.61E−02 
               
               
                 ENSG00000158477 
                 909 
                 CD1A 
                 1.84 
                 1.39E−04 
                 1.68E−02 
               
               
                 ENSG00000172336 
                 10248 
                 POP7 
                 −0.45 
                 1.40E−04 
                 1.68E−02 
               
               
                 ENSG00000138109 
                 1559 
                 CYP2C9 
                 −1.47 
                 1.44E−04 
                 1.71E−02 
               
               
                 ENSG00000124766 
                 6659 
                 SOX4 
                 −0.89 
                 1.50E−04 
                 1.77E−02 
               
               
                 ENSG00000114115 
                 5947 
                 RBP1 
                 0.96 
                 1.57E−04 
                 1.84E−02 
               
               
                 ENSG00000156463 
                 153769 
                 SH3RF2 
                 −1.28 
                 1.62E−04 
                 1.88E−02 
               
               
                 ENSG00000038358 
                 23644 
                 EDC4 
                 −0.26 
                 1.64E−04 
                 1.88E−02 
               
               
                 ENSG00000211899 
                 NA 
                 IGHM 
                 1.79 
                 1.64E−04 
                 1.88E−02 
               
               
                 ENSG00000263503 
                 NA 
                   
                 −1.70 
                 1.66E−04 
                 1.88E−02 
               
               
                 ENSG00000005955 
                 NA 
                 NA 
                 −0.32 
                 1.71E−04 
                 1.91E−02 
               
               
                 ENSG00000144040 
                 94097 
                 SFXN5 
                 0.69 
                 1.71E−04 
                 1.91E−02 
               
               
                 ENSG00000105058 
                 26017 
                 FAM32A 
                 −0.37 
                 1.90E−04 
                 2.11E−02 
               
               
                 ENSG00000135837 
                 9857 
                 CEP350 
                 −0.29 
                 1.92E−04 
                 2.12E−02 
               
               
                 ENSG00000205148 
                 NA 
                 NA 
                 1.63 
                 1.93E−04 
                 2.12E−02 
               
               
                 ENSG00000028277 
                 5452 
                 POU2F2 
                 1.61 
                 1.97E−04 
                 2.15E−02 
               
               
                 ENSG00000211747 
                 NA 
                 TRBV20-1 
                 1.78 
                 2.04E−04 
                 2.20E−02 
               
               
                 ENSG00000148730 
                 1979 
                 EIF4EBP2 
                 −0.51 
                 2.25E−04 
                 2.40E−02 
               
               
                 ENSG00000181036 
                 343413 
                 FCRL6 
                 1.52 
                 2.26E−04 
                 2.40E−02 
               
               
                 ENSG00000138660 
                 55435 
                 AP1AR 
                 −0.61 
                 2.29E−04 
                 2.41E−02 
               
               
                 ENSG00000144619 
                 152330 
                 CNTN4 
                 1.25 
                 2.28E−04 
                 2.41E−02 
               
               
                 ENSG00000000971 
                 3075 
                 CFH 
                 0.81 
                 2.42E−04 
                 2.46E−02 
               
               
                 ENSG00000099251 
                 158160 
                 HSD17B7P2 
                 0.95 
                 2.44E−04 
                 2.46E−02 
               
               
                 ENSG00000156140 
                 9508 
                 ADAMTS3 
                 1.24 
                 2.42E−04 
                 2.46E−02 
               
               
                 ENSG00000163113 
                 NA 
                 NA 
                 −0.63 
                 2.41E−04 
                 2.46E−02 
               
               
                 ENSG00000181458 
                 55076 
                 TMEM45A 
                 1.40 
                 2.37E−04 
                 2.46E−02 
               
               
                 ENSG00000251287 
                 644974 
                 ALG1L2 
                 1.42 
                 2.44E−04 
                 2.46E−02 
               
               
                 ENSG00000086544 
                 80271 
                 ITPKC 
                 −0.57 
                 2.52E−04 
                 2.52E−02 
               
               
                 ENSG00000167984 
                 197358 
                 NLRC3 
                 1.07 
                 2.55E−04 
                 2.54E−02 
               
               
                 ENSG00000149633 
                 85449 
                 KIAA1755 
                 1.69 
                 2.59E−04 
                 2.56E−02 
               
               
                 ENSG00000102271 
                 56062 
                 KLHL4 
                 1.75 
                 2.62E−04 
                 2.58E−02 
               
               
                 ENSG00000137815 
                 23168 
                 RTF1 
                 −0.36 
                 2.81E−04 
                 2.72E−02 
               
               
                 ENSG00000141682 
                 5366 
                 PMAIP1 
                 −1.36 
                 2.81E−04 
                 2.72E−02 
               
               
                 ENSG00000179909 
                 7710 
                 ZNF154 
                 1.14 
                 2.80E−04 
                 2.72E−02 
               
               
                 ENSG00000110427 
                 25758 
                 KIAA1549L 
                 1.52 
                 2.89E−04 
                 2.77E−02 
               
               
                 ENSG00000144567 
                 79137 
                 FAM134A 
                 −0.43 
                 2.97E−04 
                 2.83E−02 
               
               
                 ENSG00000206561 
                 8292 
                 COLQ 
                 0.81 
                 3.01E−04 
                 2.85E−02 
               
               
                 ENSG00000100304 
                 23170 
                 TTLL12 
                 −0.92 
                 3.11E−04 
                 2.86E−02 
               
               
                 ENSG00000108852 
                 4355 
                 MPP2 
                 1.61 
                 3.07E−04 
                 2.86E−02 
               
