Abstract:
Methods for identifying and evaluating biochemical entities useful as biomarkers for kidney cancer, target identification/validation, and monitoring of drug efficacy are provided. Also provided are suites of small molecule entities as biomarkers for kidney cancer.

Description:
[0001]    This application claims the benefit of U.S. Provisional Patent Application No. 61/568,690, filed Dec. 9, 2011, and U.S. Provisional Patent Application No. 61/677,771, filed Jul. 31, 2012, the entire contents of which are hereby incorporated herein by reference. 
     
    
     FIELD 
       [0002]    The invention generally relates to biomarkers for kidney cancer and methods based on the same biomarkers. 
       BACKGROUND 
       [0003]    In the US, 275,000 patients each year are screened for kidney cancer, and 55,000 are diagnosed with renal cell carcinoma (RCC) (American Cancer Society Facts and Figures 2010). RCC is the most common form of kidney cancer, accounting for approximately 80% of the total. The incidence of RCC is steadily increasing, and in the US increased by approximately 2% per year in the past two decades (Ries L A G, et al., eds. SEER Cancer Statistics Review, 1975-2003. Bethesda, Md.: National Cancer Institute; 2006). Because RCC is one of the deadliest cancers and does not respond to traditional chemotherapy drugs, many new targeted agents are being developed specifically to treat RCC. 
         [0004]    70% of newly diagnosed patients are diagnosed in the early stages (T1 and T2). Early stage RCC is treated by partial or total nephrectomy; this is surgery with curative intent. When RCC tumors are surgically removed at an early stage, the 5 year survival rate is 90% for stage 1 and 51% for stage 2, yet 70% of RCC patients develop metastasis during the course of their disease. 
         [0005]    Often, kidney lesions or small renal masses (SRM) are discovered incidentally during examinations unrelated to suspected malignancy. While approximately 20% of SRM are benign, the remainder are cancerous. The traditional treatment for small renal masses is radical nephrectomy. Typically cancer-positive SRMs are relatively small and have a relatively slow growth rate. As such, cancer-positive SRMs are generally considered to have less aggressive potential, and thus a watchful waiting approach may be more appropriate than surgery (Bosniak M A, et al. J. Small renal parenchymal neoplasms: further observations on growth. Radiology 1995; 197: 589-597.). However, there are also incidentally detected small renal masses that can grow rapidly and have aggressive potential (Remzi M, et al. “Are small renal tumors harmless? Analysis of histopathological features according to tumors 4 cm or less in diameter”. J. Urol. 2006; 176 (3): 896-9.). Biomarkers for distinguishing which cancer-positive SRMs will be more aggressive, requiring surgery, and which will be slower growing and warrant a watchful waiting approach would be valuable. 
         [0006]    Pharmaceutical companies have been developing targeted therapies for RCC, such as Sutent (sunitinib), Nexavar (sorafenib), Avastin (bevacizumab) and Torisel (temsirolimus). As of March 2011, there were 6 targeted agents in Phase I, 13 in Phase 2, 5 in Phase 3, and 8 with FDA approval for treatment of RCC. Currently, approximately 18% of the RCC patient population receives drug therapy. In the future, more patients are expected to receive treatment, driven by an increase in the number of treatment options, improvements in drug efficacy and the trend to use drug therapy earlier in the course of the disease (adjuvant or neo-adjuvant setting) (Espicom Business Intelligence, Market Report: Renal Cell Carcinoma Drug Futures, ISBN: 978-1-85822-396-4, March 2011). 
       SUMMARY 
       [0007]    In one aspect, the present invention provides a method of diagnosing whether a subject has kidney cancer, including subjects having an SRM, comprising analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer in the sample, where the one or more biomarkers are selected from Tables 1, 2, 4 and/or 11 and comparing the level(s) of the one or more biomarkers in the sample to kidney cancer-positive and/or kidney cancer-negative reference levels of the one or more biomarkers in order to diagnose whether the subject has kidney cancer. 
         [0008]    In a further aspect, the invention provides a method of distinguishing kidney cancer from other urological cancers (e.g., bladder cancer, prostate cancer), comprising analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer in the sample where the one or more biomarkers are selected from Table 11 and comparing the level(s) of the one or more biomarkers in the sample to kidney cancer-positive and/or kidney cancer-negative reference levels of the one or more biomarkers in order to distinguish kidney cancer from other urological cancers. 
         [0009]    In another aspect, the invention provides a method of monitoring progression/regression of kidney cancer in a subject comprising analyzing a first biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer in the sample, where the one or more biomarkers are selected from Tables 1, 2, 4, 8, 10 and/or 11 and the first sample is obtained from the subject at a first time point; analyzing a second biological sample from a subject to determine the level(s) of the one or more biomarkers, where the second sample is obtained from the subject at a second time point; and comparing the level(s) of one or more biomarkers in the second sample to the level(s) of the one or more biomarkers in (a) the first sample (b) kidney cancer-positive reference levels of the one or more biomarkers, and/or (c) kidney cancer-negative reference levels of the one or more biomarkers in order to monitor the progression/regression of kidney cancer in the subject. 
         [0010]    In another aspect, the present invention provides a method of determining the stage of kidney cancer, comprising analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer stage in the sample, where the one or more biomarkers are selected from Table 8; and comparing the level(s) of the one or more biomarkers in the sample to high stage kidney cancer and/or low stage kidney cancer reference levels of the one or more biomarkers in order to determine the stage of the subject&#39;s kidney cancer. 
         [0011]    In a further aspect, the present invention provides a method of determining the aggressiveness of kidney cancer, comprising analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer aggressiveness in the sample, where the one or more biomarkers are selected from Table 10; and comparing the level(s) of the one or more biomarkers in the sample to more aggressive kidney cancer and/or less aggressive kidney cancer reference levels of the one or more biomarkers in order to determine the aggressiveness of the subject&#39;s kidney cancer. 
         [0012]    In another aspect, the present invention provides a method of assessing the efficacy of a composition for treating kidney cancer comprising analyzing a biological sample from a subject having kidney cancer and currently or previously being treated with the composition, to determine the level(s) of one or more biomarkers for kidney cancer selected from Tables 1, 2, 4, 8, 10 and/or 11; and comparing the level(s) of the one or more biomarkers in the sample to (a) levels of the one or more biomarkers in a previously-taken biological sample from the subject, where the previously-taken biological sample was obtained from the subject before being treated with the composition, (b) kidney cancer-positive reference levels of the one or more biomarkers, and/or (c) kidney cancer-negative reference levels of the one or more biomarkers. 
         [0013]    In another aspect, the present invention provides a method for assessing the efficacy of a composition in treating kidney cancer, comprising analyzing a first biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer selected from Tables 1, 2, 4, 8, 10 and/or 11, the first sample obtained from the subject at a first time point; administering the composition to the subject; analyzing a second biological sample from the subject to determine the level(s) of the one or more biomarkers, the second sample obtained from the subject at a second time point after administration of the composition; comparing the level(s) of one or more biomarkers in the first sample to the level(s) of the one or more biomarkers in the second sample in order to assess the efficacy of the composition for treating kidney cancer. 
         [0014]    In yet another aspect, the invention provides a method of assessing the relative efficacy of two or more compositions for treating kidney cancer comprising analyzing, from a first subject having kidney cancer and currently or previously being treated with a first composition, a first biological sample to determine the level(s) of one or more biomarkers selected from Tables 1, 2, 4, 8, 10 and/or 11; analyzing, from a second subject having kidney cancer and currently or previously being treated with a second composition, a second biological sample to determine the level(s) of the one or more biomarkers; and comparing the level(s) of one or more biomarkers in the first sample to the level(s) of the one or more biomarkers in the second sample in order to assess the relative efficacy of the first and second compositions for treating kidney cancer. 
         [0015]    In another aspect, the present invention provides a method for screening a composition for activity in modulating one or more biomarkers of kidney cancer, comprising contacting one or more cells with a composition; analyzing at least a portion of the one or more cells or a biological sample associated with the cells to determine the level(s) of one or more biomarkers of kidney cancer selected from Tables 1, 2, 4, 8, 10 and/or 11; and comparing the level(s) of the one or more biomarkers with predetermined standard levels for the biomarkers to determine whether the composition modulated the level(s) of the one or more biomarkers. 
         [0016]    In yet another aspect, the invention provides a method for treating a subject having kidney cancer comprising administering to the subject an effective amount of one or more biomarkers selected from Tables 1, 2, 4, 8, 10 and/or 11 that are decreased in kidney cancer. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0017]      FIG. 1 . Graphical illustration of feature-selected principal components analysis (PCA) using biopsy tissue from kidney cancer and benign samples. An arbitrary cutoff line is drawn to illustrate that these metabolic abundance profiles can separate samples into groups with both high Negative Predictive Value (NPV) (PC1&lt;0) and high Positive Predictive Value (PPV) (PC1&gt;0). 
           [0018]      FIG. 2 . Graphical illustration of feature-selected hierarchical clustering (Euclidean distance) using biopsy tissue from kidney cancer and benign samples. Two distinct metabolic classes were identified, one containing 80% kidney cancer samples and one containing 71% benign samples. 
       
    
    