               
                 ENSG00000181350 
                 388341 
                 LRRC75A 
                 1.56 
                 3.11E−04 
                 2.86E−02 
               
               
                 ENSG00000186350 
                 6256 
                 RXRA 
                 −0.53 
                 3.08E−04 
                 2.86E−02 
               
               
                 ENSG00000253816 
                 NA 
                   
                 0.93 
                 3.05E−04 
                 2.86E−02 
               
               
                 ENSG00000026751 
                 57823 
                 SLAMF7 
                 1.36 
                 3.13E−04 
                 2.86E−02 
               
               
                 ENSG00000142178 
                 150094 
                 SIK1 
                 −1.46 
                 3.17E−04 
                 2.86E−02 
               
               
                 ENSG00000148848 
                 8038 
                 ADAM12 
                 1.19 
                 3.16E−04 
                 2.86E−02 
               
               
                 ENSG00000148339 
                 114789 
                 SLC25A25 
                 −0.71 
                 3.20E−04 
                 2.88E−02 
               
               
                 ENSG00000137747 
                 84000 
                 TMPRSS13 
                 −0.89 
                 3.23E−04 
                 2.88E−02 
               
               
                 ENSG00000164061 
                 8927 
                 BSN 
                 1.16 
                 3.29E−04 
                 2.92E−02 
               
               
                 ENSG00000102221 
                 9767 
                 JADE3 
                 −0.48 
                 3.34E−04 
                 2.95E−02 
               
               
                 ENSG00000134291 
                 79022 
                 TMEM106C 
                 −0.84 
                 3.67E−04 
                 3.20E−02 
               
               
                 ENSG00000160007 
                 2909 
                 ARHGAP35 
                 −0.32 
                 3.69E−04 
                 3.20E−02 
               
               
                 ENSG00000198060 
                 54708 
                 MARCH5 
                 −0.39 
                 3.67E−04 
                 3.20E−02 
               
               
                 ENSG00000111725 
                 5564 
                 PRKAB1 
                 −0.72 
                 3.71E−04 
                 3.20E−02 
               
               
                 ENSG00000211598 
                 NA 
                 IGKV4-1 
                 1.72 
                 3.76E−04 
                 3.23E−02 
               
               
                 ENSG00000101096 
                 4773 
                 NFATC2 
                 0.89 
                 3.82E−04 
                 3.25E−02 
               
               
                 ENSG00000215156 
                 646652 
                   
                 1.07 
                 3.83E−04 
                 3.25E−02 
               
               
                 ENSG00000117090 
                 6504 
                 SLAMF1 
                 1.64 
                 3.89E−04 
                 3.26E−02 
               
               
                 ENSG00000211892 
                 NA 
                 IGHG4 
                 1.71 
                 3.88E−04 
                 3.26E−02 
               
               
                 ENSG00000129245 
                 9513 
                 FXR2 
                 −0.35 
                 4.00E−04 
                 3.33E−02 
               
               
                 ENSG00000211685 
                 NA 
                 IGLC7 
                 1.71 
                 4.06E−04 
                 3.37E−02 
               
               
                 ENSG00000085265 
                 2219 
                 FCN1 
                 1.67 
                 4.11E−04 
                 3.38E−02 
               
               
                 ENSG00000108691 
                 6347 
                 CCL2 
                 1.64 
                 4.16E−04 
                 3.38E−02 
               
               
                 ENSG00000109787 
                 51274 
                 KLF3 
                 −0.67 
                 4.15E−04 
                 3.38E−02 
               
               
                 ENSG00000243264 
                 NA 
                 IGKV2D-29 
                 1.71 
                 4.13E−04 
                 3.38E−02 
               
               
                 ENSG00000178199 
                 340152 
                 ZC3H12D 
                 1.65 
                 4.19E−04 
                 3.38E−02 
               
               
                 ENSG00000152413 
                 9456 
                 HOMER1 
                 −0.58 
                 4.24E−04 
                 3.39E−02 
               
               
                 ENSG00000211893 
                 NA 
                 IGHG2 
                 1.70 
                 4.25E−04 
                 3.39E−02 
               
               
                 ENSG00000241755 
                 NA 
                 IGKV1-9 
                 1.70 
                 4.21E−04 
                 3.39E−02 
               
               
                 ENSG00000017797 
                 10928 
                 RALBP1 
                 −0.39 
                 4.36E−04 
                 3.44E−02 
               
               
                 ENSG00000136826 
                 9314 
                 KLF4 
                 −1.16 
                 4.37E−04 
                 3.44E−02 
               
               
                 ENSG00000102245 
                 959 
                 CD40LG 
                 1.65 
                 4.53E−04 
                 3.49E−02 
               
               
                 ENSG00000144792 
                 285349 
                 ZNF660 
                 0.91 
                 4.51E−04 
                 3.49E−02 
               
               
                 ENSG00000151012 
                 23657 
                 SLC7A11 
                 −1.55 
                 4.45E−04 
                 3.49E−02 
               
               
                 ENSG00000182218 
                 84439 
                 HHIPL1 
                 1.55 
                 4.48E−04 
                 3.49E−02 
               
               
                 ENSG00000204961 
                 9752 
                 PCDHA9 
                 1.11 
                 4.54E−04 
                 3.49E−02 
               
               
                 ENSG00000160229 
                 NA 
                 ZNF66 
                 0.77 
                 4.59E−04 
                 3.51E−02 
               