     DETAILED DESCRIPTION 
       [0019]    The present invention relates to biomarkers of kidney cancer, methods for diagnosis or aiding in diagnosis of kidney cancer, methods of determining or aiding in determining the cancer status of a small renal mass (SRM) kidney cancer, methods of staging kidney cancer, methods of determining kidney cancer aggressiveness, methods of monitoring progression/regression of kidney cancer, methods of assessing efficacy of compositions for treating kidney cancer, methods of screening compositions for activity in modulating biomarkers of kidney cancer, methods of treating kidney cancer, as well as other methods based on biomarkers of kidney cancer. Prior to describing this invention in further detail, however, the following terms will first be defined. 
       DEFINITIONS 
       [0020]    “Biomarker” means a compound, preferably a metabolite, that is differentially present (i.e., increased or decreased) in a biological sample from a subject or a group of subjects having a first phenotype (e.g., having a disease) as compared to a biological sample from a subject or group of subjects having a second phenotype (e.g., not having the disease). A biomarker may be differentially present at any level, but is generally present at a level that is increased by at least 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%, by at least 100%, by at least 110%, by at least 120%, by at least 130%, by at least 140%, by at least 150%, or more; or is generally present at a level that is decreased by at least 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%, or by 100% (i.e., absent). A biomarker is preferably differentially present at a level that is statistically significant (i.e., a p-value less than 0.05 and/or a q-value of less than 0.10 as determined using either Welch&#39;s T-test or Wilcoxon&#39;s rank-sum Test). 
         [0021]    The “level” of one or more biomarkers means the absolute or relative amount or concentration of the biomarker in the sample. 
         [0022]    “Sample” or “biological sample” means biological material isolated from a subject. The biological sample may contain any biological material suitable for detecting the desired biomarkers, and may comprise cellular and/or non-cellular material from the subject. The sample can be isolated from any suitable biological tissue or fluid such as, for example, kidney tissue, blood, blood plasma, urine, or cerebral spinal fluid (CSF). 
         [0023]    “Subject” means any animal, but is preferably a mammal, such as, for example, a human, monkey, mouse, rabbit or rat. 
         [0024]    A “reference level” of a biomarker means a level of the biomarker that is indicative of a particular disease state, phenotype, or lack thereof, as well as combinations of disease states, phenotypes, or lack thereof. A “positive” reference level of a biomarker means a level that is indicative of a particular disease state or phenotype. A “negative” reference level of a biomarker means a level that is indicative of a lack of a particular disease state or phenotype. For example, a “kidney cancer-positive reference level” of a biomarker means a level of a biomarker that is indicative of a positive diagnosis of kidney cancer in a subject, and a “kidney cancer-negative reference level” of a biomarker means a level of a biomarker that is indicative of a negative diagnosis of kidney cancer in a subject. A “reference level” of a biomarker may be an absolute or relative amount or concentration of the biomarker, a presence or absence of the biomarker, a range of amount or concentration of the biomarker, a minimum and/or maximum amount or concentration of the biomarker, a mean amount or concentration of the biomarker, and/or a median amount or concentration of the biomarker; and, in addition, “reference levels” of combinations of biomarkers may also be ratios of absolute or relative amounts or concentrations of two or more biomarkers with respect to each other. Appropriate positive and negative reference levels of biomarkers for a particular disease state, phenotype, or lack thereof may be determined by measuring levels of desired biomarkers in one or more appropriate subjects, and such reference levels may be tailored to specific populations of subjects (e.g., a reference level may be age-matched so that comparisons may be made between biomarker levels in samples from subjects of a certain age and reference levels for a particular disease state, phenotype, or lack thereof in a certain age group). Such reference levels may also be tailored to specific techniques that are used to measure levels of biomarkers in biological samples (e.g., LC-MS, GC-MS, etc.), where the levels of biomarkers may differ based on the specific technique that is used. 
         [0025]    “Non-biomarker compound” means a compound that is not differentially present in a biological sample from a subject or a group of subjects having a first phenotype (e.g., having a first disease) as compared to a biological sample from a subject or group of subjects having a second phenotype (e.g., not having the first disease). Such non-biomarker compounds may, however, be biomarkers in a biological sample from a subject or a group of subjects having a third phenotype (e.g., having a second disease) as compared to the first phenotype (e.g., having the first disease) or the second phenotype (e.g., not having the first disease). 
         [0026]    “Metabolite”, or “small molecule”, means organic and inorganic molecules which are present in a cell. The term does not include large macromolecules, such as large proteins (e.g., proteins with molecular weights over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), large nucleic acids (e.g., nucleic acids with molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), or large polysaccharides (e.g., polysaccharides with a molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000). The small molecules of the cell are generally found free in solution in the cytoplasm or in other organelles, such as the mitochondria, where they form a pool of intermediates which can be metabolized further or used to generate large molecules, called macromolecules. The term “small molecules” includes signaling molecules and intermediates in the chemical reactions that transform energy derived from food into usable forms. Examples of small molecules include sugars, fatty acids, amino acids, nucleotides, intermediates formed during cellular processes, and other small molecules found within the cell. 
         [0027]    “Metabolic profile”, or “small molecule profile”, means a complete or partial inventory of small molecules within a targeted cell, tissue, organ, organism, or fraction thereof (e.g., cellular compartment). The inventory may include the quantity and/or type of small molecules present. The “small molecule profile” may be determined using a single technique or multiple different techniques. 
         [0028]    “Metabolome” means all of the small molecules present in a given organism. 
         [0029]    “Kidney cancer” refers to a disease in which cancer develops in the kidney. 
         [0030]    “Urological Cancer” refers to a disease in which cancer develops in the bladder, kidney and/or prostate. 
         [0031]    “Staging” of kidney cancer refers to an indication of the severity of kidney cancer including tumor size and whether and/or how far the kidney tumor has spread. The tumor stage is a criteria used to select treatment options and to estimate a patient&#39;s prognosis. Kidney tumor stages range from T1 (tumor 7 cm or less in size and limited to kidney, least advanced) to T4 (tumor invades beyond Gerota&#39;s fascia, most advanced). “Low stage” or “lower stage” kidney cancer refers to kidney cancer tumors, including malignant tumors with a lower potential for recurrence, progression, invasion and/or metastasis (less advanced). Kidney tumors of stage T1 or T2 are considered “low stage”. “High stage” or “higher stage” kidney cancer refers to a kidney cancer tumor in a subject that is more likely to recur and/or progress and/or invade beyond the kidney, including malignant tumors with higher potential for metastasis (more advanced). Kidney tumors of stage T3 or T4 are considered “high stage”. 
         [0032]    “Grade” of kidney cancer refers to the appearance and/or structure of kidney cancer cellular nuclei. “Low grade” kidney cancer refers to a cancer with cellular nuclear characteristics more closely resembling normal cellular nuclei. “High grade” kidney cancer refers to a cancer with cellular nuclear characteristics less closely resembling normal cellular nuclei. 
         [0033]    “Aggressiveness” of kidney cancer or a cancer-positive small renal mass refers to a combination of the stage, grade, and metastatic potential of a kidney tumor. “More aggressive” kidney cancer refers to tumors of higher stage, grade, and/or metastatic potential. Cancer tumors that are not confined to the kidney are considered to be more aggressive kidney cancer. “Less aggressive” kidney cancer refers to tumors of lower stage, grade, and/or metastatic potential. Cancer tumors that are confined to the kidney are considered to be less aggressive kidney cancer. 
         [0034]    “Small renal mass (SRM)” refers to a kidney lesion that may be detected incidentally during an examination but is usually not yet associated with symptoms of kidney cancer. The SRM may be benign (cancer-negative) or may be a cancer tumor (cancer-positive). A cancer-positive SRM may be an indolent tumor (low stage/less aggressive) or may be a high stage, aggressive tumor. 
         [0035]    “RCC Score” is a measure or indicator of kidney cancer severity, which is based on the kidney cancer biomarkers and algorithms described herein. An RCC Score will enable a physician to place a patient on a spectrum of kidney cancer severity from normal (i.e., no kidney cancer) to high (e.g., high stage or more aggressive kidney cancer). One of ordinary skill in the art will understand that the RCC Score can have multiple uses in the diagnosis and treatment of kidney cancer. For example, an RCC Score may also be used to distinguish less aggressive kidney cancer from more aggressive kidney cancer, to distinguish low grade kidney cancer from high grade kidney cancer, and to monitor the progression and/or regression of kidney cancer. 
       I. BIOMARKERS 
       [0036]    The kidney cancer biomarkers described herein were discovered using metabolomic profiling techniques. Such metabolomic profiling techniques are described in more detail in the Examples set forth below as well as in U.S. Pat. Nos. 7,005,255, 7,329,489; 7,550,258; 7,550,260; 7,553,616; 7,635,556; 7,682,783; 7,682,784; 7,910,301; 6,947,453; 7,433,787; 7,561,975; 7,884,318, the entire contents of which are hereby incorporated herein by reference. 
         [0037]    Generally, metabolic profiles were determined for biological samples from human subjects that were positive for kidney cancer (RCC) or samples from human subjects that were cancer negative (non-cancer). The metabolic profile for biological samples positive for kidney cancer was compared to the metabolic profile for biological samples negative for kidney cancer. Those small molecules differentially present, including those small molecules differentially present at a level that is statistically significant, in the metabolic profile of samples positive for kidney cancer as compared to another group (e.g., non-cancer samples) were identified as biomarkers to distinguish those groups. 
         [0038]    The biomarkers are discussed in more detail herein. The biomarkers that were discovered correspond with biomarkers for distinguishing samples positive for kidney cancer (RCC) vs. cancer-negative samples (see Tables 1, 2, 4 and/or 11). 
         [0039]    Metabolic profiles were also determined for biological samples from human subjects diagnosed with high stage kidney cancer or human subjects diagnosed with low stage kidney cancer. The metabolic profile for biological samples from a subject having high stage kidney cancer was compared to the metabolic profile for biological samples from subjects with low stage kidney cancer. Those small molecules differentially present, including those small molecules differentially present at a level that is statistically significant, in the metabolic profile of samples from subjects with high stage kidney cancer as compared to another group (e.g., subjects not diagnosed with high stage kidney cancer) were identified as biomarkers to distinguish those groups. 
         [0040]    The biomarkers are discussed in more detail herein. The biomarkers that were discovered correspond with biomarkers for distinguishing subjects having high stage kidney cancer vs. subjects having low stage kidney cancer (see Table 8). 
         [0041]    Metabolic profiles were also determined for biological samples from human subjects diagnosed with more aggressive kidney cancer or human subjects diagnosed with less aggressive kidney cancer. The metabolic profile for biological samples from subjects having more aggressive kidney cancer were compared to the metabolic profile for biological samples from subjects having less aggressive kidney cancer. Those small molecules differentially present, including those small molecules differentially present at a level that is statistically significant, in the metabolic profile of samples from subjects with more aggressive kidney cancer as compared to another group (e.g., subjects not diagnosed with more aggressive kidney cancer) were identified as biomarkers to distinguish those groups. 
         [0042]    The biomarkers are discussed in more detail herein. The biomarkers that were discovered correspond with biomarkers for distinguishing subjects having more aggressive kidney cancer vs. subjects having less aggressive kidney cancer (see Table 10). 
       II. METHODS 
       [0043]    A. Diagnosis of kidney cancer 
         [0044]    The identification of biomarkers for kidney cancer allows for the diagnosis of (or for aiding in the diagnosis of) kidney cancer in subjects presenting with one or more symptoms consistent with the presence of kidney cancer and includes the initial diagnosis of kidney cancer in a subject not previously identified as having kidney cancer and diagnosis of recurrence of kidney cancer in a subject previously treated for kidney cancer. For example, an SRM may be detected in a subject during a medical examination making it necessary to determine if the SRM is cancer-positive or cancer-negative. A method of diagnosing (or aiding in diagnosing) whether a subject has kidney cancer comprises (1) analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers of kidney cancer in the sample and (2) comparing the level(s) of the one or more biomarkers in the sample to kidney cancer-positive and/or kidney cancer-negative reference levels of the one or more biomarkers in order to diagnose (or aid in the diagnosis of) whether the subject has kidney cancer. The one or more biomarkers that are used are selected from Tables 1, 2, 4, and/or 11 and combinations thereof. When such a method is used to aid in the diagnosis of kidney cancer, the results of the method may be used along with other methods (or the results thereof) useful in the clinical determination of whether a subject has kidney cancer. 
         [0045]    Any suitable method may be used to analyze the biological sample in order to determine the level(s) of the one or more biomarkers in the sample. Suitable methods include chromatography (e.g., HPLC, gas chromatography, liquid chromatography), mass spectrometry (e.g., MS, MS-MS), enzyme-linked immunosorbent assay (ELISA), antibody linkage, other immunochemical techniques, and combinations thereof. Further, the level(s) of the one or more biomarkers may be measured indirectly, for example, by using an assay that measures the level of a compound (or compounds) that correlates with the level of the biomarker(s) that are desired to be measured. 
         [0046]    The levels of one or more of the biomarkers of Tables 1, 2, 4, and/or 11 may be determined in the methods of diagnosing and methods of aiding in diagnosing whether a subject has kidney cancer. For example, one or more of the following biomarkers may be used alone or in combination to diagnose or aid in diagnosing kidney cancer: oxidized glutathione (GSSG), proline, 2-oleoylglycerophosphoethanolamine, 2-aminobutyrate, sphingosine, 3-dehydrocarnitine, 2-docosahexaenoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, phosphoethanolamine, glutamate, pyrophosphate (PPi), nicotinamide-adenine-dinucleotide (NAD+), 3-aminoisobutyrate, 2-arachidonoylglycerophosphoethanolamine, 2-arachidonoylglycerophosphocholine, 2-oleoylglycerophosphocholine, glycerate, choline-phosphate, pyruvate, 1-arachidonoylglycerophosphoethanolamine, adenine, 1-2-propanediol, 2-docosahexaenoylglycerophosphoethanolamine, 2-hydroxybutyrate (AHB), creatine, glycolate (hydroxyacetate), malate, 5-methylthioadenosine (MTA), stearolycarnitine, 1-arachidonoylglycerophosphoinositol, arachidonate, mannose-6-phosphate, alpha-tocopherol, flavin adenine dinucleotide (FAD), fructose-6-phosphate, maltose, maltotriose, fructose 1-phosphate, maltotetraose, 1-stearoylglycerophosphoinositol, methyl-alpha-glucopyranoside, glucose-6-phosphate (G6P), eicosenoate, 1-stearoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoinositol, 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 2-palmitoylglycerophosphoethanolamine, 1-oleoylglycerophosphoinositol, gamma-glutamylglutamate, ergothioneine, arabitol, 1-palmitoylplasmenylethanolamine, N-acetylneuraminate, malonylcarnitine, 2-hydroxyglutarate, beta-alanine, pantothenate, citrate, kynurenine, N1-methyladenosine, hippurate, glucose, N-acetylaspartate (NAA), N1-methylguanosine, pseudouridine, phenylacetylglutamine, N2-methylguanosine, 2-methylbutyrylcarnitine (C5), N-acetyl-aspartyl-glutamate (NAAG), N6-acetyllysine, dimethylarginine (SDMA+ADMA), methyl-4-hydroxybenzoate, catechol-sulfate, glycerol, 2-hydroxyhippurate (salicylurate), N(2)-furoyl-glycine, 3-hydroxyphenylacetate, gulono 1,4-lactone, 2-isopropylmalate, 2-3-dihydroxyisovalerate, 1-2-propanediol, gluconate, cinnamoylglycine, phenylacetylglycine, sorbose, sucrose, adenosine 5′-monophosphate (AMP), hexanoylglycine, methyl-indole-3-acetate, 3-hydroxyhippurate, N6-methyladenosine, 4-hydroxy-2-oxoglutaric acid, alpha-CEHC-glucuronide, phenylpropinylglycine, vanillate, ethanolamine, galactose, adipate, 2-oxindole-3-acetate, 1, 3-7-trimethylurate, and 3-4-dihydroxyphenylacetate. Additionally, for example, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Tables 1, 2, 4, and/or 11 and combinations thereof or any fraction thereof, may be determined and used in such methods. Determining levels of combinations of the biomarkers may allow greater sensitivity and specificity in diagnosing kidney cancer and aiding in the diagnosis of kidney cancer. For example, ratios of the levels of certain biomarkers (and non-biomarker compounds) in biological samples may allow greater sensitivity and specificity in diagnosing kidney cancer and aiding in the diagnosis of kidney cancer. 
         [0047]    After the level(s) of the one or more biomarkers in the sample are determined, the level(s) are compared to kidney cancer-positive and/or kidney cancer-negative reference levels to aid in diagnosing or to diagnose whether the subject has kidney cancer. Levels of the one or more biomarkers in a sample matching the kidney cancer-positive reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of a diagnosis of kidney cancer in the subject. Levels of the one or more biomarkers in a sample matching the kidney cancer-negative reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of a diagnosis of no kidney cancer in the subject. In addition, levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to kidney cancer-negative reference levels are indicative of a diagnosis of kidney cancer in the subject. Levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to kidney cancer-positive reference levels are indicative of a diagnosis of no kidney cancer in the subject. 
         [0048]    The level(s) of the one or more biomarkers may be compared to kidney cancer-positive and/or kidney cancer-negative reference levels using various techniques, including a simple comparison (e.g., a manual comparison) of the level(s) of the one or more biomarkers in the biological sample to kidney cancer-positive and/or kidney cancer-negative reference levels. The level(s) of the one or more biomarkers in the biological sample may also be compared to kidney cancer-positive and/or kidney cancer-negative reference levels using one or more statistical analyses (e.g., t-test, Welch&#39;s T-test, Wilcoxon&#39;s rank sum test, Random Forest, T-score, Z-score) or using a mathematical model (e.g., algorithm, statistical model). 
         [0049]    For example, a mathematical model comprising a single algorithm or multiple algorithms may be used to determine whether a subject has kidney cancer. A mathematical model may also be used to distinguish between kidney cancer stages. An exemplary mathematical model may use the measured levels of any number of biomarkers (for example, 2, 3, 5, 7, 9, etc.) from a subject to determine, using an algorithm or a series of algorithms based on mathematical relationships between the levels of the measured biomarkers, whether a subject has kidney cancer, whether kidney cancer is progressing or regressing in a subject, whether a subject has high stage or low stage kidney cancer, whether a subject has more aggressive or less aggressive kidney cancer, etc. 
         [0050]    The results of the method may be used along with other methods (or the results thereof) useful in the diagnosis of kidney cancer in a subject. 
         [0051]    In one aspect, the biomarkers provided herein can be used to provide a physician with an RCC Score indicating the existence and/or severity of kidney cancer in a subject. The score is based upon clinically significantly changed reference level(s) for a biomarker and/or combination of biomarkers. The reference level can be derived from an algorithm. The RCC Score can be used to place the subject in a severity range of kidney cancer from normal (i.e. no kidney cancer) to high. The RCC Score can be used in multiple ways: for example, disease progression, regression, or remission can be monitored by periodic determination and monitoring of the RCC Score; response to therapeutic intervention can be determined by monitoring the RCC Score; and drug efficacy can be evaluated using the RCC Score. 
         [0052]    Methods for determining a subject&#39;s RCC Score may be performed using one or more of the kidney cancer biomarkers identified in Tables 1, 2, 4 and/or 11 in a biological sample. The method may comprise comparing the level(s) of the one or more kidney cancer biomarkers in the sample to kidney cancer reference levels of the one or more biomarkers in order to determine the subject&#39;s RCC score. The method may employ any number of markers selected from those listed in Table 1, 2, 4 and/or 11, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more markers. Multiple biomarkers may be correlated with kidney cancer, by any method, including statistical methods such as regression analysis. 
         [0053]    After the level(s) of the one or more biomarker(s) is determined, the level(s) may be compared to kidney cancer reference level(s) or reference curves of the one or more biomarker(s) to determine a rating for each of the one or more biomarker(s) in the sample. The rating(s) may be aggregated using any algorithm to create a score, for example, an RCC score, for the subject. The algorithm may take into account any factors relating to kidney cancer including the number of biomarkers, the correlation of the biomarkers to kidney cancer, etc. 
         [0054]    In an embodiment, a mathematical model or formula containing one or more biomarkers as variables is established using regression analysis, e.g., multiple linear regressions. By way of non-limiting example, the developed formulas may include the following: 
         [0000]        A+B (Biomarker 1 )+ C (Biomarker 2 )+ D (Biomarker 3 )+ E (Biomarker 4 )= R Score 
         [0000]        A+B *ln(Biomarker 1 )+ C *ln(Biomarker 2 )+ D *ln(Biomarker 3 )+ E *ln(Biomarker 4 )=ln  R Score 
         [0055]    wherein A, B, C, D, E are constant numbers; Biomarker 1 , Biomarker 2 , Biomarker 3 , Biomarker 4  are the measured values of the analyte (Biomarker) and RScore is the measure of cancer presence or absence or cancer aggressivity. 
         [0056]    The formulas may include one or more biomarkers as variables, such as 1, 2, 3, 4, 5, 10, 15, 20 or more biomarkers. 
         [0000]    Additionally, in one embodiment, the biomarkers provided herein to diagnose or aid in the diagnosis of kidney cancer may be used to distinguish kidney cancer from other urological cancers. A method of distinguishing kidney cancer from other urological cancers in a subject comprises (1) analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers of kidney cancer in the sample and (2) comparing the level(s) of the one or more biomarkers in the sample to kidney cancer-positive and/or kidney cancer-negative reference levels of the one or more biomarkers in order to distinguish kidney cancer from other urological cancers. The one or more biomarkers that are used are selected from Table 11. For example, one or more of the following biomarkers may be used alone or in any combination to distinguish kidney cancer from other urological cancers: gluconate, 1,2-propanediol, galactose, gulono 1,4-lactone, orotidine, quinate, 1, 3-7-trimethylurate, guanine, phenylacetylglutamine, mannitol, 2-oxindole-3-acetate, 1,3-aminopropyl-2-pyrrolidone, 1,3-dimethylurate, glucuronate-galacturonate-5-keto-gluconate, glycocholate, azelate (nonanedioate), N-acetylthreonine, 7-ketodeoxycholate, 3-sialyllactose, isovalerylcarnitine, cholate, adenosine 5′ monophosphate (AMP), 2-hydroxyisobutyrate, 4-hydroxyhippurate, pipecolate, N-acetylphenylalanine, 12-dehydrocholate, alpha-ketoglutarate, sulforaphane, 3-indoxyl-sulfate, methyl-indole-3-acetate, methyl-4-hydroxybenzoate, lactate, N(2)-furoyl-glycine, N6-methyladenosine, gamma-CEHC, glycerol, 2-3-butanediol, palmitoyl-sphingomyelin, succinate, 4-hydroxyphenylacetate, caffeate, imidazole-pripionate, beta-alanine, 4-androsten-3beta-17beta-diol-disulfate-2,5-methylthioadenosine (MTA), N2-acetyllysine, sucrose, phenylacetylglycine, 4-androsten-3beta-17beta-diol-disulfate-1, cyclo-gly-pro, N-methyl-proline, catechol-sulfate, serine, vanillate, threonine, and 21-hydroxypregnenolone-disulfate. When such a method is used to distinguish kidney cancer from other urological cancers, the results of the method may be used along with other methods (or the results thereof) useful in the clinical determination of distinguishing kidney cancer from other urological cancers. 
         [0057]    B. Methods of Monitoring Progression/Regression of Kidney Cancer 
         [0058]    The identification of biomarkers for kidney cancer also allows for monitoring progression/regression of kidney cancer in a subject. A method of monitoring the progression/regression of kidney cancer in a subject comprises (1) analyzing a first biological sample from a subject to determine the level(s) of one or more biomarkers for kidney cancer selected from Tables 1, 2, 4, 8, 10 and/or 11, the first sample obtained from the subject at a first time point, (2) analyzing a second biological sample from a subject to determine the level(s) of the one or more biomarkers, the second sample obtained from the subject at a second time point, and (3) comparing the level(s) of one or more biomarkers in the first sample to the level(s) of the one or more biomarkers in the second sample in order to monitor the progression/regression of kidney cancer in the subject. The results of the method are indicative of the course of kidney cancer (i.e., progression or regression, if any change) in the subject. 
         [0059]    The levels of one or more of the biomarkers of Tables 1, 2, 4, 8, 10 and/or 11 may be determined in the methods of monitoring progression/regression of kidney cancer. For example, one or more of the following biomarkers may be used alone or in combination to monitor the progression/regression of kidney cancer: oxidized glutathione (GSSG), proline, 2-oleoylglycerophosphoethanolamine, 2-aminobutyrate, sphingosine, 3-dehydrocamitine, 2-docosahexaenoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, phosphoethanolamine, glutamate, pyrophosphate (PPi), nicotinamide-adenine-dinucleotide (NAD+), 3-aminoisobutyrate, 2-arachidonoylglycerophosphoethanolamine, 2-arachidonoylglycerophosphocholine, 2-oleoylglycerophosphocholine, glycerate, choline-phosphate, pyruvate, 1-arachidonoylglycerophosphoethanolamine, adenine, 1-2-propanediol, 2-docosahexaenoylglycerophosphoethanolamine, 2-hydroxybutyrate (AHB), creatine, glycolate (hydroxyacetate), malate, 5-methylthioadenosine (MTA), stearolycamitine, 1-arachidonoylglycerophosphoinositol, arachidonate, mannose-6-phosphate, alpha-tocopherol, flavin adenine dinucleotide (FAD), fructose-6-phosphate, maltose, maltotriose, fructose 1-phosphate, maltotetraose, 1-stearoylglycerophosphoinositol, methyl-alpha-glucopyranoside, glucose-6-phosphate (G6P), eicosenoate, 1-stearoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoinositol, 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 2-palmitoylglycerophosphoethanolamine, 1-oleoylglycerophosphoinositol, gamma-glutamylglutamate, ergothioneine, arabitol, 1-palmitoylplasmenylethanolamine, N-acetylneuraminate, malonylcarnitine, 2-hydroxyglutarate, beta-alanine, pantothenate, citrate, kynurenine, N1-methyladenosine, hippurate, glucose, N-acetylaspartate (NAA), N1-methylguanosine, pseudouridine, phenylacetylglutamine, N2-methylguanosine, 2-methylbutyrylcarnitine (C5), N-acetyl-aspartyl-glutamate (NAAG), N6-acetyllysine, dimethylarginine (SDMA+ADMA), methyl-4-hydroxybenzoate, catechol-sulfate, glycerol, 2-hydroxyhippurate (salicylurate), N(2)-furoyl-glycine, 3-hydroxyphenylacetate, gulono 1,4-lactone, 2-isopropylmalate, 2-3-dihydroxyisovalerate, 1-2-propanediol, gluconate, cinnamoylglycine, phenylacetylglycine, sorbose, sucrose, adenosine 5′-monophosphate (AMP), hexanoylglycine, methyl-indole-3-acetate, 3-hydroxyhippurate, N6-methyladenosine, 4-hydroxy-2-oxoglutaric acid, alpha-CEHC-glucuronide, phenylpropinylglycine, vanillate, ethanolamine, galactose, adipate, 2-oxindole-3-acetate, 1, 3-7-trimethylurate, 3-4-dihydroxyphenylacetate, choline, pelargonate (9:0), arginine, gamma-glutamylleucine, xanthine, tyrosine, 5-oxoproline, inositiol-1-phosphate (I1P), isoleucine, 2-ethylhexanoate, leucine, laurate (12:0), phenylalanine, mannose, uracil, xanthosine, erythritol, guanosine-5-monophosphate-5 (GMP), homocysteine, lactate, 4-hydroxybutyrate (GHB), ribose, fucose, S-adenosylhomocysteine (SAH), mannitol, hypoxanthine, and threonine. Additionally, for example, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Tables 1, 2, 4, 8, 10 and 11 or any fraction thereof, may be determined and used in methods of monitoring the progression/regression of kidney cancer in a subject. 
         [0060]    The change (if any) in the level(s) of the one or more biomarkers over time may be indicative of progression or regression of kidney cancer in the subject. In order to characterize the course of kidney cancer in the subject, the level(s) of the one or more biomarkers in the first sample, the level(s) of the one or more biomarkers in the second sample, and/or the results of the comparison of the levels of the biomarkers in the first and second samples may be compared to kidney cancer-positive and kidney cancer-negative reference levels. If the comparisons indicate that the level(s) of the one or more biomarkers are increasing or decreasing over time (e.g., in the second sample as compared to the first sample) to become more similar to the kidney cancer-positive reference levels (or less similar to the kidney cancer-negative reference levels), then the results are indicative of kidney cancer progression. If the comparisons indicate that the level(s) of the one or more biomarkers are increasing or decreasing over time to become more similar to the kidney cancer-negative reference levels (or less similar to the kidney cancer-positive reference levels), then the results are indicative of kidney cancer regression. 
         [0061]    In one embodiment, the assessment may be based on an RCC Score which is indicative of kidney cancer in the subject and which can be monitored over time. By comparing the RCC Score from a first time point sample to the RCC Score from at least a second time point sample the progression or regression of kidney cancer can be determined. Such a method of monitoring the progression/regression of kidney cancer in a subject comprises (1) analyzing a first biological sample from a subject to determine an RCC score for the first sample obtained from the subject at a first time point, (2) analyzing a second biological sample from a subject to determine a second RCC score, the second sample obtained from the subject at a second time point, and (3) comparing the RCC score in the first sample to the RCC score in the second sample in order to monitor the progression/regression of kidney cancer in the subject. 
         [0062]    The biomarkers and algorithms described herein may guide or assist a physician in deciding a treatment path, for example, whether to implement procedures such as surgical procedures (e.g., full or partial nephrectomy), treat with drug therapy, or employ a watchful waiting approach. 
         [0063]    As with the other methods described herein, the comparisons made in the methods of monitoring progression/regression of kidney cancer in a subject may be carried out using various techniques, including simple comparisons, one or more statistical analyses, mathematical models (algorithms) and combinations thereof. 
         [0064]    The results of the method may be used along with other methods (or the results thereof) useful in the clinical monitoring of progression/regression of kidney cancer in a subject. 
         [0065]    As described above in connection with methods of diagnosing (or aiding in the diagnosis of) kidney cancer, any suitable method may be used to analyze the biological samples in order to determine the level(s) of the one or more biomarkers in the samples. In addition, the level(s) one or more biomarkers, including a combination of all of the biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 or any fraction thereof, may be determined and used in methods of monitoring progression/regression of kidney cancer in a subject. 
         [0066]    Such methods could be conducted to monitor the course of kidney cancer in subjects having kidney cancer or could be used in subjects not having kidney cancer (e.g., subjects suspected of being predisposed to developing kidney cancer) in order to monitor levels of predisposition to kidney cancer. 
         [0067]    C. Methods of Staging Kidney Cancer 
         [0068]    The identification of biomarkers for kidney cancer also allows for the determination of kidney cancer stage of a subject, including the cancer stage of a subject having a cancer-positive SRM. A method of determining the stage of kidney cancer comprises (1) analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers listed in Table 8 in the sample and (2) comparing the level(s) of the one or more biomarkers in the sample to high stage kidney cancer and/or low stage kidney cancer reference levels of the one or more biomarkers in order to determine the stage of the subject&#39;s kidney cancer. The results of the method may be used along with other methods (or the results thereof) useful in the clinical determination of the stage of a subject&#39;s kidney cancer. 
         [0069]    As described above in connection with methods of diagnosing (or aiding in the diagnosis of) kidney cancer, any suitable method may be used to analyze the biological sample in order to determine the level(s) of the one or more biomarkers in the sample. 
         [0070]    The levels of one or more biomarkers listed in Table 8 and combinations thereof may be determined in the methods of determining the stage of a subject&#39;s kidney cancer. For example, one or more of the following biomarkers may be used alone or in combination to determine the stage of kidney cancer: choline, pelargonate (9:0), arginine, gamma-glutamylleucine, xanthine, tyrosine, 5-oxoproline, inositiol-1-phosphate (HP), N2-methylguanosine, isoleucine, 2-ethylhexanoate, leucine, adenine, 5-methylthioadenosine (MTA), laurate (12:0), phenylalanine, mannose, uracil, xanthosine, erythritol, guanosine-5-monophosphate-5 (GMP), homocysteine, lactate, 4-hydroxybutyrate (GHB), ribose, fucose, S-adenosylhomocysteine (SAH), mannitol, hypoxanthine, and threonine. Additionally, for example, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Table 8 or any fraction thereof, may be determined and used in methods of determining the stage of kidney cancer of a subject. 
         [0071]    After the level(s) of the one or more biomarkers in a sample are determined, the level(s) are compared to low stage kidney cancer and/or high stage kidney cancer reference levels in order to predict the stage of kidney cancer of a subject. Levels of the one or more biomarkers in a sample matching the high stage kidney cancer reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having high stage kidney cancer. Levels of the one or more biomarkers in a sample matching the low stage kidney cancer reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having low stage kidney cancer. In addition, levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to low stage kidney cancer reference levels are indicative of the subject not having low stage kidney cancer. Levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to high stage kidney cancer reference levels are indicative of the subject not having high stage kidney cancer. 
         [0072]    Studies were carried out to identify a set of biomarkers that can be used to determine the kidney cancer stage of a subject. In another embodiment, the biomarkers provided herein can be used to provide a physician with an RCC Score indicating the stage of kidney cancer in a subject. The score is based upon clinically significantly changed reference level(s) for a biomarker and/or combination of biomarkers. The reference level can be derived from an algorithm. The RCC Score can be used to determine the stage of kidney cancer in a subject from normal (i.e. no kidney cancer) to high stage kidney cancer. 