               
                 ENSG00000087842 
                 8544 
                 PIR 
                 −0.94 
                 4.67E−04 
                 3.55E−02 
               
               
                 ENSG00000108344 
                 5709 
                 PSMD3 
                 −0.35 
                 4.76E−04 
                 3.60E−02 
               
               
                 ENSG00000167077 
                 150365 
                 MEI1 
                 1.53 
                 4.87E−04 
                 3.67E−02 
               
               
                 ENSG00000211625 
                 NA 
                 IGKV3D-20 
                 1.68 
                 4.91E−04 
                 3.68E−02 
               
               
                 ENSG00000087152 
                 56970 
                 ATXN7L3 
                 −0.27 
                 5.09E−04 
                 3.80E−02 
               
               
                 ENSG00000138166 
                 1847 
                 DUSP5 
                 −1.57 
                 5.15E−04 
                 3.82E−02 
               
               
                 ENSG00000187987 
                 222696 
                 ZSCAN23 
                 1.19 
                 5.20E−04 
                 3.84E−02 
               
               
                 ENSG00000166676 
                 780776 
                 TVP23A 
                 1.60 
                 5.24E−04 
                 3.85E−02 
               
               
                 ENSG00000107736 
                 64072 
                 CDH23 
                 1.28 
                 5.27E−04 
                 3.86E−02 
               
               
                 ENSG00000109685 
                 7468 
                 WHSC1 
                 −0.43 
                 5.41E−04 
                 3.93E−02 
               
               
                 ENSG00000240382 
                 NA 
                 IGKV1-17 
                 1.67 
                 5.43E−04 
                 3.93E−02 
               
               
                 ENSG00000196724 
                 147686 
                 ZNF418 
                 0.90 
                 5.47E−04 
                 3.95E−02 
               
               
                 ENSG00000178031 
                 92949 
                 ADAMTSL1 
                 1.64 
                 5.54E−04 
                 3.98E−02 
               
               
                 ENSG00000109854 
                 10553 
                 HTATIP2 
                 −0.72 
                 5.69E−04 
                 4.03E−02 
               
               
                 ENSG00000128606 
                 10234 
                 LRRC17 
                 1.37 
                 5.69E−04 
                 4.03E−02 
               
               
                 ENSG00000211974 
                 NA 
                   
                 1.66 
                 5.69E−04 
                 4.03E−02 
               
               
                 ENSG00000145002 
                 653333 
                 FAM86B2 
                 1.42 
                 5.90E−04 
                 4.14E−02 
               
               
                 ENSG00000185271 
                 123103 
                 KLHL33 
                 1.66 
                 5.88E−04 
                 4.14E−02 
               
               
                 ENSG00000147394 
                 7739 
                 ZNF185 
                 −0.95 
                 6.04E−04 
                 4.22E−02 
               
               
                 ENSG00000105369 
                 973 
                 CD79A 
                 1.65 
                 6.09E−04 
                 4.23E−02 
               
               
                 ENSG00000205403 
                 3426 
                 CFI 
                 0.87 
                 6.11E−04 
                 4.23E−02 
               
               
                 ENSG00000242732 
                 340526 
                 RGAG4 
                 0.69 
                 6.16E−04 
                 4.24E−02 
               
               
                 ENSG00000074410 
                 771 
                 CA12 
                 −1.59 
                 6.25E−04 
                 4.29E−02 
               
               
                 ENSG00000107020 
                 55848 
                 PLGRKT 
                 0.66 
                 6.34E−04 
                 4.31E−02 
               
               
                 ENSG00000145555 
                 4651 
                 MYO10 
                 −0.45 
                 6.31E−04 
                 4.31E−02 
               
               
                 ENSG00000183486 
                 4600 
                 MX2 
                 −1.26 
                 6.46E−04 
                 4.37E−02 
               
               
                 ENSG00000066827 
                 57623 
                 ZFAT 
                 0.33 
                 6.62E−04 
                 4.46E−02 
               
               
                 ENSG00000225217 
                 NA 
                 HSPA7 
                 1.46 
                 6.65E−04 
                 4.46E−02 
               
               
                 ENSG00000143851 
                 5778 
                 PTPN7 
                 1.35 
                 6.77E−04 
                 4.50E−02 
               
               
                 ENSG00000161381 
                 57125 
                 PLXDC1 
                 1.44 
                 6.76E−04 
                 4.50E−02 
               
               
                 ENSG00000134775 
                 80206 
                 FHOD3 
                 1.24 
                 6.89E−04 
                 4.55E−02 
               
               
                 ENSG00000154040 
                 26256 
                 CABYR 
                 −1.18 
                 6.89E−04 
                 4.55E−02 
               
               
                 ENSG00000239951 
                 NA 
                 IGKV3-20 
                 1.64 
                 6.97E−04 
                 4.58E−02 
               
               
                 ENSG00000137709 
                 25833 
                 POU2F3 
                 −0.82 
                 7.04E−04 
                 4.60E−02 
               
               
                 ENSG00000123159 
                 10755 
                 GIPC1 
                 −0.48 
                 7.11E−04 
                 4.61E−02 
               
               
                 ENSG00000211939 
                 NA 
                 NA 
                 1.63 
                 7.10E−04 
                 4.61E−02 
               
               
                 ENSG00000211666 
                 NA 
                 IGLV2-14 
                 1.63 
                 7.17E−04 
                 4.63E−02 
               
               
                 ENSG00000227507 
                 4050 
                 LTB 
                 1.60 
                 7.24E−04 
                 4.66E−02 
               