         [0073]    The biomarkers and algorithms described herein may guide or assist a physician in deciding a treatment path, for example, whether to implement procedures such as surgical procedures (e.g., full or partial nephrectomy), treat with drug therapy, or employ a watchful waiting approach. 
         [0074]    As with the methods described above, the level(s) of the one or more biomarkers may be compared to high stage kidney cancer and/or low stage kidney cancer reference levels using various techniques, including a simple comparison, one or more statistical analyses, and combinations thereof. 
         [0075]    As with the methods of diagnosing (or aiding in diagnosing) whether a subject has kidney cancer, the methods of determining the stage of kidney cancer of a subject may further comprise analyzing the biological sample to determine the level(s) of one or more non-biomarker compounds. 
         [0076]    D. Methods of Distinguishing Less Aggressive Kidney Cancer from More aggressive Kidney Cancer 
         [0077]    The identification of biomarkers for kidney cancer also allows for the identification of biomarkers for distinguishing less aggressive kidney cancer from more aggressive kidney cancer, including distinguishing less aggressive cancer-positive SRMs from more aggressive cancer-positive SRMs. A method of distinguishing less aggressive kidney cancer from more aggressive kidney cancer in a subject having kidney cancer comprises (1) analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers listed in Table 10 in the sample and (2) comparing the level(s) of the one or more biomarkers in the sample to less aggressive kidney cancer and/or more aggressive kidney cancer reference levels of the one or more biomarkers in order to determine the aggressiveness of the subject&#39;s kidney cancer. The results of the method may be used along with other methods (or the results thereof) useful in the clinical determination of the aggressiveness of a subject&#39;s kidney cancer. 
         [0078]    As described above in connection with methods of diagnosing (or aiding in the diagnosis of) kidney cancer, any suitable method may be used to analyze the biological sample in order to determine the level(s) of the one or more biomarkers in the sample. 
         [0079]    The levels of one or more biomarkers listed in Tables 4 and/or 10 may be determined in the methods of determining the aggressiveness of a subject&#39;s kidney cancer. For example, one or more of the following biomarkers may be used alone or in combination to determine the aggressiveness of a subject&#39;s kidney cancer:pelargonate (9:0), laurate (12:0), homocysteine, 2′-deoxyinosine, S-adenosylmethionine (SAM), glycylthreonine, aspartylphenylalanine, phenylalanylglycine, cytidine 5′-diphosphocholine, alanylglycine, lysylmethionine, glycylisoleucine, ribose, aspartylleucine, 2-ethylhexanoate, asparagine, homoserine, 2′-deoxyguanosine, valerylcarnitine, 4-hydroxybutyrate (GHB), caprate (10:0), galactose, heme, butyrylcarnitine, choline, isoleucine, mannitol, fucose, tyrosine, xanthine, 5-oxoproline, 5-methylthioadenosine (MTA), phenylalanine, leucine, threonate, gamma-glutamylleucine, benzoate, proline, methionine, glycylproline, N2-methylguanosine, adenine, 2-methylbutyroylcarnitine, S-adenosylhomocysteine (SAH), citrate, xanthosine, 5,6-dihydrouracil, threonine, valine, and pantothenate. Additionally, for example, as with the methods of diagnosing (or aiding in the diagnosis of) kidney cancer described above, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Tables 4 and 10 or any fraction thereof, may be determined and used in methods of determining the aggressiveness of kidney cancer of a subject. 
         [0080]    After the level(s) of the one or more biomarkers in the sample are determined, the level(s) are compared to less aggressive kidney cancer and/or more aggressive kidney cancer reference levels in order to determine the aggressiveness of kidney cancer of a subject. Levels of the one or more biomarkers in a sample matching the more aggressive kidney cancer reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having more aggressive kidney cancer. Levels of the one or more biomarkers in a sample matching the less aggressive kidney cancer reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having less aggressive kidney cancer. In addition, levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to less aggressive kidney cancer reference levels are indicative of the subject not having less aggressive kidney cancer. Levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to more aggressive kidney cancer reference levels are indicative of the subject not having more aggressive kidney cancer. 
         [0081]    Studies were carried out to identify a set of biomarkers that can be used to distinguish less aggressive kidney cancer from more aggressive kidney cancer. In another embodiment, the biomarkers provided herein can be used to provide a physician with an RCC Score indicating the aggressiveness of kidney cancer in a subject. The score is based upon clinically significantly changed reference level(s) for a biomarker and/or combination of biomarkers. The reference level can be derived from an algorithm. The RCC Score can be used to determine the aggressiveness of kidney cancer in a subject from normal (i.e. no kidney cancer) to more aggressive kidney cancer. 
         [0082]    The biomarkers and algorithms described herein may guide or assist a physician in deciding a treatment path, for example, whether to implement procedures such as surgical procedures (e.g., full or partial nephrectomy), treat with drug therapy, or employ a watchful waiting approach. 
         [0083]    As with the methods described above, the level(s) of the one or more biomarkers may be compared to more aggressive kidney cancer and/or less aggressive kidney cancer reference levels using various techniques, including a simple comparison, one or more statistical analyses, and combinations thereof. 
         [0084]    As with the methods of diagnosing (or aiding in diagnosing) whether a subject has kidney cancer, the methods of determining the aggressiveness of kidney cancer of a subject may further comprise analyzing the biological sample to determine the level(s) of one or more non-biomarker compounds. 
         [0085]    E. Methods of Determining Whether a Small Renal Mass (SRM) is Cancerous 
         [0086]    The identification of biomarkers for kidney cancer also allows for the determination of whether a subject discovered as having an SRM has a benign SRM or an SRM that is cancerous. A method of determining the cancer status of an SRM comprises (1) analyzing a biological sample from a subject to determine the level(s) of one or more biomarkers listed in Tables 1, 2, 4, 8, 10, and/or 11 in the sample and (2) comparing the level(s) of the one or more biomarkers in the sample to kidney cancer-positive and/or kidney cancer-negative reference levels of the one or more biomarkers in order to determine the cancer status of the subject&#39;s SRM. The results of the method may be used along with other methods (or the results thereof) useful in the clinical determination of the cancer status of a subject&#39;s SRM. 
         [0087]    As described above in connection with methods of diagnosing (or aiding in the diagnosis of) kidney cancer, any suitable method may be used to analyze the biological sample in order to determine the level(s) of the one or more biomarkers in the sample. 
         [0088]    As with the methods of diagnosing (or aiding in the diagnosis of) kidney cancer described above, the level(s) of one or more of the biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 may be determined in the methods of determining the cancer status of an SRM. For example, one or more of the following biomarkers may be used alone or in combination to determine the cancer status of a subject&#39;s SRM: oxidized glutathione (GSSG), proline, 2-oleoylglycerophosphoethanolamine, 2-aminobutyrate, sphingosine, 3-dehydrocarnitine, 2-docosahexaenoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, phosphoethanolamine, glutamate, pyrophosphate (PPi), nicotinamide-adenine-dinucleotide (NAD+), 3-aminoisobutyrate, 2-arachidonoylglycerophosphoethanolamine, 2-arachidonoylglycerophosphocholine, 2-oleoylglycerophosphocholine, glycerate, choline-phosphate, pyruvate, 1-arachidonoylglycerophosphoethanolamine, adenine, 1-2-propanediol, 2-docosahexaenoylglycerophosphoethanolamine, 2-hydroxybutyrate (AHB), creatine, glycolate (hydroxyacetate), malate, 5-methylthioadenosine (MTA), stearolycamitine, 1-arachidonoylglycerophosphoinositol, arachidonate, mannose-6-phosphate, alpha-tocopherol, flavin adenine dinucleotide (FAD), fructose-6-phosphate, maltose, maltotriose, fructose 1-phosphate, maltotetraose, 1-stearoylglycerophosphoinositol, methyl-alpha-glucopyranoside, glucose-6-phosphate (G6P), eicosenoate, 1-stearoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoinositol, 1-ol eoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 2-palmitoylglycerophosphoethanolamine, 1-oleoylglycerophosphoinositol, gamma-glutamylglutamate, ergothioneine, arabitol, 1-palmitoylplasmenylethanolamine, N-acetylneuraminate, malonylcarnitine, 2-hydroxyglutarate, beta-alanine, pantothenate, citrate, kynurenine, N1-methyladenosine, hippurate, glucose, N-acetylaspartate (NAA), N1-methylguanosine, pseudouridine, phenylacetylglutamine, N2-methylguanosine, 2-methylbutyrylcarnitine (C5), N-acetyl-aspartyl-glutamate (NAAG), N6-acetyllysine, dimethylarginine (SDMA+ADMA), methyl-4-hydroxybenzoate, catechol-sulfate, glycerol, 2-hydroxyhippurate (salicylurate), N(2)-furoyl-glycine, 3-hydroxyphenylacetate, gulono 1,4-lactone, 2-isopropylmalate, 2-3-dihydroxyisovalerate, 1-2-propanediol, gluconate, cinnamoylglycine, phenylacetylglycine, sorbose, sucrose, adenosine 5′-monophosphate (AMP), hexanoylglycine, methyl-indole-3-acetate, 3-hydroxyhippurate, N6-methyladenosine, 4-hydroxy-2-oxoglutaric acid, alpha-CEHC-glucuronide, phenylpropinylglycine, vanillate, ethanolamine, galactose, adipate, 2-oxindole-3-acetate, 1, 3-7-trimethylurate, and 3-4-dihydroxyphenylacetate. Additionally, for example, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Tables 1, 2, 4, 8, 10, and/or 11 or any fraction thereof, may be determined and used in methods of determining the cancer status of a subject&#39;s SRM. 
         [0089]    After the level(s) of the one or more biomarkers in a sample are determined, the level(s) are compared to kidney cancer-positive and/or kidney cancer-negative reference levels in order to determine the cancer status of a subject&#39;s SRM. Levels of the one or more biomarkers in a sample matching the kidney cancer-positive reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having a cancer-positive SRM. Levels of the one or more biomarkers in a sample matching the kidney cancer-negative reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the subject having a cancer-negative SRM. In addition, levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to kidney cancer-negative reference levels are indicative of a diagnosis of a cancer-positive SRM. Levels of the one or more biomarkers that are differentially present (especially at a level that is statistically significant) in the sample as compared to kidney cancer-positive reference levels are indicative of the subject not having a cancer-positive SRM. 
         [0090]    As with the methods described above, the level(s) of the one or more biomarkers may be compared to kidney cancer-positive and/or kidney cancer-negative reference levels using various techniques, including a simple comparison, one or more statistical analyses, and combinations thereof. An RCC Score may also be used in indicating the existence and/or severity of cancer in a SRM. 
         [0091]    As with the methods of diagnosing (or aiding in diagnosing) whether a subject has kidney cancer, the methods of assessing the cancer status of a SRM of a subject may further comprise analyzing the biological sample to determine the level(s) of one or more non-biomarker compounds. 
         [0092]    F. Methods of Assessing Efficacy of Compositions for Treating Kidney Cancer 
         [0093]    The identification of biomarkers for kidney cancer also allows for assessment of the efficacy of a composition for treating kidney cancer as well as the assessment of the relative efficacy of two or more compositions for treating kidney cancer. Such assessments may be used, for example, in efficacy studies as well as in lead selection of compositions for treating kidney cancer. 
         [0094]    A method of assessing the efficacy of a composition for treating kidney cancer comprises (1) analyzing, from a subject having kidney cancer and currently or previously being treated with a composition, a biological sample to determine the level(s) of one or more biomarkers selected from Tables 1, 2, 4, 8, 10 and/or 11, and (2) comparing the level(s) of the one or more biomarkers in the sample to (a) level(s) of the one or more biomarkers in a previously-taken biological sample from the subject, wherein the previously-taken biological sample was obtained from the subject before being treated with the composition, (b) kidney cancer-positive reference levels of the one or more biomarkers, and (c) kidney cancer-negative reference levels of the one or more biomarkers. The results of the comparison are indicative of the efficacy of the composition for treating kidney cancer. 
         [0095]    The levels of one or more of the biomarkers of Tables 1, 2, 4, 8, 10 and/or 11 may be determined in the methods of assessing the efficacy of a composition for treating kidney cancer. For example, one or more of the following biomarkers may be used alone or in combination to assess the efficacy of a composition for treating kidney cancer: oxidized glutathione (GSSG), proline, 2-oleoylglycerophosphoethanolamine, 2-aminobutyrate, sphingosine, 3-dehydrocarnitine, 2-docosahexaenoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, phosphoethanolamine, glutamate, pyrophosphate (PPi), nicotinamide-adenine-dinucleotide (NAD+), 3-aminoisobutyrate, 2-arachidonoylglycerophosphoethanolamine, 2-arachidonoylglycerophosphocholine, 2-oleoylglycerophosphocholine, glycerate, choline-phosphate, pyruvate, 1-arachidonoylglycerophosphoethanolamine, adenine, 1-2-propanediol, 2-docosahexaenoylglycerophosphoethanolamine, 2-hydroxybutyrate (AHB), creatine, glycolate (hydroxyacetate), malate, 5-methylthioadenosine (MTA), stearolycarnitine, 1-arachidonoylglycerophosphoinositol, arachidonate, mannose-6-phosphate, alpha-tocopherol, flavin adenine dinucleotide (FAD), fructose-6-phosphate, maltose, maltotriose, fructose 1-phosphate, maltotetraose, 1-stearoylglycerophosphoinositol, methyl-alpha-glucopyranoside, glucose-6-phosphate (G6P), eicosenoate, 1-stearoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoinositol, 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 2-palmitoylglycerophosphoethanolamine, 1-oleoylglycerophosphoinositol, gamma-glutamylglutamate, ergothioneine, arabitol, 1-palmitoylplasmenylethanolamine, N-acetylneuraminate, malonylcarnitine, 2-hydroxyglutarate, beta-alanine, pantothenate, citrate, kynurenine, N1-methyladenosine, hippurate, glucose, N-acetylaspartate (NAA), N1-methylguanosine, pseudouridine, phenylacetylglutamine, N2-methylguanosine, 2-methylbutyrylcarnitine (C5), N-acetyl-aspartyl-glutamate (NAAG), N 6 -acetyllysine, dimethylarginine (SDMA+ADMA), methyl-4-hydroxybenzoate, catechol-sulfate, glycerol, 2-hydroxyhippurate (salicylurate), N(2)-furoyl-glycine, 3-hydroxyphenylacetate, gulono 1,4-lactone, 2-isopropylmalate, 2-3-dihydroxyisovalerate, 1-2-propanediol, gluconate, cinnamoylglycine, phenylacetylglycine, sorbose, sucrose, adenosine 5′-monophosphate (AMP), hexanoylglycine, methyl-indole-3-acetate, 3-hydroxyhippurate, N6-methyladenosine, 4-hydroxy-2-oxoglutaric acid, alpha-CEHC-glucuronide, phenylpropinylglycine, vanillate, ethanolamine, galactose, adipate, 2-oxindole-3-acetate, 1, 3-7-trimethylurate, 3-4-dihydroxyphenylacetate, choline, pelargonate (9:0), arginine, gamma-glutamylleucine, xanthine, tyrosine, 5-oxoproline, inositiol-1-phosphate (11P), isoleucine, 2-ethylhexanoate, leucine, laurate (12:0), phenylalanine, mannose, uracil, xanthosine, erythritol, guanosine-5-monophosphate-5 (GMP), homocysteine, lactate, 4-hydroxybutyrate (GHB), ribose, fucose, S-adenosylhomocysteine (SAH), mannitol, hypoxanthine, and threonine. Additionally, for example, the level(s) of one biomarker, two or more biomarkers, three or more biomarkers, four or more biomarkers, five or more biomarkers, six or more biomarkers, seven or more biomarkers, eight or more biomarkers, nine or more biomarkers, ten or more biomarkers, etc., including a combination of all of the biomarkers in Tables 1, 2, 4, 8, 10 and 11 or any fraction thereof, may be determined and used in methods of assessing the efficacy of a composition for treating kidney cancer. 
         [0096]    Thus, in order to characterize the efficacy of the composition for treating kidney cancer, the level(s) of the one or more biomarkers in the biological sample are compared to (1) kidney cancer-positive reference levels, (2) kidney cancer-negative reference levels, and (3) previous levels of the one or more biomarkers in the subject before treatment with the composition. 
         [0097]    When comparing the level(s) of the one or more biomarkers in the biological sample (from a subject having kidney cancer and currently or previously being treated with a composition) to kidney cancer-positive reference levels and/or kidney cancer-negative reference levels, level(s) in the sample matching the kidney cancer-negative reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the composition having efficacy for treating kidney cancer. Levels of the one or more biomarkers in the sample matching the kidney cancer-positive reference levels (e.g., levels that are the same as the reference levels, substantially the same as the reference levels, above and/or below the minimum and/or maximum of the reference levels, and/or within the range of the reference levels) are indicative of the composition not having efficacy for treating kidney cancer. The comparisons may also indicate degrees of efficacy for treating kidney cancer based on the level(s) of the one or more biomarkers. 
         [0098]    When the level(s) of the one or more biomarkers in the biological sample (from a subject having kidney cancer and currently or previously being treated with a composition) are compared to level(s) of the one or more biomarkers in a previously-taken biological sample from the subject before treatment with the composition, any changes in the level(s) of the one or more biomarkers are indicative of the efficacy of the composition for treating kidney cancer. That is, if the comparisons indicate that the level(s) of the one or more biomarkers have increased or decreased after treatment with the composition to become more similar to the kidney cancer-negative reference levels (or less similar to the kidney cancer-positive reference levels), then the results are indicative of the composition having efficacy for treating kidney cancer. If the comparisons indicate that the level(s) of the one or more biomarkers have not increased or decreased after treatment with the composition to become more similar to the kidney cancer-negative reference levels (or less similar to the kidney cancer-positive reference levels), then the results are indicative of the composition not having efficacy for treating kidney cancer. The comparisons may also indicate degrees of efficacy for treating kidney cancer based on the amount of changes observed in the level(s) of the one or more biomarkers after treatment. In order to help characterize such a comparison, the changes in the level(s) of the one or more biomarkers, the level(s) of the one or more biomarkers before treatment, and/or the level(s) of the one or more biomarkers in the subject currently or previously being treated with the composition may be compared to kidney cancer-positive reference levels, and/or to kidney cancer-negative reference levels. 
         [0099]    Another method for assessing the efficacy of a composition in treating kidney cancer comprises (1) analyzing a first biological sample from a subject to determine the level(s) of one or more biomarkers selected from Tables 1, 2, 4, 8, 10 and/or 11, the first sample obtained from the subject at a first time point, (2) administering the composition to the subject, (3) analyzing a second biological sample from a subject to determine the level(s) of the one or more biomarkers, the second sample obtained from the subject at a second time point after administration of the composition, and (4) comparing the level(s) of one or more biomarkers in the first sample to the level(s) of the one or more biomarkers in the second sample in order to assess the efficacy of the composition for treating kidney cancer. As indicated above, if the comparison of the samples indicates that the level(s) of the one or more biomarkers have increased or decreased after administration of the composition to become more similar to the kidney cancer-negative reference levels, then the results are indicative of the composition having efficacy for treating kidney cancer. If the comparisons indicate that the level(s) of the one or more biomarkers have not increased or decreased after treatment with the composition to become more similar to the kidney cancer-negative reference levels (or less similar to the kidney cancer-positive reference levels) then the results are indicative of the composition not having efficacy for treating kidney cancer. The comparison may also indicate a degree of efficacy for treating kidney cancer based on the amount of changes observed in the level(s) of the one or more biomarkers after administration of the composition as discussed above. 
         [0100]    A method of assessing the relative efficacy of two or more compositions for treating kidney cancer comprises (1) analyzing, from a first subject having kidney cancer and currently or previously being treated with a first composition, a first biological sample to determine the level(s) of one or more biomarkers selected from Tables 1, 2, 4, 8, 10 and/or 11 (2) analyzing, from a second subject having kidney cancer and currently or previously being treated with a second composition, a second biological sample to determine the level(s) of the one or more biomarkers, and (3) comparing the level(s) of one or more biomarkers in the first sample to the level(s) of the one or more biomarkers in the second sample in order to assess the relative efficacy of the first and second compositions for treating kidney cancer. The results are indicative of the relative efficacy of the two compositions, and the results (or the levels of the one or more biomarkers in the first sample and/or the level(s) of the one or more biomarkers in the second sample) may be compared to kidney cancer-positive reference levels, kidney cancer-negative reference levels to aid in characterizing the relative efficacy. 
         [0101]    Each of the methods of assessing efficacy may be conducted on one or more subjects or one or more groups of subjects (e.g., a first group being treated with a first composition and a second group being treated with a second composition). 
         [0102]    As with the other methods described herein, the comparisons made in the methods of assessing efficacy (or relative efficacy) of compositions for treating kidney cancer may be carried out using various techniques, including simple comparisons, one or more statistical analyses, mathematical models, algorithms and combinations thereof. An example of a technique that may be used is determining the RCC score for a subject. Any suitable method may be used to analyze the biological samples in order to determine the level(s) of the one or more biomarkers in the samples. In addition, the level(s) of one or more biomarkers, including a combination of all of the biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 or any fraction thereof, may be determined and used in methods of assessing efficacy (or relative efficacy) of compositions for treating kidney cancer. 
         [0103]    Finally, the methods of assessing efficacy (or relative efficacy) of one or more compositions for treating kidney cancer may further comprise analyzing the biological sample to determine the level(s) of one or more non-biomarker compounds. The non-biomarker compounds may then be compared to reference levels of non-biomarker compounds for subjects having (or not having) kidney cancer. 
         [0104]    G. Methods of Screening a Composition for Activity in Modulating Biomarkers Associated with Kidney Cancer 
         [0105]    The identification of biomarkers for kidney cancer also allows for the screening of compositions for activity in modulating biomarkers associated with kidney cancer, which may be useful in treating kidney cancer. Methods of screening compositions useful for treatment of kidney cancer comprise assaying test compositions for activity in modulating the levels of one or more biomarkers in Tables 1, 2, 4, 8, 10 and/or 11. Such screening assays may be conducted in vitro and/or in vivo, and may be in any form known in the art useful for assaying modulation of such biomarkers in the presence of a test composition such as, for example, cell culture assays, organ culture assays, and in vivo assays (e.g., assays involving animal models). 
         [0106]    In one embodiment, a method for screening a composition for activity in modulating one or more biomarkers of kidney cancer comprises (1) contacting one or more cells with a composition, (2) analyzing at least a portion of the one or more cells or a biological sample associated with the cells to determine the level(s) of one or more biomarkers of kidney cancer selected from Tables 1, 2, 4, 8, 10 and/or 11; and (3) comparing the level(s) of the one or more biomarkers with predetermined standard levels for the one or more biomarkers to determine whether the composition modulated the level(s) of the one or more biomarkers. As discussed above, the cells may be contacted with the composition in vitro and/or in vivo. The predetermined standard levels for the one or more biomarkers may be the levels of the one or more biomarkers in the one or more cells in the absence of the composition. The predetermined standard levels for the one or more biomarkers may also be the level(s) of the one or more biomarkers in control cells not contacted with the composition. 
         [0107]    In addition, the methods may further comprise analyzing at least a portion of the one or more cells or a biological sample associated with the cells to determine the level(s) of one or more non-biomarker compounds of kidney cancer. The levels of the non-biomarker compounds may then be compared to predetermined standard levels of the one or more non-biomarker compounds. 
         [0108]    Any suitable method may be used to analyze at least a portion of the one or more cells or a biological sample associated with the cells in order to determine the level(s) of the one or more biomarkers (or levels of non-biomarker compounds). 
         [0109]    Suitable methods include chromatography (e.g., HPLC, gas chromatograph, liquid chromatography), mass spectrometry (e.g., MS, MS-MS), ELISA, antibody linkage, other immunochemical techniques, and combinations thereof. Further, the level(s) of the one or more biomarkers (or levels of non-biomarker compounds) may be measured indirectly, for example, by using an assay that measures the level of a compound (or compounds) that correlates with the level of the biomarker(s) (or non-biomarker compounds) that are desired to be measured. 
         [0110]    H. Methods of Treating Kidney Cancer 
         [0111]    The identification of biomarkers for kidney cancer also allows for the treatment of kidney cancer. For example, in order to treat a subject having kidney cancer, an effective amount of one or more kidney cancer biomarkers that are lowered in kidney cancer as compared to a healthy subject not having kidney cancer may be administered to the subject. The biomarkers that may be administered may comprise one or more of the biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 that are decreased in kidney cancer. In some embodiments, the biomarkers that are administered are one or more biomarkers listed in Tables 1, 2, 4, 8, 10 and/or 11 that are decreased in kidney cancer and that have a p-value less than 0.10. In other embodiments, the biomarkers that are administered are one or biomarkers listed in Tables 1, 2, 4, 8, 10 and/or 11 that are decreased in kidney cancer by at least 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%, or by 100% (i.e., absent). 
       III. OTHER METHODS 
       [0112]    Other methods of using the biomarkers discussed herein are also contemplated. For example, the methods described in U.S. Pat. No. 7,005,255, 
         [0113]    U.S. Pat. No. 7,329,489, U.S. Pat. No. 7,553,616, U.S. Pat. No. 7,550,260, U.S. Pat. No. 7,550,258, U.S. Pat. No. 7,635,556, U.S. patent application Ser. No. 11/728,826, U.S. patent application Ser. No. 12/463,690 and U.S. patent application Ser. No. 12/182,828 may be conducted using a small molecule profile comprising one or more of the biomarkers disclosed herein. 
         [0114]    In any of the methods listed herein, the biomarkers that are used may be selected from those biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 having p-values of less than 0.05. The biomarkers that are used in any of the methods described herein may also be selected from those biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 that are decreased in kidney cancer (as compared to the control) or that are decreased in high stage (as compared to control or low stage) or that are decreased in more aggressive (as compared to control or less aggressive) by at least 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%, or by 100% (i.e., absent); and/or those biomarkers in Tables 1, 2, 4, 8, 10 and/or 11 that are increased in kidney cancer (as compared to the control or remission) or that are increased high stage (as compared to control or low stage) or that are increased in more aggressive (as compared to control or less aggressive) by at least 5%, by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, by at least 95%, by at least 100%, by at least 110%, by at least 120%, by at least 130%, by at least 140%, by at least 150%, or more. 
       IV. EXAMPLES 
       [0115]    The invention will be further explained by the following illustrative examples that are intended to be non-limiting. 
         [0116]    I. General Methods 
         [0117]    A. Identification of Metabolic profiles for kidney cancer 
         [0118]    Each sample was analyzed to determine the concentration of several hundred metabolites. Analytical techniques such as GC-MS (gas chromatography-mass spectrometry) and LC-MS (liquid chromatography-mass spectrometry) were used to analyze the metabolites. Multiple aliquots were simultaneously, and in parallel, analyzed, and, after appropriate quality control (QC), the information derived from each analysis was recombined. Every sample was characterized according to several thousand characteristics, which ultimately amount to several hundred chemical species. The techniques used were able to identify novel and chemically unnamed compounds. 
         [0119]    B. Statistical Analysis 
         [0120]    The data was analyzed using T-tests to identify molecules present at differential levels in a definable population or subpopulation (e.g., biomarkers for kidney cancer biological samples compared to control biological samples or compared to patients in remission from kidney cancer) useful for distinguishing between the definable populations (e.g., kidney cancer and control). Other molecules in the definable population or subpopulation were also identified. 
         [0121]    Data was also analyzed using Random Forest Analysis. Random Forests give an estimate of how well individuals in a new data set can be classified into existing groups. Random Forest Analysis creates a set of classification trees based on continual sampling of the experimental units and compounds. Then each observation is classified based on the majority votes from all the classification trees. In statistics, a classification tree classifies the observations into groups based on combinations of the variables (in this instance variables are metabolites or compounds). There are many variations on the algorithms used to create trees. A tree algorithm searches for the metabolite (compound) that provides the largest split between the two groups. This produces nodes. Then at each node, the metabolite that provides the best split is used and so on. If the node cannot be improved on, then it stops at that node and any observation in that node is classified as the majority group. 
         [0122]    Random Forests classify based on a large number (e.g. thousands) of trees. A subset of compounds and a subset of observations are used to create each tree. The observations used to create the tree are called the in-bag samples, and the remaining samples are called the out-of-bag samples. The classification tree is created from the in-bag samples, and the out-of-bag samples are predicted from this tree. To get the final classification for an observation, the “votes” for each group are counted based on the times it was an out-of-bag sample. For example, suppose observation 1 was classified as a “Control” by 2,000 trees, but classified as “Disease” by 3,000 trees. Using “majority wins” as the criterion, this sample is classified as “Disease.” 
         [0123]    The results of the Random Forest are summarized in a Confusion Matrix. The rows correspond to the true grouping, and the columns correspond to the classification from the random forest. Thus, the diagonal elements indicate the correct classifications. A 50% error would occur by random chance for 2 groups, 66.67% error for three groups by random chance, etc. The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the random forest model (e.g., whether a sample is from a diseased subject or a control subject). 
         [0124]    It is also of interest to see which variables are more “important” in the final classifications. The “Importance Plot” shows the top compounds ranked in terms of their importance. There are different criteria for ranking the importance, but the general idea is that removing an important variable will cause a greater decrease in accuracy than a variable that is less important. 
         [0125]    The data were also analyzed using a mixed model which consists of both fixed effect and random effect and is widely used for clustered data to build models that are useful to identify the biomarker compounds that are associated with kidney cancer. This method allows for the ability to control the known confounding factors (e.g., age, gender, BMI) to reduce the likelihood of a spurious relationship and thus reduce the probability of false positives. To assess biomarkers for tumor aggressiveness, Fisher&#39;s method was used following the mixed model analysis to combine the results of stage, grade and metastatic potential. Biomarker compounds that are useful to predict kidney cancer and that are positively or negatively correlated with kidney cancer were identified in these analyses. 
         [0126]    C. Biomarker Identification 
         [0127]    Various peaks identified in the analyses (e.g. GC-MS, LC-MS, LC-MS-MS), including those identified as statistically significant, were subjected to a mass spectrometry based chemical identification process. 
       Example 1 
     Intact Biopsy Tissue Biomarkers for Kidney Cancer 
       [0128]    Biomarkers were discovered by (1) analyzing tissue samples from human subjects to determine the levels of metabolites in the samples and then (2) statistically analyzing the results to determine those metabolites that were differentially present in the kidney cancer tissue samples compared to the benign tissue samples. 
         [0129]    Six kidney cancer positive and 6 patient-matched non-cancer human kidney core biopsies were obtained post-nephrectomy using an 18 gauge biopsy gun and placed into cryovials (Nalgene) containing 2 ml of 80% methanol. A single biopsy was placed in each vial and incubated for 24-72 hours at room temperature (22-24° C.). Following incubation, the tissues were removed from the solvent for histological analysis, and the solvent was prepared for metabolomics analysis. The cancer status of the sample was verified by histopathology analysis. Histological analysis was performed by a board-certified pathologist. 
         [0130]    For metabolomics analysis, the solvent extracts were evaporated to dryness under a stream of nitrogen gas at 40° C. in a Turbovap LV evaporator (Zymark). The dried extracts were reconstituted in 550 μl methanol:water (80:20) containing recovery standards (D,L-2-fluorophenylglycine, D,L-4-chlorophenylalanine, tridecanoic acid, D6 cholesterol). The reconstituted solution was analyzed by metabolomics. 
         [0131]    After the levels of metabolites were determined, statistical analysis was performed to identify metabolites that were significantly altered in the kidney cancer samples compared to the patient-matched non-cancer samples. The results of the matched pairs t-test analysis showed that 91 metabolites were significantly (p&lt;0.1) altered in kidney cancer samples compared to the non-cancer samples. Table 1 lists the identified biomarkers having a p-value of less than 0.1. Table 1 includes, for each listed biomarker, the biochemical name of the biomarker, an indication of the percentage difference in the cancer sample mean as compared to the non-cancer sample mean (positive values represent an increase in kidney cancer, and negative values represent a decrease in kidney cancer), the p-value, and the q-value determined in the statistical analysis of the data concerning the biomarkers. Also included in Table 1 are: the identifier for that biomarker compound in the Kyoto Encyclopedia of Genes and Genomes (KEGG), if available; and the identifier for that biomarker compound in the Human Metabolome Database (HMDB), if available. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Kidney Cancer Tissue Biomarkers, p &lt; 0.1 
               