               
                 ENSG00000171714 
                 203859 
                 ANO5 
                 1.12 
                 7.41E−04 
                 4.75E−02 
               
               
                 ENSG00000078589 
                 27334 
                 P2RY10 
                 1.38 
                 7.53E−04 
                 4.76E−02 
               
               
                 ENSG00000108381 
                 443 
                 ASPA 
                 1.44 
                 7.50E−04 
                 4.76E−02 
               
               
                 ENSG00000186310 
                 4675 
                 NAP1L3 
                 1.58 
                 7.47E−04 
                 4.76E−02 
               
               
                 ENSG00000164398 
                 23305 
                 ACSL6 
                 1.19 
                 7.61E−04 
                 4.80E−02 
               
               
                 ENSG00000117122 
                 4237 
                 MFAP2 
                 1.28 
                 7.65E−04 
                 4.80E−02 
               
               
                 ENSG00000145536 
                 170690 
                 ADAMTS16 
                 1.62 
                 7.71E−04 
                 4.80E−02 
               
               
                 ENSG00000251402 
                 NA 
                 FAM90A25P 
                 1.02 
                 7.70E−04 
                 4.80E−02 
               
               
                 ENSG00000161681 
                 50944 
                 SHANK1 
                 1.62 
                 7.95E−04 
                 4.93E−02 
               
               
                 ENSG00000130584 
                 140685 
                 ZBTB46 
                 0.99 
                 8.00E−04 
                 4.93E−02 
               
               
                 ENSG00000204839 
                 642475 
                 MROH6 
                 −1.17 
                 8.02E−04 
                 4.93E−02 
               
               
                 ENSG00000204544 
                 394263 
                 MUC21 
                 −1.52 
                 8.06E−04 
                 4.94E−02 
               
               
                 ENSG00000112245 
                 7803 
                 PTP4A1 
                 −0.59 
                 8.14E−04 
                 4.97E−02 
               
               
                 ENSG00000137265 
                 3662 
                 IRF4 
                 1.61 
                 8.28E−04 
                 5.04E−02 
               
               
                 ENSG00000105364 
                 51073 
                 MRPL4 
                 −0.56 
                 8.39E−04 
                 5.06E−02 
               
               
                 ENSG00000178922 
                 81888 
                 HYI 
                 0.84 
                 8.36E−04 
                 5.06E−02 
               
               
                 ENSG00000118849 
                 5918 
                 RARRES1 
                 1.24 
                 8.47E−04 
                 5.09E−02 
               
               
                 ENSG00000212743 
                 NA 
                   
                 1.23 
                 8.58E−04 
                 5.13E−02 
               
               
                 ENSG00000135074 
                 8728 
                 ADAM19 
                 1.42 
                 8.76E−04 
                 5.16E−02 
               
               
                 ENSG00000152689 
                 25780 
                 RASGRP3 
                 1.42 
                 8.72E−04 
                 5.16E−02 
               
               
                 ENSG00000154640 
                 10950 
                 BTG3 
                 −0.77 
                 8.74E−04 
                 5.16E−02 
               
               
                 ENSG00000196581 
                 55966 
                 AJAP1 
                 −1.59 
                 8.74E−04 
                 5.16E−02 
               
               
                 ENSG00000211950 
                 NA 
                 IGHV1-24 
                 1.60 
                 9.04E−04 
                 5.30E−02 
               
               
                 ENSG00000188171 
                 199777 
                 ZNF626 
                 0.72 
                 9.17E−04 
                 5.36E−02 
               
               
                 ENSG00000134490 
                 85019 
                 TMEM241 
                 0.50 
                 9.27E−04 
                 5.40E−02 
               
               
                 ENSG00000186854 
                 129293 
                 TRABD2A 
                 1.13 
                 9.34E−04 
                 5.42E−02 
               
               
                 ENSG00000173198 
                 10800 
                 CYSLTR1 
                 1.16 
                 9.39E−04 
                 5.43E−02 
               
               
                 ENSG00000132669 
                 54453 
                 RIN2 
                 −0.47 
                 9.54E−04 
                 5.48E−02 
               
               
                 ENSG00000211640 
                 NA 
                 IGLV6-57 
                 1.59 
                 9.52E−04 
                 5.48E−02 
               
               
                 ENSG00000159450 
                 7062 
                 TCHH 
                 −1.34 
                 9.59E−04 
                 5.48E−02 
               
               
                 ENSG00000143515 
                 57198 
                 ATP8B2 
                 0.79 
                 9.73E−04 
                 5.54E−02 
               
               
                 ENSG00000198734 
                 2153 
                 F5 
                 1.10 
                 9.90E−04 
                 5.62E−02 
               
               
                 ENSG00000229645 
                 NA 
                 NA 
                 1.32 
                 9.99E−04 
                 5.65E−02 
               
               
                 ENSG00000106333 
                 5118 
                 PCOLCE 
                 1.21 
                 1.02E−03 
                 5.66E−02 
               
               
                 ENSG00000166869 
                 63928 
                 CHP2 
                 1.49 
                 1.01E−03 
                 5.66E−02 
               
               
                 ENSG00000243238 
                 NA 
                 IGKV2-30 
                 1.59 
                 1.02E−03 
                 5.66E−02 
               
               
                 ENSG00000259236 
                 NA 
                 GOLGA8VP 
                 1.52 
                 1.01E−03 
                 5.66E−02 
               
               
                 ENSG00000240864 
                 NA 
                 IGKV1-16 
                 1.59 
                 1.02E−03 
                 5.67E−02 
               
               
                 ENSG00000170509 
                 345275 
                 HSD17B13 
                 1.49 
                 1.03E−03 
                 5.68E−02 
               
               
                 ENSG00000235602 
                 642559 
                 POU5F1P3 
                 1.51 
                 1.06E−03 
                 5.84E−02 
               
               
                 ENSG00000125813 
                 5075 
                 PAX1 
                 1.57 
                 1.10E−03 
                 6.04E−02 
               
               
                 ENSG00000138413 
                 3417 
                 IDH1 
                 −0.69 
                 1.11E−03 
                 6.04E−02 
               
               
                 ENSG00000161896 
                 117283 
                 IP6K3 
                 −1.20 
                 1.11E−03 
                 6.04E−02 
               
               
                 ENSG00000183624 
                 56941 
                 HMCES 
                 −0.49 
                 1.11E−03 
                 6.04E−02 
               
               
                 ENSG00000196834 
                 653269 
                 POTEI 
                 1.56 
                 1.11E−03 
                 6.04E−02 
               
               
                 ENSG00000110777 
                 5450 
                 POU2AF1 
                 1.42 
                 1.14E−03 
                 6.10E−02 
               
               
                 ENSG00000183773 
                 150209 
                 AIFM3 
                 1.17 
                 1.14E−03 
                 6.10E−02 
               
               
                 ENSG00000225698 
                 NA 
                 IGHV3-72 
                 1.57 
                 1.13E−03 
                 6.10E−02 
               
               
                 ENSG00000023445 
                 330 
                 BIRC3 
                 0.84 
                 1.18E−03 
                 6.27E−02 
               
               
                 ENSG00000100078 
                 50487 
                 PLA2G3 
                 1.42 
                 1.18E−03 
                 6.27E−02 
               
               
                 ENSG00000116690 
                 10216 
                 PRG4 
                 1.56 
                 1.19E−03 
                 6.27E−02 
               
               
                 ENSG00000136011 
                 55576 
                 STAB2 
                 1.54 
                 1.19E−03 
                 6.27E−02 
               
               
                 ENSG00000172986 
                 727936 
                 GXYLT2 
                 0.82 
                 1.19E−03 
                 6.27E−02 
               
               
                 ENSG00000196344 
                 131 
                 ADH7 
                 −1.54 
                 1.19E−03 
                 6.27E−02 
               
               
                 ENSG00000197006 
                 51108 
                 METTL9 
                 −0.35 
                 1.21E−03 
                 6.33E−02 
               
               
                 ENSG00000087303 
                 22795 
                 NID2 
                 1.37 
                 1.22E−03 
                 6.34E−02 
               
               
                 ENSG00000211947 
                 NA 
                 IGHV3-21 
                 1.56 
                 1.23E−03 
                 6.38E−02 
               
               
                 ENSG00000170471 
                 57148 
                 RALGAPB 
                 −0.27 
                 1.23E−03 
                 6.39E−02 
               
               
                 ENSG00000146374 
                 84870 
                 RSPO3 
                 1.55 
                 1.25E−03 
                 6.45E−02 
               
               
                 ENSG00000221970 
                 346528 
                 OR2A1 
                 1.49 
                 1.26E−03 
                 6.48E−02 
               
               
                 ENSG00000163354 
                 127579 
                 DCST2 
                 1.15 
                 1.27E−03 
                 6.50E−02 
               
               
                 ENSG00000008277 
                 53616 
                 ADAM22 
                 0.80 
                 1.28E−03 
                 6.51E−02 
               
               
                 ENSG00000198829 
                 56670 
                 SUCNR1 
                 1.51 
                 1.27E−03 
                 6.51E−02 
               
               
                 ENSG00000145808 
                 171019 
                 ADAMTS19 
                 1.13 
                 1.29E−03 
                 6.51E−02 
               
               
                 ENSG00000197102 
                 1778 
                 DYNC1H1 
                 −0.25 
                 1.29E−03 
                 6.51E−02 
               
               
                 ENSG00000198821 
                 919 
                 CD247 
                 1.40 
                 1.30E−03 
                 6.58E−02 
               
               
                 ENSG00000221914 
                 5520 
                 PPP2R2A 
                 −0.36 
                 1.32E−03 
                 6.64E−02 
               
               
                 ENSG00000078898 
                 80341 
                 BPIFB2 
                 −1.47 
                 1.36E−03 
                 6.69E−02 
               
               
                 ENSG00000122140 
                 51116 
                 MRPS2 
                 −0.56 
                 1.35E−03 
                 6.69E−02 
               
               
                 ENSG00000123595 
                 9367 
                 RAB9A 
                 −0.50 
                 1.35E−03 
                 6.69E−02 
               
               
                 ENSG00000145782 
                 9140 
                 ATG12 
                 0.46 
                 1.35E−03 
                 6.69E−02 
               
               
                 ENSG00000163297 
                 118429 
                 ANTXR2 
                 0.84 
                 1.35E−03 
                 6.69E−02 
               
               
                 ENSG00000180479 
                 51276 
                 ZNF571 
                 0.65 
                 1.36E−03 
                 6.69E−02 
               
               
                 ENSG00000182578 
                 1436 
                 CSF1R 
                 1.23 
                 1.35E−03 
                 6.69E−02 
               
               
                 ENSG00000185518 
                 9899 
                 SV2B 
                 1.22 
                 1.37E−03 
                 6.71E−02 
               