             
          
           
               
                   
                 % change 
                   
                   
                   
                   
               
               
                 Biochemical Name 
                 in cancer 
                 P-Value 
                 Q-Value 
                 Kegg 
                 HMDB 
               
               
                   
               
             
          
           
               
                 glycerate 
                 175% 
                 0.0242 
                 0.065 
                 C00258 
                 HMDB00139 
               
               
                 sphingosine 
                 716% 
                 0.0212 
                 0.065 
                 C00319 
                 HMDB00252 
               
               
                 phosphoethanolamine 
                 779% 
                 0.0365 
                 0.0667 
                 C00346 
                 HMDB00224 
               
               
                 choline phosphate 
                 229% 
                 0.0576 
                 0.0798 
                   
                   
               
               
                 pyrophosphate (PPi) 
                 446% 
                 0.0611 
                 0.082 
                 C00013 
                 HMDB00250 
               
               
                 2-oleoylglycerophosphoethanolamine 
                 374% 
                 0.0011 
                 0.0522 
                   
                   
               
               
                 2-docosahexaenoylglycerophosphocholine 
                 124% 
                 0.0059 
                 0.065 
                   
                   
               
               
                 2-docosahexaenoylglycerophosphoethanolamine 
                 379% 
                 0.0153 
                 0.065 
                   
                   
               
               
                 glutathione, oxidized (GSSG) 
                 433% 
                 0.0158 
                 0.065 
                 C00127 
                 HMDB03337 
               
               
                 2-arachidonoylglycerophosphoethanolamine 
                 731% 
                 0.0172 
                 0.065 
                   
                   
               
               
                 2-arachidonoylglycerophosphocholine 
                 701% 
                 0.0236 
                 0.065 
                   
                   
               
               
                 2-oleoylglycerophosphocholine 
                 327% 
                 0.0251 
                 0.065 
                   
                   
               
               
                 1-arachidonoylglycerophosphoinositol 
                 160% 
                 0.0359 
                 0.0667 
                   
                   
               
               
                 nicotinamide adenine dinucleotide 
                 188% 
                 0.0366 
                 0.0667 
                 C00003 
                 HMDB00902 
               
               
                 (NAD+) 
                   
                   
                   
                   
                   
               
               
                 2-linoleoylglycerophosphocholine 
                 185% 
                 0.0616 
                 0.082 
                   
                   
               
               
                 1-arachidonoylglycerophosphoethanolamine 
                 192% 
                 0.0724 
                 0.093 
                   
                 HMDB11517 
               
               
                 methyl-alpha-glucopyranoside 
                 354% 
                 &lt;0.001 
                 0.0272 
                 C04942, 
                   
               
               
                   
                   
                   
                   
                 C02603 
                   
               
               
                 margarate (17:0) 
                  54% 
                 0.0061 
                 0.065 
                   
                 HMDB02259 
               
               
                 cholesterol 
                  75% 
                 0.0071 
                 0.065 
                 C00187 
                 HMDB00067 
               
               
                 stearate (18:0) 
                  38% 
                 0.0073 
                 0.065 
                 C01530 
                 HMDB00827 
               
               
                 palmitate (16:0) 
                  25% 
                 0.0086 
                 0.065 
                 C00249 
                 HMDB00220 
               
               
                 deoxycarnitine 
                 186% 
                 0.0114 
                 0.065 
                 C01181 
                 HMDB01161 
               
               
                 arginine 
                  26% 
                 0.0208 
                 0.065 
                 C00062 
                 HMDB00517 
               
               
                 2-palmitoylglycerophosphocholine 
                 342% 
                 0.0223 
                 0.065 
                   
                   
               
               
                 1-palmitoylglycerophosphocholine 
                 522% 
                 0.0224 
                 0.065 
                   
                   
               
               
                 betaine 
                 139% 
                 0.0242 
                 0.065 
                   
                 HMDB00043 
               
               
                 1-linoleoylglycerophosphocholine 
                 450% 
                 0.0282 
                 0.066 
                 C04100 
                   
               
               
                 1-oleoylglycerophosphocholine 
                 320% 
                 0.0304 
                 0.0667 
                   
                   
               
               
                 uridine 
                  60% 
                 0.0316 
                 0.0667 
                 C00299 
                 HMDB00296 
               
               
                 ornithine 
                  73% 
                 0.0342 
                 0.0667 
                 C00077 
                 HMDB03374 
               
               
                 butyrylcarnitine 
                 163% 
                 0.0344 
                 0.0667 
                   
                   
               
               
                 phosphate 
                 102% 
                 0.0348 
                 0.0667 
                 C00009 
                 HMDB01429 
               
               
                 1-linoleoylglycerophosphoethanolamine 
                 128% 
                 0.0363 
                 0.0667 
                   