               
                 ENSG00000056586 
                 54542 
                 RC3H2 
                 −0.24 
                 1.38E−03 
                 6.74E−02 
               
               
                 ENSG00000021574 
                 6683 
                 SPAST 
                 −0.28 
                 1.39E−03 
                 6.76E−02 
               
               
                 ENSG00000008394 
                 4257 
                 MGST1 
                 −0.73 
                 1.40E−03 
                 6.77E−02 
               
               
                 ENSG00000112715 
                 7422 
                 VEGFA 
                 −1.09 
                 1.40E−03 
                 6.77E−02 
               
               
                 ENSG00000171724 
                 57687 
                 VAT1L 
                 1.54 
                 1.41E−03 
                 6.81E−02 
               
               
                 ENSG00000124226 
                 55905 
                 RNF114 
                 −0.35 
                 1.43E−03 
                 6.87E−02 
               
               
                 ENSG00000147459 
                 80005 
                 DOCK5 
                 −0.44 
                 1.45E−03 
                 6.93E−02 
               
               
                 ENSG00000147140 
                 4841 
                 NONO 
                 −0.27 
                 1.46E−03 
                 6.99E−02 
               
               
                 ENSG00000118922 
                 11278 
                 KLF12 
                 0.79 
                 1.49E−03 
                 7.08E−02 
               
               
                 ENSG00000142731 
                 10733 
                 PLK4 
                 −1.30 
                 1.50E−03 
                 7.12E−02 
               
               
                 ENSG00000159388 
                 7832 
                 BTG2 
                 −1.23 
                 1.50E−03 
                 7.12E−02 
               
               
                 ENSG00000168904 
                 123355 
                 LRRC28 
                 −0.39 
                 1.53E−03 
                 7.20E−02 
               
               
                 ENSG00000234231 
                 NA 
                   
                 1.34 
                 1.53E−03 
                 7.20E−02 
               
               
                 ENSG00000187446 
                 11261 
                 CHP1 
                 −0.52 
                 1.54E−03 
                 7.22E−02 
               
               
                 ENSG00000180251 
                 389015 
                 SLC9A4 
                 −1.51 
                 1.55E−03 
                 7.25E−02 
               
               
                 ENSG00000165912 
                 29763 
                 PACSIN3 
                 −0.86 
                 1.55E−03 
                 7.25E−02 
               
               
                 ENSG00000165178 
                 654817 
                 NCF1C 
                 1.35 
                 1.56E−03 
                 7.25E−02 
               
               
                 ENSG00000128383 
                 200315 
                 APOBEC3A 
                 1.48 
                 1.59E−03 
                 7.39E−02 
               
               
                 ENSG00000155158 
                 158219 
                 TTC39B 
                 −0.49 
                 1.60E−03 
                 7.40E−02 
               
               
                 ENSG00000224041 
                 NA 
                 IGKV3D-15 
                 1.51 
                 1.62E−03 
                 7.45E−02 
               
               
                 ENSG00000101782 
                 8780 
                 RIOK3 
                 −0.40 
                 1.65E−03 
                 7.55E−02 
               
               
                 ENSG00000108671 
                 5717 
                 PSMD11 
                 −0.30 
                 1.65E−03 
                 7.55E−02 
               
               
                 ENSG00000135821 
                 2752 
                 GLUL 
                 −0.54 
                 1.65E−03 
                 7.55E−02 
               
               
                 ENSG00000076053 
                 10179 
                 RBM7 
                 −0.35 
                 1.68E−03 
                 7.62E−02 
               
               
                 ENSG00000122966 
                 11113 
                 CIT 
                 −1.03 
                 1.68E−03 
                 7.62E−02 
               
               
                 ENSG00000253755 
                 NA 
                 IGHGP 
                 1.52 
                 1.68E−03 
                 7.62E−02 
               
               
                 ENSG00000120129 
                 1843 
                 DUSP1 
                 −1.38 
                 1.73E−03 
                 7.64E−02 
               
               
                 ENSG00000121807 
                 729230 
                 CCR2 
                 1.29 
                 1.72E−03 
                 7.64E−02 
               
               
                 ENSG00000134046 
                 8932 
                 MBD2 
                 −0.24 
                 1.73E−03 
                 7.64E−02 
               
               
                 ENSG00000135773 
                 10753 
                 CAPN9 
                 −1.11 
                 1.73E−03 
                 7.64E−02 
               
               
                 ENSG00000136830 
                 64855 
                 FAM129B 
                 −0.31 
                 1.72E−03 
                 7.64E−02 
               
               
                 ENSG00000157601 
                 4599 
                 MX1 
                 −1.06 
                 1.72E−03 
                 7.64E−02 
               
               
                 ENSG00000162949 
                 92291 
                 CAPN13 
                 0.99 
                 1.69E−03 
                 7.64E−02 
               
               
                 ENSG00000173653 
                 9986 
                 RCE1 
                 −0.43 
                 1.73E−03 
                 7.64E−02 
               
               
                 ENSG00000177106 
                 64787 
                 EPS8L2 
                 −0.65 
                 1.73E−03 
                 7.64E−02 
               
               
                 ENSG00000115590 
                 7850 
                 IL1R2 
                 −1.50 
                 1.74E−03 
                 7.65E−02 
               
               
                 ENSG00000136816 
                 27348 
                 TOR1B 
                 −0.45 
                 1.75E−03 
                 7.68E−02 
               
               
                 ENSG00000091831 
                 2099 
                 ESR1 
                 1.43 
                 1.78E−03 
                 7.76E−02 
               
               
                 ENSG00000101544 
                 22850 
                 ADNP2 
                 −0.34 
                 1.78E−03 
                 7.76E−02 
               
               
                 ENSG00000086548 
                 4680 
                 CEACAM6 
                 −1.10 
                 1.79E−03 
                 7.78E−02 
               
               
                 ENSG00000141738 
                 2886 
                 GRB7 
                 −0.76 
                 1.79E−03 
                 7.78E−02 
               
               
                 ENSG00000224078 
                 NA 
                 SNHG14 
                 0.61 
                 1.80E−03 
                 7.78E−02 
               
               
                 ENSG00000131408 
                 7376 
                 NR1H2 
                 −0.42 
                 1.81E−03 
                 7.80E−02 
               
               
                 ENSG00000111412 
                 79794 
                 C12orf49 
                 −0.81 
                 1.82E−03 
                 7.84E−02 
               
               
                 ENSG00000124356 
                 10617 
                 STAMBP 
                 −0.33 
                 1.85E−03 
                 7.95E−02 
               
               
                 ENSG00000232216 
                 NA 
                 IGHV3-43 
                 1.49 
                 1.86E−03 
                 7.96E−02 
               
               
                 ENSG00000115963 
                 390 
                 RND3 
                 −0.89 
                 1.90E−03 
                 8.05E−02 
               
               
                 ENSG00000120647 
                 84318 
                 CCDC77 
                 −0.46 
                 1.90E−03 
                 8.05E−02 
               
               
                 ENSG00000141540 
                 94015 
                 TTYH2 
                 1.04 
                 1.90E−03 
                 8.05E−02 
               
               
                 ENSG00000147234 
                 84443 
                 FRMPD3 
                 1.24 
                 1.90E−03 
                 8.05E−02 
               
               
                 ENSG00000189221 
                 4128 
                 MAOA 
                 −1.08 
                 1.91E−03 
                 8.08E−02 
               
               
                 ENSG00000125430 
                 9953 
                 HS3ST3B1 
                 −0.95 
                 1.94E−03 
                 8.15E−02 
               
               
                 ENSG00000144191 
                 1261 
                 CNGA3 
                 1.43 
                 1.94E−03 
                 8.15E−02 
               
               
                 ENSG00000132405 
                 57533 
                 TBC1D14 
                 −0.40 
                 1.95E−03 
                 8.16E−02 
               
               
                 ENSG00000179840 
                 644997 
                 PIK3CD-AS1 
                 1.50 
                 1.96E−03 
                 8.16E−02 
               
               
                 ENSG00000259261 
                 NA 
                 IGHV4OR15-8 
                 1.49 
                 1.96E−03 
                 8.16E−02 
               
               
                 ENSG00000147168 
                 3561 
                 IL2RG 
                 1.31 
                 1.98E−03 
                 8.21E−02 
               
               
                 ENSG00000164692 
                 1278 
                 COL1A2 
                 1.46 
                 2.03E−03 
                 8.40E−02 
               
               
                 ENSG00000013563 
                 1774 
                 DNASE1L1 
                 −0.82 
                 2.04E−03 
                 8.42E−02 
               
               
                 ENSG00000103522 
                 50615 
                 IL21R 
                 1.46 
                 2.04E−03 
                 8.42E−02 
               
               
                 ENSG00000108091 
                 8030 
                 CCDC6 
                 −0.30 
                 2.11E−03 
                 8.64E−02 
               
               
                 ENSG00000157954 
                 26100 
                 WIPI2 
                 −0.40 
                 2.11E−03 
                 8.64E−02 
               
               
                 ENSG00000070214 
                 23446 
                 SLC44A1 
                 −0.42 
                 2.13E−03 
                 8.70E−02 
               
               
                 ENSG00000156671 
                 142891 
                 SAMD8 
                 −0.39 
                 2.17E−03 
                 8.80E−02 
               
               
                 ENSG00000174807 
                 57124 
                 CD248 
                 1.46 
                 2.17E−03 
                 8.80E−02 
               
               
                 ENSG00000154277 
                 7345 
                 UCHL1 
                 −1.35 
                 2.19E−03 
                 8.82E−02 
               
               
                 ENSG00000157766 
                 176 
                 ACAN 
                 1.48 
                 2.18E−03 
                 8.82E−02 
               
               
                 ENSG00000171475 
                 147179 
                 WIPF2 
                 −0.44 
                 2.19E−03 
                 8.82E−02 
               
               
                 ENSG00000211945 
                 NA 
                 IGHV1-18 
                 1.48 
                 2.19E−03 
                 8.82E−02 
               
               
                 ENSG00000186407 
                 342510 
                 CD300E 
                 1.46 
                 2.21E−03 
                 8.86E−02 
               
               
                 ENSG00000211659 
                 NA 
                 IGLV3-25 
                 1.48 
                 2.21E−03 
                 8.86E−02 
               
               
                 ENSG00000167797 
                 10263 
                 CDK2AP2 
                 −0.53 
                 2.24E−03 
                 8.92E−02 
               
               
                 ENSG00000132465 
                 3512 
                 JCHAIN 
                 1.47 
                 2.25E−03 
                 8.95E−02 
               
               
                 ENSG00000201643 
                 677801 
                 SNORA14A 
                 0.93 
                 2.25E−03 
                 8.95E−02 
               
               
                 ENSG00000036530 
                 10858 
                 CYP46A1 
                 1.15 
                 2.26E−03 
                 8.96E−02 
               