                 HMDB11507 
               
               
                 urea 
                 417% 
                 0.0413 
                 0.069 
                 C00086 
                 HMDB00294 
               
               
                 oleoylcarnitine 
                 1134%  
                 0.0454 
                 0.0724 
                   
                 HMDB05065 
               
               
                 1-arachidonoylglycerophosphocholine 
                 110% 
                 0.0496 
                 0.0746 
                 C05208 
                   
               
               
                 phosphoglycerate (2 or 3) 
                  43% 
                 0.0497 
                 0.0746 
                   
                   
               
               
                 palmitoylcarnitine 
                 1333%  
                 0.0501 
                 0.0746 
                   
                   
               
               
                 methylphosphate 
                 141% 
                 0.0575 
                 0.0798 
                   
                   
               
               
                 eicosenoate (20:1n9 or 11) 
                  95% 
                 0.0623 
                 0.082 
                   
                 HMDB02231 
               
               
                 inositol 1-phosphate (I1P) 
                 430% 
                 0.0693 
                 0.0901 
                   
                 HMDB00213 
               
               
                 ophthalmate 
                 284% 
                 0.0867 
                 0.1061 
                   
                 HMDB05765 
               
               
                 1-stearoylglycerophosphocholine 
                 319% 
                 0.0902 
                 0.1081 
                   
                   
               
               
                 1-palmitoylplasmenylethanolamine 
                 114% 
                 0.0919 
                 0.1081 
                   
                   
               
               
                 trans-4-hydroxyproline 
                 227% 
                 0.0924 
                 0.1081 
                 C01157 
                 HMDB00725 
               
               
                 6-phosphogluconate 
                 235% 
                 0.0971 
                 0.1124 
                 C00345 
                 HMDB01316 
               
               
                 2-hydroxybutyrate (AHB) 
                  41% 
                 0.002 
                 0.0522 
                 C05984 
                 HMDB00008 
               
               
                 glycerol 
                  60% 
                 0.0037 
                 0.0648 
                 C00116 
                 HMDB00131 
               
               
                 2-hydroxyglutarate 
                 205% 
                 0.0295 
                 0.066 
                 C02630 
                 HMDB00606 
               
               
                 stearoylcarnitine 
                 548% 
                 0.0337 
                 0.0667 
                   
                 HMDB00848 
               
               
                 N-acetylneuraminate 
                 365% 
                 0.0424 
                 0.0698 
                 C00270 
                 HMDB00230 
               
               
                 1,5-anhydroglucitol (1,5-AG) 
                  16% 
                 0.076 
                 0.0963 
                 C07326 
                 HMDB02712 
               
               
                 5-oxoproline 
                  93% 
                 0.002 
                 0.0522 
                 C01879 
                 HMDB00267 
               
               
                 3-hydroxybutyrate (BHBA) 
                  85% 
                 0.0029 
                 0.0602 
                 C01089 
                 HMDB00357 
               
               
                 lactate 
                  89% 
                 0.0075 
                 0.065 
                 C00186 
                 HMDB00190 
               
               
                 tyrosine 
                  55% 
                 0.0076 
                 0.065 
                 C00082 
                 HMDB00158 
               
               
                 isoleucine 
                  56% 
                 0.0098 
                 0.065 
                 C00407 
                 HMDB00172 
               
               
                 leucine 
                  48% 
                 0.0102 
                 0.065 
                 C00123 
                 HMDB00687 
               
               
                 valine 
                  36% 
                 0.0103 
                 0.065 
                 C00183 
                 HMDB00883 
               
               
                 3-dehydrocarnitine 
                 172% 
                 0.0132 
                 0.065 
                 C02636 
                 HMDB12154 
               
               
                 lysine 
                  38% 
                 0.0139 
                 0.065 
                 C00047 
                 HMDB00182 
               
               
                 3-aminoisobutyrate 
                 418% 
                 0.0144 
                 0.065 
                 C05145 
                 HMDB03911 
               
               
                 acetylcarnitine 
                 233% 
                 0.0149 
                 0.065 
                 C02571 
                 HMDB00201 
               
               
                 adenine 
                  96% 
                 0.0171 
                 0.065 
                 C00147 
                 HMDB00034 
               
               
                 serine 
                 131% 
                 0.0178 
                 0.065 
                 C00065 
                 HMDB03406 
               
               
                 phenylalanine 
                  50% 
                 0.0226 
                 0.065 
                 C00079 
                 HMDB00159 
               
               
                 5-methylthioadenosine (MTA) 
                 270% 
                 0.0229 
                 0.065 
                 C00170 
                 HMDB01173 
               
               
                 tryptophan 
                  56% 
                 0.0239 
                 0.065 
                 C00078 
                 HMDB00929 
               
               
                 succinate 
                 206% 
                 0.0248 
                 0.065 
                 C00042 
                 HMDB00254 
               
               
                 hexanoylcarnitine 
                 187% 
                 0.0253 
                 0.065 
                 C01585 
                 HMDB00705 
               
               
                 carnitine 
                  79% 
                 0.0253 
                 0.065 
                   
                   
               
               
                 pyruvate 
                 431% 
                 0.0254 
                 0.065 
                 C00022 
                 HMDB00243 
               
               
                 proline 
                 107% 
                 0.0259 
                 0.065 
                 C00148 
                 HMDB00162 
               
               
                 stachydrine 
                  82% 
                 0.0272 
                 0.066 
                 C10172 
                 HMDB04827 
               
               
                 histidine 
                  41% 
                 0.028 
                 0.066 
                 C00135 
                 HMDB00177 
               
               
                 pyroglutamine 
                 255% 
                 0.0295 
                 0.066 
                   
                   
               
               
                 5,6-dihydrouracil 
                  84% 
                 0.037 
                 0.0667 
                 C00429 
                 HMDB00076 
               
               
                 2-aminobutyrate 
                  66% 
                 0.0379 
                 0.0667 
                 CO2261 
                 HMDB00650 
               
               
                 alanine 
                 168% 
                 0.0383 
                 0.0667 
                 C00041 
                 HMDB00161 
               
               
                 malate 
                 321% 
                 0.0389 
                 0.0667 
                 C00149 
                 HMDB00156 
               
               
                 glutamine 
                  40% 
                 0.0393 
                 0.0667 
                 C00064 
                 HMDB00641 
               
               
                 glycine 
                 114% 
                 0.0446 
                 0.0723 
                 C00037 
                 HMDB00123 
               
               
                 threonine 
                  58% 
                 0.0462 
                 0.0726 
                 C00188 
                 HMDB00167 
               
               
                 creatine 
                 127% 
                 0.0503 
                 0.0746 
                 C00300 
                 HMDB00064 
               
               
                 hypoxanthine 
                  53% 
                 0.0516 
                 0.0754 
                 C00262 
                 HMDB00157 
               
               
                 erythritol 
                 133% 
                 0.0548 
                 0.079 
                 C00503 
                 HMDB02994 
               
               
                 glycerol 3-phosphate (G3P) 
                  89% 
                 0.0573 
                 0.0798 
                 C00093 
                 HMDB00126 
               
               
                 glutamate 
                 158% 
                 0.0613 
                 0.082 
                 C00025 
                 HMDB03339 
               
               
                 octanoylcarnitine 
                  55% 
                 0.0771 
                 0.0966 
                   
                   
               
               
                 choline 
                  61% 
                 0.0842 
                 0.1042 
                   
                   
               
               
                 glycolate (hydroxyacetate) 
                  33% 
                 0.0924 
                 0.1081 
                 C00160 
                 HMDB00115 
               
               
                   
               
             
          
         
       
     
         [0132]    Listed in Table 2 are biomarkers that were identified as differentially present between kidney cancer samples compared to the patient-matched non-cancer samples where p&gt;0.1. All of the biomarkers in Table 2 differentially increase or decrease at least 5% in the kidney cancer samples. Table 2 includes, for each listed biomarker, the biochemical name of the biomarker, an indication of the percentage difference in the cancer sample mean as compared to the benign sample mean (positive values represent an increase in cancer, and negative values represent a decrease in cancer), the p-value and the q-value. Also included in Table 2 are: the identifier for that biomarker compound in the Kyoto Encyclopedia of Genes and Genomes (KEGG), if available; and the identifier for that biomarker compound in the Human Metabolome Database (HMDB), if available. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Kidney Cancer Biomarkers, p &gt; 0.1 
               
             
          
           
               
                   
                 % change 
                   
                   
                   
                   
               
               
                 Biochemical Name 
                 in cancer 
                 P-Value 
                 Q-Value 
                 Kegg 
                 HMDB 
               
               
                   
               
             
          
           
               
                 1,2-propanediol 
                 182% 
                 0.3703 
                 0.2515 
                 C00717, 
                 HMDB01881 
               
               
                   
                   
                   
                   
                 C02912, 
                   
               
               
                   
                   
                   
                   
                 C00583, 
                   
               
               
                   
                   
                   
                   
                 C01506, 
                   
               
               
                   
                   
                   
                   
                 C02917 
                   
               
               
                 glutamate, gamma-methyl ester 
                 483% 
                 0.1085 
                 0.1241 
                   
                   
               
               
                 Isobar: fructose 1,6-diphosphate, glucose 
                 220% 
                 0.1099 
                 0.1241 
                   
                   
               
               
                 1,6-diphosphate 
                   
                   
                   
                   
                   
               
               
                 cytidine 5′-monophosphate (5′-CMP) 
                  48% 
                 0.1125 
                 0.1241 
                 C00055 
                 HMDB00095 
               
               
                 adrenate (22:4n6) 
                 107% 
                 0.1219 
                 0.1301 
                 C16527 
                 HMDB02226 
               
               
                 taurine 
                  82% 
                 0.1301 
                 0.1342 
                 C00245 
                 HMDB00251 
               
               
                 1-stearoylglycerophosphoinositol 
                 133% 
                 0.1385 
                 0.1376 
                   
                   
               
               
                 inosine 
                  71% 
                 0.1424 
                 0.1401 
                   
                   
               
               
                 hypotaurine 
                  28% 
                 0.1473 
                 0.1436 
                 C00519 
                 HMDB00965 
               
               
                 ethanolamine 
                 398% 
                 0.1496 
                 0.1444 
                 C00189 
                 HMDB00149 
               
               
                 adenosine 5&#39;-monophosphate (AMP) 
                 307% 
                 0.1527 
                 0.1448 
                 C00020 
                 HMDB00045 
               
               
                 10-heptadecenoate (17:1n7) 
                  43% 
                 0.1647 
                 0.1546 
                   
                   
               
               
                 2-linoleoylglycerophosphoethanolamine 
                 322% 
                 0.1659 
                 0.1546 
                   
                   
               
               
                 2-docosapentaenoylglycerophosphoethanolamine 
                 529% 
                 0.1686 
                 0.1557 
                   
                   
               
               
                 glycylleucine 
                  46% 
                 0.181 
                 0.1657 
                 C02155 
                 HMDB00759 
               
               
                 nicotinamide 
                 157% 
                 0.192 
                 0.1728 
                 C00153 
                 HMDB01406 
               
               
                 1-oleoylglycerophosphoethanolamine 
                 113% 
                 0.1993 
                 0.1763 
                   
                 HMDB11506 
               
               
                 glucose 1-phosphate 
                 126% 
                 0.2102 
                 0.1813 
                 C00103 
                 HMDB01586 
               
               
                 palmitoyl sphingomyelin 
                  78% 
                 0.2132 
                 0.1814 
                   
                   
               
               
                 1-oleoylglycerol (1-monoolein) 
                 −24% 
                 0.2137 
                 0.1814 
                   
                 HMDB11567 
               
               
                 glutathione, reduced (GSH) 
                 1351%  
                 0.2199 
                 0.1837 
                 C00051 
                 HMDB00125 
               
               
                 ergothioneine 
                 111% 
                 0.2236 
                 0.1839 
                 C05570 
                 HMDB03045 
               
               
                 nicotinamide adenine dinucleotide 
                  67% 
                 0.2373 
                 0.1883 
                 C00004 
                 HMDB01487 
               
               
                 reduced (NADH) 
                   
                   
                   
                   
                   
               
               
                 1-stearoylglycerophosphoethanolamine 
                 163% 
                 0.2383 
                 0.1883 
                   
                 HMDB11130 
               
               
                 pentadecanoate (15:0) 
                  28% 
                 0.2412 
                 0.1883 
                 C16537 
                 HMDB00826 
               
               
                 methyl palmitate (15 or 2) 
                  20% 
                 0.2414 
                 0.1883 
                   
                   
               
               
                 4-hydroxybutyrate (GHB) 
                 254% 
                 0.2839 
                 0.2165 
                 C00989 
                 HMDB00710 
               
               
                 dihomo-linoleate (20:2n6) 
                  79% 
                 0.2917 
                 0.2194 
                 C16525 
                   
               
               
                 cysteine-glutathione disulfide 
                 −19% 
                 0.307 
                 0.2292 
                   
                 HMDB00656 
               
               
                 glucose-6-phosphate (G6P) 
                 383% 
                 0.3097 
                 0.2296 
                 C00668 
                 HMDB01401 
               
               
                 heme 
                 1219%  
                 0.3325 
                 0.2448 
                   
                   
               
               
                 citalopram 
                  49% 
                 0.3632 
                 0.2483 
                 C07572 
                 HMDB05038 
               
               
                 S-adenosylmethionine (SAM) 
                  11% 
                 0.3632 
                 0.2483 
                   
                   
               
               
                 gamma-glutamylglutamate 
                  85% 
                 0.3932 
                 0.2637 
                   
                   
               
               
                 glycerol 2-phosphate 
                 113% 
                 0.4122 
                 0.2713 
                 C02979, 
                 HMDB02520 
               
               
                   
                   
                   
                   
                 D01488 
                   
               
               
                 docosapentaenoate (n3 DPA; 22:5n3) 
                  23% 
                 0.4656 
                 0.2989 
                 C16513 
                 HMDB01976 
               
               
                 1-behenoyl glycerol (1-monobehenin) 
                  −6% 
                 0.4747 
                 0.3029 
                   
                   
               
               
                 oleate (18:1n9) 
                  18% 
                 0.4965 
                 0.3111 
                 C00712 
                 HMDB00207 
               
               
                 citrulline 
                  14% 
                 0.5164 
                 0.3198 
                 C00327 
                 HMDB00904 
               
               
                 arabitol 
                  −6% 
                 0.5263 
                 0.324 
                 C00474 
                 HMDB01851 
               
               
                 caproate (6:0) 
                 350% 
                 0.5763 
                 0.3507 
                 C01585 
                 HMDB00535 
               
               
                 arachidonate (20:4n6) 
                  6% 
                 0.5829 
                 0.3527 
                 C00219 
                 HMDB01043 
               
               
                 octaethylene glycol 
                  58% 
                 0.6077 
                 0.3615 
                   
                   
               
               
                 docosapentaenoate (n6 DPA; 22:5n6) 
                  17% 
                 0.6078 
                 0.3615 
                 C06429 
                 HMDB13123 
               
               
                 1 -palmitoylglycerophosphoethanolamine 
                  57% 
                 0.6128 
                 0.3623 
                   
                 HMDB11503 
               
               
                 2-hydroxypalmitate 
                  29% 
                 0.639 
                 0.3737 
                   
                   
               
               
                 linoleate (18:2n6) 
                  12% 
                 0.6593 
                 0.3813 
                 C01595 
                 HMDB00673 
               
               
                 heptaethylene glycol 
                  66% 
                 0.6691 
                 0.3849 
                   
                   
               
               
                 13-methylmyristic acid 
                  62% 
                 0.6781 
                 0.3864 
                   
                   
               
               
                 1-myristoylglycerol (1-monomyristin) 
                  41% 
                 0.679 
                 0.3864 
                   
                 HMDB11561 
               
               
                 2-hydroxystearate 
                  34% 
                 0.7269 
                 0.4071 
                 C03045 
                   
               
               
                 pelargonate (9:0) 
                  18% 
                 0.7533 
                 0.413 
                 C01601 
                 HMDB00847 
               
               
                 tetraethylene glycol 
                 767% 
                 0.7963 
                 0.4323 
                   
                   
               
               
                 myristate (14:0) 
                  7% 
                 0.7967 
                 0.4323 
                 C06424 
                 HMDB00806 
               
               
                 2-ethylhexanoate 
                  56% 
                 0.803 
                 0.4326 
                   
                   
               
               
                 heptanoate (7:0) 
                  15% 
                 0.8149 
                 0.4352 
                 C17714 
                 HMDB00666 
               
               
                 palmitoleate (16:1n7) 
                  32% 
                 0.8214 
                 0.4352 
                 C08362 
                 HMDB03229 
               
               
                 hexaethylene glycol 
                 111% 
                 0.8227 
                 0.4352 
                   
                   
               
               
                 2-stearoylglycerol (2-monostearin) 
                  8% 
                 0.8349 
                 0.4391 
                   
                   
               
               
                 triethyleneglycol 
                 323% 
                 0.8384 
                 0.4391 
                   
                   
               
               
                 1-heptadecanoylglycerol (1-monoheptadecanoin) 
                  35% 
                 0.8509 
                 0.4403 
                   
                   
               
               
                 docosahexaenoate (DHA; 22:6n3) 
                  19% 
                 0.8694 
                 0.4443 
                 C06429 
                 HMDB02183 
               
               
                 caprate (10:0) 
                  10% 
                 0.9059 
                 0.4607 
                 C01571 
                 HMDB00511 
               
               
                 1-stearoyl glycerol (1-monostearin) 
                  15% 
                 0.9147 
                 0.4629 
                 D01947 
                   
               
               
                 dihomo-linolenate (20:3n3 or n6) 
                  34% 
                 0.9299 
                 0.4684 
                 C03242 
                 HMDB02925 
               
               
                 linoleamide (18:2n6) 
                  84% 
                 0.9344 
                 0.4684 
                   
                   
               
               
                 caprylate (8:0) 
                  26% 
                 0.9446 
                 0.4694 
                 C06423 
                 HMDB00482 
               
               
                 linolenate [alpha or gamma; (18:3n3 or 6)] 
                  15% 
                 0.9454 
                 0.4694 
                 C06427 
                 HMDB01388 
               
               
                 1-octadecanol 
                  7% 
                 0.9575 
                 0.4732 
                 D01924 
                 HMDB02350 
               
               
                 pentaethylene glycol 
                 199% 
                 0.9722 
                 0.4783 
                   
                   
               
               
                 n-Butyl Oleate 
                  20% 
                 0.9868 
                 0.4832 
                   
                   
               
               
                 1-palmitoylglycerol (1-monopalmitin) 
                  14% 
                 0.997 
                 0.4837 
                   
                   
               
               
                 C-glycosyltryptophan 
                  38% 
                 0.125 
                 0.1303 
                   
                   
               
               
                 trizma acetate 
                 −28% 
                 0.2347 
                 0.1883 
                 C07182 
                   
               
               
                 4-methyl-2-oxopentanoate 
                  37% 
                 0.4105 
                 0.2713 
                 C00233 
                 HMDB00695 
               
               
                 glucose 
                 297% 
                 0.112 
                 0.1241 
                 C00293 
                 HMDB00122 
               
               
                 methionine 
                  10% 
                 0.1131 
                 0.1241 
                 C00073 
                 HMDB00696 
               
               
                 glycerophosphorylcholine (GPC) 
                  41% 
                 0.1199 
                 0.1301 
                 C00670 
                 HMDB00086 
               
               
                 aspartate 
                 197% 
                 0.1223 
                 0.1301 
                 C00049 
                 HMDB00191 
               
               
                 ribitol 
                 195% 
                 0.1247 
                 0.1303 
                 C00474 
                 HMDB00508 
               
               
                 beta-alanine 
                  93% 
                 0.1326 
                 0.1355  
                 C00099 
                 HMDB00056 
               
               
                 fumarate 
                 245% 
                 0.1356  
                 10.1363 
                 C00122 
                 HMDB00134 
               
               
                 citrate 
                  55% 
                 0.136 
                 0.1363  
                 C00158 
                 HMDB00094 
               
               
                 propionylcarnitine 
                 167% 
                 0.1509 
                 0.1444 
                 C03017 
                 HMDB00824 
               
               
                 uracil 
                  54% 
                 0.185 
                 0.1679 
                 C00106 
                 HMDB00300 
               
               
                 scyllo-inositol 
                 234% 
                 0.1982 
                 0.1763 
                 C06153 
                 HMDB06088 
               
               
                 pantothenate 
                  81% 
                 0.2079 
                 0.1813 
                 C00864 
                 HMDB00210 
               
               
                 sorbitol 
                  75% 
                 0.2087 
                 0.1813 
                 C00794 
                 HMDB00247 
               
               
                 isobutyrylcarnitine 
                  83% 
                 0.2183 
                 0.1837 
                   
                   
               
               
                 kynurenine 
                  60% 
                 0.2223 
                 0.1839 
                 C00328 
                 HMDB00684 
               
               
                 threonate 
                 103% 
                 0.2279 
                 0.185 
                 C01620 
                 HMDB00943 
               
               
                 gluconate 
                  33% 
                 0.2285 
                 0.185 
                 C00257 
                 HMDB00625 
               
               
                 2-aminoadipate 
                 138% 
                 0.2719 
                 0.2105 
                 C00956 
                 HMDB00510 
               
               
                 xanthine 
                  72% 
                 0.2766 
                 0.2126 
                 C00385 
                 HMDB00292 
               
               
                 erythronate 
                  83% 
                 0.2905 
                 0.2194 
                   
                 HMDB00613 
               
               
                 pipecolate 
                  41% 
                 0.3578 
                 0.2483  
                 C00408 
                 HMDB00070 
               
               
                 3-methyl-2-oxovalerate 
                  30% 
                 0.3632 
                 0.2483 
                 C00671 
                 HMDB03736 
               
               
                 p-acetamidophenylglucuronide 
                  6% 
                 0.3632 
                 0.2483 
                   
                 HMDB10316 
               
               
                 glutaroyl carnitine 
                  −7% 
                 0.3632 
                 0.2483 
                   
                 HMDB13130 
               
               
                 pseudouridine 
                 −13% 
                 0.3632 
                 0.2483 
                 C02067 
                 HMDB00767 
               
               
                 myo-inositol 
                 186% 
                 0.3752 
                 0.2532 
                 C00137 
                 HMDB00211 
               
               
                 pro-hydroxy-pro 
                 −12% 
                 0.4123 
                 0.2713 
                   
                 HMDB06695 
               
               
                 fructose 
                 186% 
                 0.4202 
                 0.2747 
                 C00095 
                 HMDB00660 
               
               
                 adenosine 
                  97% 
                 0.431 
                 0.2801 
                 C00212 
                 HMDB00050 
               
               
                 p-cresol sulfate 
                  −5% 
                 0.4362 
                 0.2817  
                 C01468 
                   
               
               
                 gamma-aminobutyrate (GABA) 
                  −5% 
                 0.4786 
                 0.3035 
                 C00334 
                 HMDB00112 
               
               
                 1-methylnicotinamide 
                  19% 
                 0.4853 
                 0.3059 
                 C02918 
                 HMDB00699 
               
               
                 benzoate 
                  43% 
                 0.5148 
                 0.3198 
                 C00180 
                 HMDB01870 
               
               
                 mannitol 
                  6% 
                 0.616 
                 0.3623 
                 C00392 
                 HMDB00765 
               
               
                 xylitol 
                  7% 
                 0.687 
                 0.3888 
                 C00379 
                 HMDB00568 
               
               
                 N-acetylaspartate (NAA) 
                  12% 
                 0.7133 
                 0.4015 
                 C01042 
                 HMDB00812 
               
               
                 phenylacetylglutamine 
                 186% 
                 0.7351 
                 0.4091 
                 C05597 
                 HMDB06344 
               
               
                 urate 
                  60% 
                 0.7423 
                 0.4091 
                 C00366 
                 HMDB00289 
               
               
                 creatinine 
                  9% 
                 0.8054 
                 0.4326 
                 C00791 
                 HMDB00562 
               
               
                 cysteine 
                  57% 
                 0.8551 
                 0.4403 
                 C00097 
                 HMDB00574 
               
               
                 metoprolol acid metabolite 
                  40% 
                 0.9946 
                 0.4837 
               
               
                   
               
             
          
         
       
     
       Example 2 
     Statistical Analysis for the Classification of Subjects Based on Tissue Biomarkers 
       [0133]    The data obtained in Example 1 concerning biopsy samples was used to create a statistical (mathematical) model to classify the samples into kidney cancer or non-cancer groups. 
         [0134]    Random Forest Analysis was used to classify kidney samples into kidney cancer positive (kidney cancer) or cancer negative groups. Random Forests give an estimate of how well individuals in a new data set can be classified into each group. This is in contrast to a t-test, which tests whether or not the unknown means for two populations are different. Random forests create a set of classification trees based on continual sampling of the experimental units and compounds. Then each observation is classified based on the majority votes from all the classification trees. 
         [0135]    Random forest results show that the samples can be classified correctly with 83% prediction accuracy. The Confusion Matrix presented in Table 3 shows the number of samples predicted for each classification and the actual in each group (Kidney Cancer or Non-Cancer). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest Model (e.g., whether a sample contains tumor (cancer-positive) or is cancer-negative). The OOB error from this Random Forest was approximately 17%, and the model estimated that, when used on a new set of samples, the identity of kidney cancer positive samples could be predicted correctly 67% of the time and non-cancer samples could be predicted correctly 100% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Random Forest Classification of cancer-positive and benign kidney tissue 
               
               
                 samples. 
               
             
          
           
               
                   
                   
                 Random Forest Prediction 
                 Class 
               
             
          
           
               
                   
                   
                 Kidney Cancer 
                 Non-Cancer 
                 Error 
               
               
                   
               
               
                 Histologically 
                 Kidney Cancer 
                 4 
                 2 
                 0.333 
               
               
                 confirmed 
                 Acutal 
                   
                   
                   
               
               
                 patient 
                 Non-Cancer 
                 0 
                 6 
                 0     
               
               
                 samples 
                 Acutal 
                   
                   
                   
               
             
          
           
               
                   
                 Predictive accuracy = 83% 
               
               
                   
               
             
          
         
       
     
         [0136]    Based on the OOB Error rate of 17%, the Random Forest model that was created predicted whether a sample was kidney cancer positive with about 83% accuracy based on the levels of the biomarkers measured in samples from the subjects. Exemplary biomarkers for distinguishing the groups are oxidized glutathione (GSSG), proline, 2-oleoylglycerophosphoethanolamine, 2-aminobutyrate, sphingosine, 3-dehydrocamitine, 2-docosahexaenoylglycerophosphocholine, 2-linoleoylglycerophosphocholine, phosphoethanolamine, glutamate, pyrophosphate (PPi), nicotinamide-adenine-dinucleotide (NAD+), 3-aminoisobutyrate, 2-arachidonoylglycerophosphoethanolamine, 2-arachidonoylglycerophosphocholine, 2-oleoylglycerophosphocholine, glycerate, choline-phosphate, pyruvate, 1-arachidonoylglycerophosphoethanolamine, adenine, 1-2-propanediol, 2-docosahexaenoylglycerophosphoethanolamine, 2-hydroxybutyrate (AHB), creatine, glycolate (hydroxyacetate), malate, 5-methylthioadenosine (MTA), stearolycarnitine, and 1-arachidonoylglycerophosphoinositol. 
         [0137]    The Random Forest analysis demonstrated that by using the biomarkers, kidney cancer positive samples were distinguished from non-cancer samples with 67% sensitivity, 100% specificity, 100% Positive Predictive Value (PPV), and 75% Negative Predictive Value (NPV). 
         [0138]    In addition, Principal Component Analysis (PCA) was carried out using the biomarkers where p&lt;0.05 obtained from biopsy samples in Example 1 to classify the samples as non-cancer or Kidney Cancer (RCC). 
         [0139]    Using the mathematical model created using PCA, it was found that 6 of 6 cancer-negative samples were correctly classified as cancer negative while 5 of 6 kidney cancer-positive samples were correctly classified as kidney cancer based on the biomarker abundance. A graphical depiction of the PCA results is presented in  FIG. 1 . 
         [0140]    Hierarchical clustering (Euclidean distance) using the biomarkers where p&lt;0.05 identified from biopsy samples in Example 1 was also used to classify the subjects. This analysis resulted in the subjects being divided into two distinct groups. One group consisted of four cancer biopsies and one non-cancer biopsy, and the other group consisted of two cancer biopsies and five non-cancer biopsies. These data suggest that there are multiple metabolic types of kidney disease and/or kidney cancer that can be distinguished using tissue biopsy biomarker metabolite levels. For example, the cancer-containing samples identified in the second group may have a less aggressive faun of kidney cancer or may be at an earlier stage of cancer. Distinguishing between types of cancer (e.g., less vs. more aggressive) and stage of cancer may be valuable information to a doctor determining a course of treatment.  FIG. 2  provides a graphical depiction of the results of the hierarchical clustering. 
       Example 3 
     Tissue Biomarkers for Kidney Cancer 
       [0141]    Biomarkers were discovered by (1) analyzing different groups of tissue samples from human subjects to determine the levels of metabolites in the samples and then (2) statistically analyzing the results to determine those metabolites that are differentially present in the following groups: normal tissue compared to tumor tissue; early stage (T1) cancer tissue compared to normal tissue; and later stage (T3) cancer tissue compared to normal tissue. 
         [0142]    The samples used for the analysis were matched pairs of RCC tumor and adjacent normal kidney tissue collected from 140 subjects with RCC. Subjects were further divided based on tumor stage with 43 subjects having Stage 1 (T1), 13 subjects with Stage 2 (T2), 80 subjects with Stage 3 (T3) and 4 subjects with Stage 4 (T4) kidney cancer. 
         [0143]    After the levels of metabolites were determined, the data were analyzed using Welch&#39;s two-sample t-tests. Three comparisons were used to identify biomarkers for kidney cancer: Kidney cancer vs. Normal; T1 Kidney cancer vs. Normal; T3 Kidney cancer vs. Normal. As listed in Table 4 below, the analysis of named compounds resulted in the identification of biomarkers that are differentially present between a) kidney cancer and Normal tissue b) early stage (T1) kidney cancer and Normal tissue and/or c) later stage (T3) kidney cancer and Normal tissue. 
         [0144]    Table 4 includes, for each biomarker, the biochemical name of the biomarker, the fold change (FC) of the biomarker in kidney cancer compared to non-kidney cancer samples (Tumor/Normal, T1 Tumor/T1 Normal and T3 Tumor/T3 Normal) which is the ratio of the mean level of the biomarker in kidney cancer samples as compared to the non-kidney cancer mean level and the p-value determined in the statistical analysis of the data concerning the biomarkers. Bold values indicate a fold of change with a p-value of ≦0.1. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Tissue Biomarkers for Kidney Cancer 
               
             
          
           
               
                   
                 Tumor 
                 T1 Tumor 
                 T3 Tumor 
               
               
                   
                 
                   Normal 
                 
                 
                   T1 Normal 
                 
                 
                   T3 Normal 
                 
               
             
          
           
               
                 Biochemical Name 
                 FC 
                 p-value 
                 FC 
                 p-value 
                 FC 
                 p-value 
               
               
                   
               
             
          
           
               
                 eicosenoate (20:1n9 or 11) 
                 
                   4.91 
                 
                 p &lt; 0.0001 
                 
                   5.42 
                 
                 p &lt; 0.0001 
                 
                   4.66 
                 
                 p &lt; 0.0001 
               
               
                 arachidonate (20:4n6) 
                 
                   0.3 
                 
                 p &lt; 0.0001 
                 
                   0.29 
                 
                 p &lt; 0.0001 
                 
                   0.31 
                 
                 p &lt; 0.0001 
               
               
                 mannose-6-phosphate 
                 
                   8.39 
                 
                 p &lt; 0.0001 
                 
                   5.38 
                 
                 3.81E−09 
                 
                   9.28 
                 
                 p &lt; 0.0001 
               
               
                 alpha-tocopherol 
                 
                   8.76 
                 
                 p &lt; 0.0001 
                 
                   8.84 
                 
                 2.74E−12 
                 
                   9.21 
                 
                 p &lt; 0.0001 
               
               
                 flavin adenine dinucleotide (FAD) 
                 
                   0.24 
                 
                 p &lt; 0.0001 
                 
                   0.23 
                 
                 7.43E−12 
                 
                   0.25 
                 
                 p &lt; 0.0001 
               
               
                 fructose-6-phosphate 
                 
                   6.92 
                 
                 p &lt; 0.0001 
                 
                   6.1 
                 
                 2.00E−15 
                 
                   7.02 
                 
                 p &lt; 0.0001 
               
               
                 maltose 
                 
                   17.03 
                 
                 p &lt; 0.0001 
                 
                   13.98 
                 
                 p &lt; 0.0001 
                 
                   17.5 
                 
                 p &lt; 0.0001 
               
               
                 maltotriose 
                 
                   21.95 
                 
                 p &lt; 0.0001 
                 
                   14.41 
                 
                 p &lt; 0.0001 
                 
                   26.14 
                 
                 p &lt; 0.0001 
               
               
                 fructose 1-phosphate 
                 
                   9.62 
                 
                 p &lt; 0.0001 
                 
                   10.09 
                 
                 9.38E−11 
                 
                   9.48 
                 
                 p &lt; 0.0001 
               
               
                 maltotetraose 
                 
                   13.04 
                 
                 p &lt; 0.0001 
                 
                   8.7 
                 
                 2.52E−11 
                 
                   14.42 
                 
                 p &lt; 0.0001 
               
               
                 1-stearoylglycerophosphoinositol 
                 
                   0.29 
                 
                 p &lt; 0.0001 
                 
                   0.22 
                 
                 1.00E−15 
                 
                   0.33 
                 
                 p &lt; 0.0001 
               
               
                 methyl-alpha-glucopyranoside 
                 
                   4.65 
                 
                 p &lt; 0.0001 
                 
                   3.85 
                 
                 1.51E−07 
                 
                   5.32 
                 
                 p &lt; 0.0001 
               
               
                 glucose-6-phosphate (G6P) 
                 
                   9.38 
                 
                 p &lt; 0.0001 
                 
                   6.63 
                 
                 3.40E−14 
                 
                   10.24 
                 
                 p &lt; 0.0001 
               
               
                 1-stearoylglycerophosphoethanolamine 
                 
                   0.1 
                 
                 p &lt; 0.0001 
                 
                   0.07 
                 
                 p &lt; 0.0001 
                 
                   0.11 
                 
                 p &lt; 0.0001 
               
               
                 1-palmitoylglycerophosphoinositol 
                 
                   0.21 
                 
                 p &lt; 0.0001 
                 
                   0.19 
                 
                 3.00E−15 
                 
                   0.23 
                 
                 p &lt; 0.0001 
               
               
                 1-oleoylglycerophosphoethanolamine 
                 
                   0.05 
                 
                 p &lt; 0.0001 
                 
                   0.04 
                 
                 p &lt; 0.0001 
                 
                   0.06 
                 
                 p &lt; 0.0001 
               
               
                 1-palmitoylglycerophosphoethanolamine 
                 
                   0.03 
                 
                 p &lt; 0.0001 
                 
                   0.02 
                 
                 p &lt; 0.0001 
                 
                   0.03 
                 
                 p &lt; 0.0001 
               
               
                 2-oleoylglycerophosphoethanolamine 
                 
                   0.09 
                 
                 p &lt; 0.0001 
                 
                   0.08 
                 
                 p &lt; 0.0001 
                 
                   0.1 
                 
                 p &lt; 0.0001 
               
               
                 2-palmitoylglycerophosphoethanolamine 
                 
                   0.03 
                 
                 p &lt; 0.0001 
                 
                   0.02 
                 
                 p &lt; 0.0001 
                 
                   0.03 
                 
                 p &lt; 0.0001 
               
               
                 1-oleoylglycerophosphoinositol 
                 
                   0.34 
                 
                 p &lt; 0.0001 
                 
                   0.33 
                 
                 1.42E−12 
                 
                   0.35 
                 
                 p &lt; 0.0001 
               
               
                 gamma-glutamylglutamate 
                 
                   4.6 
                 
                 p &lt; 0.0001 
                 
                   7.25 
                 
                 2.68E−12 
                 
                   3.7 
                 
                 1.42E−13 
               
               
                 ergothioneine 
                 
                   4.22 
                 
                 p &lt; 0.0001 
                 
                   3.8 
                 
                 6.58E−12 
                 
                   4.61 
                 
                 p &lt; 0.0001 
               
               
                 arabitol 
                 
                   0.38 
                 
                 p &lt; 0.0001 
                 
                   0.45 
                 
                 5.06E−08 
                 
                   0.37 
                 
                 p &lt; 0.0001 
               
               
                 1-palmitoylplasmenylethanolamine 
                 
                   0.12 
                 
                 p &lt; 0.0001 
                 
                   0.1 
                 
                 1.00E−15 
                 
                   0.14 
                 
                 p &lt; 0.0001 
               
               
                 phosphoenolpyruvate (PEP) 
                 
                   0.37 
                 
                 p &lt; 0.0001 
                 
                   0.36 
                 
                 3.30E−06 
                 
                   0.37 
                 
                 1.66E−09 
               
               
                 putrescine 
                 
                   4.65 
                 
                 p &lt; 0.0001 
                 
                   5.7 
                 
                 4.04E−06 
                 
                   4.94 
                 
                 1.00E−15 
               
               
                 inositol 1-phosphate (I1P) 
                 
                   0.4 
                 
                 p &lt; 0.0001 
                 
                   0.45 
                 
                 7.10E−10 
                 
                   0.36 
                 
                 p &lt; 0.0001 
               
               
                 ethanolamine 
                 
                   0.4 
                 
                 p &lt; 0.0001 
                 
                   0.39 
                 
                 5.62E−07 
                 
                   0.42 
                 
                 1.13E−08 
               
               
                 erucate (22:1n9) 
                 
                   4.63 
                 
                 p &lt; 0.0001 
                 
                   5.69 
                 
                 3.03E−12 
                 
                   4.17 
                 
                 8.60E−14 
               
               
                 3,4-dihydroxyphenethyleneglycol 
                 
                   0.27 
                 
                 p &lt; 0.0001 
                 
                   0.25 
                 
                 6.73E−12 
                 
                   0.28 
                 
                 1.60E−14 
               
               
                 N-acetylalanine 
                 
                   0.44 
                 
                 p &lt; 0.0001 
                 
                   0.42 
                 
                 1.19E−13 
                 
                   0.45 
                 
                 p &lt; 0.0001 
               
               
                 N-acetylmethionine 
                 
                   2.46 
                 
                 p &lt; 0.0001 
                 
                   2.02 
                 
                 7.54E−05 
                 
                   2.7 
                 
                 1.00E−15 
               
               
                 pyridoxal 
                 
                   0.36 
                 
                 p &lt; 0.0001 
                 
                   0.32 
                 
                 1.21E−13 
                 
                   0.41 
                 
                 p &lt; 0.0001 
               
               
                 urea 
                 
                   0.52 
                 
                 p &lt; 0.0001 
                 
                   0.6 
                 
                 0.0001 
                 
                   0.53 
                 
                 6.12E−10 
               
               
                 glutathione, reduced (GSH) 
                 
                   37.54 
                 
                 p &lt; 0.0001 
                 
                   9.03 
                 
                 1.04E−05 
                 
                   43.43 
                 
                 2.40E−14 
               
               
                 asparagine 
                 
                   0.38 
                 
                 p &lt; 0.0001 
                 
                   0.34 
                 
                 5.91E−10 
                 
                   0.41 
                 
                 3.03E−09 
               
               
                 glucose 1-phosphate 
                 
                   9.38 
                 
                 p &lt; 0.0001 
                 
                   9.92 
                 
                 0.00E+00 
                 
                   8.26 
                 
                 p &lt; 0.0001 
               
               
                 dihomo-linoleate (20:2n6) 
                 