               
                 ENSG00000162782 
                 163589 
                 TDRD5 
                 1.42 
                 2.27E−03 
                 8.96E−02 
               
               
                 ENSG00000224373 
                 NA 
                 IGHV4-59 
                 1.47 
                 2.28E−03 
                 8.96E−02 
               
               
                 ENSG00000132938 
                 23281 
                 MTUS2 
                 1.44 
                 2.28E−03 
                 8.96E−02 
               
               
                 ENSG00000112299 
                 8876 
                 VNN1 
                 1.37 
                 2.35E−03 
                 9.19E−02 
               
               
                 ENSG00000164100 
                 9348 
                 NDST3 
                 1.12 
                 2.36E−03 
                 9.22E−02 
               
               
                 ENSG00000165949 
                 3429 
                 IFI27 
                 −1.30 
                 2.36E−03 
                 9.22E−02 
               
               
                 ENSG00000107643 
                 5599 
                 MARK8 
                 −0.33 
                 2.39E−03 
                 9.29E−02 
               
               
                 ENSG00000184481 
                 4303 
                 FOXO4 
                 −0.55 
                 2.40E−03 
                 9.29E−02 
               
               
                 ENSG00000105122 
                 64926 
                 RASAL3 
                 1.32 
                 2.43E−03 
                 9.40E−02 
               
               
                 ENSG00000167100 
                 201191 
                 SAMD14 
                 1.44 
                 2.44E−03 
                 9.42E−02 
               
               
                 ENSG00000198848 
                 1066 
                 CES1 
                 −1.10 
                 2.51E−03 
                 9.63E−02 
               
               
                 ENSG00000211964 
                 NA 
                 IGHV3-48 
                 1.45 
                 2.50E−03 
                 9.63E−02 
               
               
                 ENSG00000099958 
                 91319 
                 DERL3 
                 0.90 
                 2.51E−03 
                 9.63E−02 
               
               
                 ENSG00000010017 
                 10048 
                 RANBP9 
                 −0.43 
                 2.54E−03 
                 9.69E−02 
               
               
                 ENSG00000189056 
                 5649 
                 RELN 
                 1.38 
                 2.54E−03 
                 9.69E−02 
               
               
                 ENSG00000213988 
                 7643 
                 ZNF90 
                 0.83 
                 2.57E−03 
                 9.74E−02 
               
               
                 ENSG00000232810 
                 7124 
                 TNF 
                 1.30 
                 2.57E−03 
                 9.74E−02 
               
               
                 ENSG00000011295 
                 54902 
                 TTC19 
                 −0.30 
                 2.58E−03 
                 9.75E−02 
               
               
                 ENSG00000126062 
                 11070 
                 TMEM115 
                 −0.34 
                 2.61E−03 
                 9.82E−02 
               
               
                 ENSG00000211933 
                 NA 
                 IGHV6-1 
                 1.44 
                 2.61E−03 
                 9.82E−02 
               
               
                 ENSG00000181588 
                 399664 
                 MEX3D 
                 −0.62 
                 2.62E−03 
                 9.84E−02 
               
               
                 ENSG00000122188 
                 54900 
                 LAX1 
                 1.37 
                 2.64E−03 
                 9.89E−02 
               
               
                 ENSG00000162772 
                 467 
                 ATF3 
                 −1.35 
                 2.65E−03 
                 9.90E−02 
               
               
                 ENSG00000157064 
                 23057 
                 NMNAT2 
                 1.33 
                 2.67E−03 
                 9.95E−02 
               
               
                   
               
               
                 UIP (n = 12 samples); Non UIP (n = 4 samples). Positive log2 fold change value indicates over-expression in UIP relative to Non UIP; negative log2 value indicates under-expression in UIP relative to Non UIP. In this analysis only patients with a smoking history were evaluated, hence this subset harbored only smokers 
               
            
           
         
       
     
     The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent application, foreign patents, foreign patent application and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, application and publications to provide yet further embodiments. 
     These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. 
     Some embodiments described herein relate to a computer storage product with a non-transitory computer-readable medium (also can be referred to as a non-transitory processor-readable medium) having instructions or computer code thereon for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also can be referred to as code) may be those designed and constructed for the specific purpose or purposes. Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as Compact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; and hardware devices that are specially configured to store and execute program code, such as Application-Specific Integrated Circuits (ASICs), Programmable Logic Devices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM) devices. Other embodiments described herein relate to a computer program product, which can include, for example, the instructions and/or computer code discussed herein. 
     Some embodiments and/or methods described herein can be performed by software (executed on hardware), hardware, or a combination thereof. Hardware modules may include, for example, a general-purpose processor, a field programmable gate array (FPGA), and/or an application specific integrated circuit (ASIC). Software modules (executed on hardware) can be expressed in a variety of software languages (e.g., computer code), including C, C++, Java™, Ruby, Visual Basic™, R, and/or other object-oriented, procedural, statistical, or other programming language and development tools. Examples of computer code include, but are not limited to, micro-code or micro-instructions, machine instructions, such as produced by a compiler, code used to produce a web service, and files containing higher-level instructions that are executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages (e.g., C, Fortran, etc.), functional programming languages (e.g., Haskell, Erlang, etc.), logical programming languages (e.g., Prolog), object-oriented programming languages (e.g., Java, C++, etc.), statistical programming languages and/or environments (e.g., R, etc.) or other suitable programming languages and/or development tools. Additional examples of computer code include, but are not limited to, control signals, encrypted code, and compressed code. 
     REFERENCES 
     All of the following references are incorporated herein in their entirety.
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