                   2.57 
                 
                 p &lt; 0.0001 
                 
                   2.57 
                 
                 2.69E−09 
                 
                   2.66 
                 
                 p &lt; 0.0001 
               
               
                 5-methyltetrahydrofolate (5MeTHF) 
                 
                   0.22 
                 
                 p &lt; 0.0001 
                 
                   0.2 
                 
                 1.00E−15 
                 
                   0.24 
                 
                 p &lt; 0.0001 
               
               
                 glycylvaline 
                 
                   0.4 
                 
                 p &lt; 0.0001 
                 
                   0.38 
                 
                 6.70E−14 
                 
                   0.44 
                 
                 6.28E−12 
               
               
                 eicosapentaenoate (EPA; 20:5n3) 
                 
                   0.45 
                 
                 p &lt; 0.0001 
                 
                   0.43 
                 
                 6.54E−09 
                 
                   0.48 
                 
                 3.89E−08 
               
               
                 1-oleoylglycerophosphoserine 
                 
                   0.45 
                 
                 p &lt; 0.0001 
                 
                   0.38 
                 
                 5.57E−10 
                 
                   0.52 
                 
                 1.45E−12 
               
               
                 docosahexaenoate (DHA; 22:6n3) 
                 
                   0.4 
                 
                 p &lt; 0.0001 
                 
                   0.37 
                 
                 3.50E−14 
                 
                   0.42 
                 
                 3.00E−15 
               
               
                 glycylglycine 
                 
                   0.37 
                 
                 p &lt; 0.0001 
                 
                   0.36 
                 
                 5.63E−12 
                 
                   0.4 
                 
                 1.76E−12 
               
               
                 docosadienoate (22:2n6) 
                 
                   3.52 
                 
                 p &lt; 0.0001 
                 
                   3.9 
                 
                 1.23E−11 
                 
                   3.49 
                 
                 p &lt; 0.0001 
               
               
                 docosatrienoate (22:3n3) 
                 
                   2.63 
                 
                 p &lt; 0.0001 
                 
                   2.3 
                 
                 2.65E−07 
                 
                   2.93 
                 
                 p &lt; 0.0001 
               
               
                 myristoleate (14:1n5) 
                 
                   0.7 
                 
                 p &lt; 0.0001 
                 
                   0.77 
                 
                 0.0001 
                 
                   0.69 
                 
                 2.20E−10 
               
               
                 1-linoleoylglycerophosphoethanolamine 
                 
                   0.12 
                 
                 p &lt; 0.0001 
                 
                   0.11 
                 
                 4.40E−14 
                 
                   0.14 
                 
                 p &lt; 0.0001 
               
               
                 gamma-tocopherol 
                 
                   5.03 
                 
                 p &lt; 0.0001 
                 
                   5.62 
                 
                 2.69E−11 
                 
                   4.85 
                 
                 1.44E−13 
               
               
                 glutamate, gamma-methyl ester 
                 
                   0.43 
                 
                 p &lt; 0.0001 
                 
                   0.36 
                 
                 1.67E−07 
                 
                   0.5 
                 
                 2.55E−08 
               
               
                 10-nonadecenoate (19:1n9) 
                 
                   2.23 
                 
                 p &lt; 0.0001 
                 
                   2.26 
                 
                 2.13E−08 
                 
                   2.2 
                 
                 4.00E−15 
               
               
                 1-arachidonoylglycerophosphoinositol 
                 
                   0.54 
                 
                 p &lt; 0.0001 
                 
                   0.53 
                 
                 2.39E−07 
                 
                   0.57 
                 
                 3.97E−13 
               
               
                 valerylcarnitine 
                 
                   0.55 
                 
                 p &lt; 0.0001 
                 
                   0.37 
                 
                 1.56E−10 
                 
                   0.68 
                 
                 1.06E−05 
               
               
                 laurylcarnitine 
                 
                   2.73 
                 
                 p &lt; 0.0001 
                 
                   2.6 
                 
                 2.89E−07 
                 
                   2.87 
                 
                 1.97E−11 
               
               
                 1-palmitoleoylglycerophosphoethanolamine 
                 
                   0.08 
                 
                 p &lt; 0.0001 
                 
                   0.06 
                 
                 5.70E−14 
                 
                   0.09 
                 
                 p &lt; 0.0001 
               
               
                 adenosine 3′-monophosphate (3′-AMP) 
                 
                   0.48 
                 
                 p &lt; 0.0001 
                 
                   0.42 
                 
                 2.17E−06 
                 
                   0.5 
                 
                 1.18E−12 
               
               
                 cysteine-glutathione disulfide 
                 
                   6.25 
                 
                 p &lt; 0.0001 
                 
                   3.14 
                 
                 1.34E−07 
                 
                   7.96 
                 
                 1.39E−13 
               
               
                 maltopentaose 
                 
                   4.44 
                 
                 p &lt; 0.0001 
                 
                   4.9 
                 
                 1.58E−06 
                 
                   3.84 
                 
                 2.09E−10 
               
               
                 1-arachidonoylglycerophosphoethanolamine 
                 
                   0.42 
                 
                 p &lt; 0.0001 
                 
                   0.4 
                 
                 3.49E−10 
                 
                   0.45 
                 
                 p &lt; 0.0001 
               
               
                 VGAHAGEYGAEALER 
                 
                   4.98 
                 
                 p &lt; 0.0001 
                 
                   6.75 
                 
                 1.21E−08 
                 
                   4.5 
                 
                 1.75E−07 
               
               
                 1-myristoylglycerophosphoethanolamine 
                 
                   0.15 
                 
                 p &lt; 0.0001 
                 
                   0.11 
                 
                 3.62E−10 
                 
                   0.18 
                 
                 1.00E−14 
               
               
                 2-linoleoylglycerophosphoethanolamine 
                 
                   0.36 
                 
                 p &lt; 0.0001 
                 
                   0.33 
                 
                 2.45E−07 
                 
                   0.42 
                 
                 6.47E−11 
               
               
                 7-alpha-hydroxy-3-oxo-4-cholestenoate 
                 
                   4.08 
                 
                 p &lt; 0.0001 
                 
                   3.85 
                 
                 2.86E−10 
                 
                   4.35 
                 
                 3.00E−15 
               
               
                 (7-Hoca) 
               
               
                 5-HETE 
                 
                   0.22 
                 
                 p &lt; 0.0001 
                 
                   0.25 
                 
                 1.65E−07 
                 
                   0.2 
                 
                 p &lt; 0.0001 
               
               
                 1-pentadecanoylglycerophosphocholine 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.15 
                 
                 1.79E−11 
                 
                   0.38 
                 
                 5.41E−07 
               
               
                 1-heptadecanoylglycerophosphoethanolamine 
                 
                   0.04 
                 
                 p &lt; 0.0001 
                 
                   0.03 
                 
                 p &lt; 0.0001 
                 
                   0.06 
                 
                 p &lt; 0.0001 
               
               
                 glycerophosphoethanolamine 
                 
                   0.41 
                 
                 p &lt; 0.0001 
                 
                   0.34 
                 
                 1.97E−07 
                 
                   0.46 
                 
                 7.12E−08 
               
               
                 docosapentaenoate (n6 DPA; 22:5n6) 
                 
                   0.54 
                 
                 p &lt; 0.0001 
                 
                   0.45 
                 
                 2.88E−07 
                 
                   0.59 
                 
                 2.98E−09 
               
               
                 5-oxoETE 
                 
                   0.25 
                 
                 p &lt; 0.0001 
                 
                   0.27 
                 
                 2.93E−10 
                 
                   0.24 
                 
                 1.00E−15 
               
               
                 3-hydroxyhippurate 
                 
                   0.11 
                 
                 p &lt; 0.0001 
                 
                   0.08 
                 
                 1.06E−07 
                 
                   0.13 
                 
                 p &lt; 0.0001 
               
               
                 phenylalanylserine 
                 
                   4.43 
                 
                 p &lt; 0.0001 
                 
                   4.2 
                 
                 1.18E−11 
                 
                   4.36 
                 
                 p &lt; 0.0001 
               
               
                 histidylleucine 
                 
                   3.07 
                 
                 p &lt; 0.0001 
                 
                   2.87 
                 
                 1.78E−06 
                 
                   3.23 
                 
                 3.80E−12 
               
               
                 prolylglycine 
                 
                   0.45 
                 
                 p &lt; 0.0001 
                 
                   0.44 
                 
                 8.56E−09 
                 
                   0.47 
                 
                 1.55E−10 
               
               
                 2-stearoylglycerophosphoethanolamine 
                 
                   0.03 
                 
                 p &lt; 0.0001 
                 
                   0.02 
                 
                 1.22E−10 
                 
                   0.04 
                 
                 8.00E−15 
               
               
                 phenylalanylglycine 
                 
                   2.86 
                 
                 p &lt; 0.0001 
                 
                   1.92 
                 
                 1.04E−05 
                 
                   3.33 
                 
                 2.34E−11 
               
               
                 phenylalanylalanine 
                 
                   7.89 
                 
                 p &lt; 0.0001 
                 
                   7.84 
                 
                 8.04E−11 
                 
                   7.85 
                 
                 p &lt; 0.0001 
               
               
                 tyrosylvaline 
                 
                   3.01 
                 
                 p &lt; 0.0001 
                 
                   3.22 
                 
                 4.02E−06 
                 
                   2.9 
                 
                 1.44E−11 
               
               
                 nervonate (24:1n9) 
                 
                   3.84 
                 
                 p &lt; 0.0001 
                 
                   5.53 
                 
                 4.56E−08 
                 
                   3.6 
                 
                 3.40E−11 
               
               
                 glycylthreonine 
                 
                   0.3 
                 
                 p &lt; 0.0001 
                 
                   0.26 
                 
                 p &lt; 0.0001 
                 
                   0.35 
                 
                 3.49E−11 
               
               
                 lysyltyrosine 
                 
                   4.76 
                 
                 p &lt; 0.0001 
                 
                   2.47 
                 
                 2.49E−06 
                 
                   6.07 
                 
                 4.08E−11 
               
               
                 guanosine 
                 
                   1.84 
                 
                 1.00E−15 
                 
                   1.75 
                 
                 0.0001 
                 
                   1.99 
                 
                 6.36E−12 
               
               
                 6-phosphogluconate 
                 
                   3.14 
                 
                 1.00E−15 
                 
                   3.29 
                 
                 2.89E−07 
                 
                   3.38 
                 
                 1.21E−09 
               
               
                 1-heptadecanoylglycerophosphocholine 
                 
                   0.26 
                 
                 1.00E−15 
                 
                   0.14 
                 
                 1.61E−09 
                 
                   0.36 
                 
                 5.31E−08 
               
               
                 beta-tocopherol 
                 
                   4.38 
                 
                 1.00E−15 
                 
                   5.75 
                 
                 2.33E−07 
                 
                   4.16 
                 
                 1.99E−09 
               
               
                 Isobar: ribulose 5-phosphate, xylulose 
                 
                   2.16 
                 
                 1.00E−15 
                 
                   1.62 
                 
                 0.0006 
                 
                   2.56 
                 
                 8.41E−13 
               
               
                 5-phosphate 
               
               
                 3-(4-hydroxyphenyl)lactate 
                 
                   1.53 
                 
                 2.00E−15 
                 
                   1.83 
                 
                 6.75E−07 
                 
                   1.47 
                 
                 4.38E−08 
               
               
                 10-heptadecenoate (17:1n7) 
                 
                   1.62 
                 
                 2.00E−15 
                 
                   1.71 
                 
                 1.89E−06 
                 
                   1.61 
                 
                 6.55E−10 
               
               
                 phenylalanylproline 
                 
                   2.74 
                 
                 2.00E−15 
                 
                   2.35 
                 
                 1.28E−05 
                 
                   2.94 
                 
                 5.28E−11 
               
               
                 serylleucine 
                 
                   4.27 
                 
                 3.00E−15 
                 
                   3.42 
                 
                 8.75E−05 
                 
                   4.76 
                 
                 6.70E−12 
               
               
                 phenylalanylaspartate 
                 
                   3.73 
                 
                 3.00E−15 
                 
                   4.38 
                 
                 1.56E−06 
                 
                   3.58 
                 
                 6.85E−11 
               
               
                 N-methylglutamate 
                 
                   0.3 
                 
                 4.00E−15 
                 
                   0.23 
                 
                 2.11E−06 
                 
                   0.33 
                 
                 1.28E−07 
               
               
                 adenosine 2′-monophosphate (2′-AMP) 
                 
                   0.54 
                 
                 4.00E−15 
                 
                   0.45 
                 
                 2.69E−06 
                 
                   0.6 
                 
                 3.32E−08 
               
               
                 1-oleoylglycerophosphocholine 
                 
                   0.3 
                 
                 7.00E−15 
                 
                   0.14 
                 
                 2.43E−10 
                 
                   0.44 
                 
                 5.71E−06 
               
               
                 1-palmitoylglycerophosphocholine 
                 
                   0.35 
                 
                 8.00E−15 
                 
                   0.24 
                 
                 1.04E−08 
                 
                   0.41 
                 
                 2.44E−07 
               
               
                 arachidate (20:0) 
                 
                   2.39 
                 
                 1.20E−14 
                 
                   2.6 
                 
                 2.45E−08 
                 
                   2.32 
                 
                 1.19E−07 
               
               
                 15-methylpalmitate (isobar with 2- 
                 
                   1.36 
                 
                 1.20E−14 
                 
                   1.45 
                 
                 1.61E−06 
                 
                   1.33 
                 
                 9.03E−09 
               
               
                 methylpalmitate) 
               
               
                 N-acetylserine 
                 
                   0.57 
                 
                 2.80E−14 
                 
                   0.51 
                 
                 5.11E−07 
                 
                   0.64 
                 
                 5.46E−07 
               
               
                 nicotinamide adenine dinucleotide 
                 
                   0.55 
                 
                 7.60E−14 
                 
                   0.35 
                 
                 5.26E−07 
                 
                   0.78 
                 
                 6.45E−06 
               
               
                 (NAD+) 
               
               
                 N1-Methyl-2-pyridone-5-carboxamide 
                 
                   0.66 
                 
                 1.15E−13 
                 
                   0.77 
                 
                 0.0039 
                 
                   0.62 
                 
                 1.89E−09 
               
               
                 2-palmitoleoylglycerophosphocholine 
                 
                   2.81 
                 
                 1.36E−13 
                 
                   1.98 
                 
                 0.0247 
                 
                   3.47 
                 
                 1.23E−12 
               
               
                 4-hydroxyglutamate 
                 
                   6.7 
                 
                 1.39E−13 
                 
                   5.59 
                 
                 6.31E−05 
                 
                   6.38 
                 
                 1.44E−08 
               
               
                 threonylphenylalanine 
                 
                   5.4 
                 
                 1.84E−13 
                 
                   3.91 
                 
                 0.0022 
                 
                   5.69 
                 
                 1.70E−11 
               
               
                 phenylalanyltyrosine 
                 
                   2.9 
                 
                 1.94E−13 
                 
                   2.97 
                 
                 7.30E−05 
                 
                   2.94 
                 
                 5.60E−09 
               
               
                 cytidine 5′-monophosphate (5′-CMP) 
                 
                   2.21 
                 
                 2.23E−13 
                 
                   2.44 
                 
                 2.34E−07 
                 
                   2.28 
                 
                 1.40E−09 
               
               
                 tyrosylalanine 
                 
                   2.36 
                 
                 2.37E−13 
                 
                   2.09 
                 
                 0.0007 
                 
                   2.5 
                 
                 3.58E−10 
               
               
                 tyrosylphenylalanine 
                 
                   2.4 
                 
                 2.61E−13 
                 
                   2.45 
                 
                 7.82E−06 
                 
                   2.37 
                 
                 1.37E−08 
               
               
                 1-stearoylglycerol (1-monostearin) 
                 
                   0.61 
                 
                 4.85E−13 
                 
                   0.58 
                 
                 1.48E−06 
                 
                   0.64 
                 
                 1.98E−06 
               
               
                 oleoylcarnitine 
                 
                   2.02 
                 
                 5.01E−13 
                 
                   1.54 
                 
                 0.0008 
                 
                   2.61 
                 
                 3.04E−09 
               
               
                 aspartylleucine 
                 
                   2.73 
                 
                 1.28E−12 
                 
                   2.41 
                 
                 0.0006 
                 
                   2.98 
                 
                 3.12E−10 
               
               
                 glycylphenylalanine 
                 
                   2.16 
                 
                 1.34E−12 
                 
                   1.96 
                 
                 0.0002 
                 
                   2.35 
                 
                 3.40E−09 
               
               
                 N-acetylglucosamine 6-phosphate 
                 
                   1.94 
                 
                 1.38E−12 
                 
                   1.63 
                 
                 0.0022 
                 
                   2.21 
                 
                 6.44E−11 
               
               
                 arginylphenylalanine 
                 
                   3.98 
                 
                 1.48E−12 
                 
                   2.71 
                 
                 0.0002 
                 
                   4.55 
                 
                 3.18E−09 
               
               
                 xylitol 
                 
                   0.55 
                 
                 1.72E−12 
                 
                   0.43 
                 
                 1.47E−06 
                 
                   0.66 
                 
                 2.86E−05 
               
               
                 leucylhistidine 
                 
                   2.03 
                 
                 2.66E−12 
                 
                   2.06 
                 
                 0.0039 
                 
                   1.77 
                 
                 1.84E−08 
               
               
                 guanosine 5′-monophosphate (5′-GMP) 
                 
                   2.93 
                 
                 2.86E−12 
                 
                   3.53 
                 
                 1.04E−06 
                 
                   2.62 
                 
                 4.70E−07 
               
               
                 cytidine-3′-monophosphate (3′-CMP) 
                 
                   0.59 
                 
                 3.88E−12 
                 
                   0.56 
                 
                 1.39E−05 
                 
                   0.61 
                 
                 2.15E−06 
               
               
                 phenylalanylleucine 
                 
                   4.3 
                 
                 4.50E−12 
                 
                   3.51 
                 
                 2.52E−06 
                 
                   4.67 
                 
                 1.74E−07 
               
               
                 uridine monophosphate (5′ or 3′) 
                 
                   2.72 
                 
                 5.60E−12 
                 
                   3 
                 
                 2.88E−06 
                 
                   2.71 
                 
                 4.81E−07 
               
               
                 1-myristoylglycerophosphocholine 
                 
                   0.38 
                 
                 6.99E−12 
                 
                   0.2 
                 
                 1.95E−08 
                 
                   0.51 
                 
                 3.98E−05 
               
               
                 spermidine 
                 
                   1.7 
                 
                 7.32E−12 
                 
                   1.84 
                 
                 6.39E−06 
                 
                   1.66 
                 
                 5.36E−07 
               
               
                 tyrosylglutamine 
                 
                   2.03 
                 
                 8.13E−12 
                 
                   1.91 
                 
                 2.74E−06 
                 
                   2.08 
                 
                 5.39E−07 
               
               
                 cytidine 
                 
                   0.49 
                 
                 1.21E−11 
                 
                   0.34 
                 
                 1.52E−07 
                 
                   0.57 
                 
                 4.74E−05 
               
               
                 L-urobilin 
                 
                   0.29 
                 
                 1.32E−11 
                 
                   0.26 
                 
                 0.0017 
                 
                   0.33 
                 
                 7.50E−09 
               
               
                 Isobar: fructose 1,6-diphosphate, 
                 
                   2.99 
                 
                 1.84E−11 
                 
                   3.14 
                 
                 3.20E−06 
                 
                   2.9 
                 
                 5.23E−06 
               
               
                 glucose 1,6-diphosphate, myo-inositol 
               
               
                 1,4 or 1,3-diphosphate 
               
               
                 maltohexaose 
                 
                   1.64 
                 
                 1.86E−11 
                 
                   1.91 
                 
                 0.0001 
                 
                   1.42 
                 
                 4.01E−06 
               
               
                 sphingosine 
                 
                   2.58 
                 
                 2.25E−11 
                 
                   1.83 
                 
                 0.0024 
                 
                   3.11 
                 
                 1.41E−07 
               
               
                 phenylalanylphenylalanine 
                 
                   2.76 
                 
                 2.39E−11 
                 
                   2.73 
                 
                 5.78E−05 
                 
                   2.86 
                 
                 7.96E−07 
               
               
                 alanylleucine 
                 
                   4.55 
                 
                 3.18E−11 
                 
                   3.15 
                 
                 0.0059 
                 
                   5.23 
                 
                 4.69E−09 
               
               
                 gamma-glutamylglutamine 
                 
                   4.2 
                 
                 5.55E−11 
                 
                   3.54 
                 
                 5.82E−06 
                 
                   4.52 
                 
                 0.0001 
               
               
                 serylphenyalanine 
                 
                   2.74 
                 
                 6.12E−11 
                 
                   2.48 
                 
                 1.75E−05 
                 
                   2.98 
                 
                 5.21E−08 
               
               
                 citrulline 
                 
                   1.4 
                 
                 6.91E−11 
                 
                   1.57 
                 
                 3.29E−06 
                 
                   1.29 
                 
                 0.0002 
               
               
                 methionylalanine 
                 
                   6.38 
                 
                 8.26E−11 
                 
                   5.2 
                 
                 0.0216 
                 
                   6.48 
                 
                 7.52E−09 
               
               
                 squalene 
                 
                   0.6 
                 
                 1.02E−10 
                 
                   0.62 
                 
                 1.64E−06 
                 
                   0.64 
                 
                 0.0003 
               
               
                 homoserine 
                 
                   1.97 
                 
                 1.18E−10 
                 
                   1.47 
                 
                 0.0492 
                 
                   2.25 
                 
                 7.80E−11 
               
               
                 arginine 
                 
                   0.7 
                 
                 1.65E−10 
                 
                   0.69 
                 
                 7.02E−05 
                 
                   0.73 
                 
                 2.54E−05 
               
               
                 undecanedioate 
                 
                   1.4 
                 
                 2.13E−10 
                 
                   1.49 
                 
                 0.0004 
                 
                   1.41 
                 
                 1.40E−07 
               
               
                 2-hydroxypalmitate 
                 
                   1.83 
                 
                 2.86E−10 
                 
                   1.34 
                 
                 0.0005 
                 
                   2.13 
                 
                 6.44E−06 
               
               
                 stearidonate (18:4n3) 
                 
                   1.96 
                 
                 2.92E−10 
                 
                   1.93 
                 
                 8.26E−05 
                 
                   2.07 
                 
                 4.95E−06 
               
               
                 saccharopine 
                 
                   5.43 
                 
                 2.99E−10 
                 
                   4.81 
                 
                 4.47E−05 
                 
                   5.78 
                 
                 2.24E−05 
               
               
                 glutathione, oxidized (GSSG) 
                 
                   31.39 
                 
                 3.57E−10 
                 
                   21.01 
                 
                 0.0366 
                 
                   32.2 
                 
                 1.53E−07 
               
               
                 leucylserine 
                 
                   4.22 
                 
                 3.64E−10 
                 
                   3.06 
                 
                 0.0454 
                 
                   4.6 
                 
                 2.02E−09 
               
               
                 laurate (12:0) 
                 
                   0.79 
                 
                 3.94E−10 
                 0.98 
                 0.3717 
                 
                   0.67 
                 
                 1.06E−11 
               
               
                 tryptophylleucine 
                 
                   2.62 
                 
                 1.31E−09 
                 
                   3.15 
                 
                 0.0001 
                 
                   2.38 
                 
                 1.94E−05 
               
               
                 arginylleucine 
                 
                   3.88 
                 
                 1.71E−09 
                 
                   3.2 
                 
                 0.0011 
                 
                   4.12 
                 
                 2.56E−07 
               
               
                 valylmethionine 
                 
                   4.01 
                 
                 2.69E−09 
                 
                   2.49 
                 
                 0.0304 
                 
                   4.77 
                 
                 4.06E−08 
               
               
                 alanylphenylalanine 
                 
                   4.1 
                 
                 2.78E−09 
                 
                   3.5 
                 
                 0.002 
                 
                   4.41 
                 
                 4.83E−08 
               
               
                 phenylalanylmethionine 
                 
                   2.49 
                 
                 3.30E−09 
                 
                   2.14 
                 
                 0.0014 
                 
                   2.59 
                 
                 8.97E−06 
               
               
                 phenylalanylglutamate 
                 
                   3.4 
                 
                 3.36E−09 
                 
                   2.57 
                 
                 2.84E−06 
                 
                   3.93 
                 
                 7.16E−08 
               
               
                 caprate (10:0) 
                 
                   0.82 
                 
                 3.57E−09 
                 
                   0.91 
                 
                 0.068 
                 
                   0.77 
                 
                 2.25E−08 
               
               
                 pregnanediol-3-glucuronide 
                 
                   0.7 
                 
                 4.21E−09 
                 
                   0.68 
                 
                 0.0018 
                 
                   0.68 
                 
                 1.94E−06 
               
               
                 stearate (18:0) 
                 
                   1.29 
                 
                 5.26E−09 
                 
                   1.33 
                 
                 0.0002 
                 
                   1.27 
                 
                 3.40E−05 
               
               
                 myristoylcarnitine 
                 
                   1.85 
                 
                 6.64E−09 
                 
                   1.64 
                 
                 0.0122 
                 
                   2.08 
                 
                 2.15E−07 
               
               
                 1-palmitoleoylglycerophosphocholine 
                 
                   0.42 
                 
                 9.63E−09 
                 
                   0.22 
                 
                 2.06E−07 
                 
                   0.58 
                 
                 0.0045 
               
               
                 Ac-Ser-Asp-Lys-Pro-OH 
                 
                   1.57 
                 
                 1.09E−08 
                 
                   1.6 
                 
                 0.0002 
                 
                   1.6 
                 
                 2.98E−05 
               
               
                 palmitoleate (16:1n7) 
                 
                   1.41 
                 
                 1.44E−08 
                 
                   1.54 
                 
                 2.61E−05 
                 
                   1.39 
                 
                 2.59E−05 
               
               
                 linolenate [alpha or gamma; (18:3n3 or 6)] 
                 
                   1.64 
                 
                 1.54E−08 
                 
                   1.76 
                 
                 2.17E−05 
                 
                   1.67 
                 
                 1.12E−05 
               
               
                 methylphosphate 
                 
                   0.65 
                 
                 1.63E−08 
                 
                   0.56 
                 
                 0.0004 
                 
                   0.73 
                 
                 0.0003 
               
               
                 sphinganine 
                 
                   2.21 
                 
                 1.99E−08 
                 
                   1.63 
                 
                 0.0569 
                 
                   2.6 
                 
                 5.63E−07 
               
               
                 palmitoylcarnitine 
                 
                   1.54 
                 
                 2.31E−08 
                 
                   1.19 
                 
                 0.0332 
                 
                   1.89 
                 
                 3.08E−06 
               
               
                 1-docosahexaenoylglycerophosphocholine 
                 
                   0.54 
                 
                 2.97E−08 
                 
                   0.32 
                 
                 7.39E−10 
                 
                   0.65 
                 
                 0.007 
               
               
                 2-stearoylglycerophosphocholine 
                 
                   0.3 
                 
                 3.84E−08 
                 
                   0.15 
                 
                 4.75E−07 
                 
                   0.46 
                 
                 0.0036 
               
               
                 isoleucyltyrosine 
                 
                   3.86 
                 
                 4.04E−08 
                 2.75 
                 0.1293 
                 
                   4.39 
                 
                 4.97E−08 
               
               
                 1-stearoylglycerophosphocholine 
                 
                   0.38 
                 
                 4.60E−08 
                 
                   0.21 
                 
                 1.37E−06 
                 
                   0.5 
                 
                 0.0012 
               
               
                 ophthalmate 
                 
                   1.74 
                 
                 4.76E−08 
                 1.22 
                 0.1967 
                 
                   2.07 
                 
                 7.95E−07 
               
               
                 tyrosylleucine 
                 
                   3.93 
                 
                 6.12E−08 
                 
                   3.54 
                 
                 0.0037 
                 
                   4.15 
                 
                 3.11E−07 
               
               
                 cinnamoylglycine 
                 
                   0.75 
                 
                 6.45E−08 
                 
                   0.75 
                 
                 0.0158 
                 
                   0.75 
                 
                 1.04E−05 
               
               
                 phosphate 
                 
                   0.8 
                 
                 7.35E−08 
                 
                   0.77 
                 
                 0.0016 
                 
                   0.84 
                 
                 0.001 
               
               
                 histamine 
                 
                   2.57 
                 
                 9.15E−08 
                 
                   2.99 
                 
                 0.0011 
                 
                   2.32 
                 
                 0.0009 
               
               
                 trans-4-hydroxyproline 
                 
                   0.82 
                 
                 1.01E−07 
                 
                   0.58 
                 
                 0.002 
                 
                   0.92 
                 
                 5.28E−05 
               
               
                 3′-dephosphocoenzyme A 
                 
                   0.53 
                 
                 1.25E−07 
                 
                   0.46 
                 
                 0.0003 
                 
                   0.63 
                 
                 0.0018 
               
               
                 caproate (6:0) 
                 
                   0.82 
                 
                 1.61E−07 
                 0.93 
                 0.4299 
                 
                   0.75 
                 
                 2.64E−08 
               
               
                 cysteinylglycine 
                 
                   6.85 
                 
                 1.75E−07 
                 
                   1.95 
                 
                 0.0866 
                 
                   9.79 
                 
                 8.35E−06 
               
               
                 aspartyltryptophan 
                 
                   0.75 
                 
                 2.12E−07 
                 
                   0.6 
                 
                 5.37E−07 
                 
                   0.88 
                 
                 0.0412 
               
               
                 cytosine-2′,3′-cyclic monophosphate 
                 
                   0.84 
                 
                 2.21E−07 
                 
                   0.57 
                 
                 1.31E−08 
                 
                   1 
                 
                 0.0461 
               
               
                 aspartate-glutamate 
                 
                   0.84 
                 
                 2.34E−07 
                 
                   0.66 
                 
                 5.97E−06 
                 
                   0.98 
                 
                 0.0216 
               
               
                 nicotinamide ribonucleotide (NMN) 
                 
                   0.52 
                 
                 3.22E−07 
                 
                   0.39 
                 
                 0.0005 
                 
                   0.68 
                 
                 0.0029 
               
               
                 gamma-glutamylcysteine 
                 
                   2.72 
                 
                 3.44E−07 
                 
                   2.54 
                 
                 0.0384 
                 
                   2.9 
                 
                 1.32E−06 
               
               
                 pelargonate (9:0) 
                 
                   0.88 
                 
                 5.72E−07 
                 1.01 
                 0.5819 
                 
                   0.79 
                 
                 3.33E−08 
               
               
                 valyltryptophan 
                 
                   3.45 
                 
                 8.20E−07 
                 
                   2.77 
                 
                 0.0094 
                 
                   4.07 
                 
                 4.47E−06 
               
               
                 inosine 
                 
                   1.27 
                 
                 8.34E−07 
                 1.13 
                 0.116 
                 
                   1.41 
                 
                 3.62E−08 
               
               
                 2-myristoylglycerophosphocholine 
                 
                   1.72 
                 
                 8.48E−07 
                 1.5 
                 0.1114 
                 
                   1.83 
                 
                 2.33E−05 
               
               
                 methionylglycine 
                 
                   2.49 
                 
                 8.80E−07 
                 1.58 
                 0.3241 
                 
                   2.85 
                 
                 5.56E−07 
               
               
                 threonylleucine 
                 
                   3.1 
                 
                 8.91E−07 
                 
                   2.21 
                 
                 0.0363 
                 
                   3.53 
                 
                 1.70E−06 
               
               
                 linoleate (18:2n6) 
                 
                   1.34 
                 
                 1.35E−06 
                 
                   1.37 
                 
                 0.0004 
                 
                   1.34 
                 
                 0.0002 
               
               
                 histidylphenylalanine 
                 
                   2.41 
                 
                 2.47E−06 
                 
                   2.49 
                 
                 0.0165 
                 
                   2.47 
                 
                 0.0001 
               
               
                 tyrosylglycine 
                 
                   1.37 
                 
                 2.93E−06 
                 
                   1.45 
                 
                 0.0487 
                 
                   1.37 
                 
                 7.88E−06 
               
               
                 sorbitol 6-phosphate 
                 
                   2.19 
                 
                 3.11E−06 
                 2.14 
                 0.1707 
                 
                   2.4 
                 
                 3.53E−06 
               
               
                 isoleucylglycine 
                 
                   0.8 
                 
                 6.58E−06 
                 
                   0.74 
                 
                 3.00E−06 
                 0.88 
                 0.1275 
               
               
                 alanyltyrosine 
                 
                   2.35 
                 
                 7.20E−06 
                 
                   2.24 
                 
                 0.0003 
                 
                   2.49 
                 
                 0.0002 
               
               
                 imidazole propionate 
                 
                   0.87 
                 
                 8.19E−06 
                 
                   0.87 
                 
                 0.0702 
                 
                   0.86 
                 
                 4.55E−05 
               
               
                 methionylleucine 
                 
                   3.35 
                 
                 8.35E−06 
                 2.39 
                 0.1661 
                 
                   3.55 
                 
                 9.16E−05 
               
               
                 ribulose 
                 
                   1.62 
                 
                 8.82E−06 
                 1.2 
                 0.1179 
                 
                   1.88 
                 
                 1.23E−05 
               
               
                 tyrosylhistidine 
                 
                   1.81 
                 
                 9.40E−06 
                 
                   2.03 
                 
                 4.04E−05 
                 
                   1.81 
                 
                 0.0004 
               
               
                 3-phosphoglycerate 
                 
                   0.59 
                 
                 9.94E−06 
                 0.79 
                 0.3998 
                 
                   0.52 
                 
                 7.36E−05 
               
               
                 phenylalanylvaline 
                 
                   2.41 
                 
                 1.13E−05 
                 
                   2.21 
                 
                 0.0737 
                 
                   2.49 
                 
                 1.90E−05 
               
               
                 2-oleoylglycerol (2-monoolein) 
                 
                   2.61 
                 
                 1.64E−05 
                 
                   2.4 
                 
                 0.0676 
                 
                   3.21 
                 
                 2.07E−05 
               
               
                 leucylleucine 
                 
                   3.55 
                 
                 1.75E−05 
                 
                   2.76 
                 
                 0.0361 
                 
                   3.99 
                 
                 2.66E−05 
               
               
                 leucylalanine 
                 
                   2.54 
                 
                 1.76E−05 
                 1.86 
                 0.2007 
                 
                   2.86 
                 
                 5.92E−05 
               
               
                 glycyltyrosine 
                 
                   1.48 
                 
                 1.81E−05 
                 
                   1.47 
                 
                 0.0065 
                 
                   1.55 
                 
                 6.69E−05 
               
               
                 heme 
                 
                   2.6 
                 
                 1.97E−05 
                 
                   11.64 
                 
                 8.19E−05 
                 
                   1.49 
                 
                 0.0552 
               
               
                 deoxycarnitine 
                 
                   1.27 
                 
                 2.02E−05 
                 1.15 
                 0.3199 
                 
                   1.37 
                 
                 6.53E−06 
               
               
                 valylleucine 
                 
                   4.02 
                 
                 2.23E−05 
                 
                   2.16 
                 
                 0.0923 
                 
                   5.08 
                 
                 0.0001 
               
               
                 butyrylcarnitine 
                 
                   1.47 
                 
                 2.59E−05 
                 1.39 
                 0.5491 
                 
                   1.66 
                 
                 1.19E−07 
               
               
                 arginyltyrosine 
                 
                   2.11 
                 
                 2.93E−05 
                 
                   2.2 
                 
                 0.0967 
                 
                   2.07 
                 
                 0.0006 
               
               
                 leucylglutamate 
                 
                   2.74 
                 
                 3.09E−05 
                 2.13 
                 0.1254 
                 
                   3.12 
                 
                 4.94E−05 
               
               
                 valylphenylalanine 
                 
                   3.62 
                 
                 3.19E−05 
                 2.2 
                 0.1674 
                 
                   4.31 
                 
                 1.52E−05 
               
               
                 sedoheptulose-7-phosphate 
                 
                   1.52 
                 
                 4.23E−05 
                 0.94 
                 0.9353 
                 
                   1.94 
                 
                 1.69E−06 
               
               
                 methionylasparagine 
                 
                   1.94 
                 
                 4.60E−05 
                 
                   2.26 
                 
                 0.0059 
                 
                   1.87 
                 
                 0.0031 
               
               
                 spermine 
                 
                   1.17 
                 
                 4.63E−05 
                 
                   4.94 
                 
                 0.0048 
                 
                   0.97 
                 
                 0.0005 
               
               
                 histidyltryptophan 
                 
                   1.69 
                 
                 5.94E−05 
                 
                   1.59 
                 
                 0.0565 
                 
                   1.77 
                 
                 0.0003 
               
               
                 lysylleucine 
                 
                   2.48 
                 
                 6.35E−05 
                 1.75 
                 0.6591 
                 
                   2.91 
                 
                 1.55E−06 
               
               
                 pentadecanoate (15:0) 
                 
                   1.3 
                 
                 6.59E−05 
                 
                   1.34 
                 
                 0.0075 
                 
                   1.35 
                 
                 0.0001 
               
               
                 cis-vaccenate (18:1n7) 
                 
                   1.57 
                 
                 6.63E−05 
                 
                   1.51 
                 
                 0.098 
                 
                   1.66 
                 
                 1.02E−05 
               
               
                 caprylate (8:0) 
                 
                   0.86 
                 
                 6.95E−05 
                 1.05 
                 0.7927 
                 
                   0.76 
                 
                 4.65E−06 
               
               
                 5-methyluridine (ribothymidine) 
                 
                   0.81 
                 
                 7.09E−05 
                 
                   0.85 
                 
                 0.0057 
                 
                   0.78 
                 
                 0.0069 
               
               
                 histidyltyrosine 
                 
                   2.03 
                 
                 7.44E−05 
                 
                   3.37 
                 
                 0.0503 
                 
                   1.7 
                 
                 0.0015 
               
               
                 alanylglutamate 
                 
                   2.05 
                 
                 8.45E−05 
                 1.43 
                 0.3645 
                 
                   2.27 
                 
                 2.80E−06 
               
               
                 2-linoleoylglycerol (2-monolinolein) 
                 
                   2.25 
                 
                 8.78E−05 
                 
                   2.61 
                 
                 0.0026 
                 
                   2.18 
                 
                 0.0049 
               
               
                 histidylmethionine 
                 
                   2.23 
                 
                 9.00E−05 
                 
                   2.68 
                 
                 0.023 
                 
                   2.23 
                 
                 0.0008 
               
               
                 bilirubin (Z,Z) 
                 
                   1.5 
                 
                 0.0001 
                 
                   1.4 
                 
                 0.0046 
                 
                   1.17 
                 
                 0.0373 
               
               
                 methionylglutamate 
                 
                   1.99 
                 
                 0.0001 
                 
                   1.88 
                 
                 0.091 
                 
                   2.14 
                 
                 0.0014 
               
               
                 1-palmitoylglycerol (1-monopalmitin) 
                 
                   0.78 
                 
                 0.0002 
                 
                   0.65 
                 
                 0.0028 
                 0.89 
                 0.1082 
               
               
                 3-hydroxyoctanoate 
                 
                   0.8 
                 
                 0.0002 
                 
                   0.78 
                 
                 0.0118 
                 
                   0.79 
                 
                 0.0078 
               
               
                 glycylisoleucine 
                 
                   0.83 
                 
                 0.0002 
                 
                   0.67 
                 
                 7.07E−05 
                 0.97 
                 0.3598 
               
               
                 isoleucylmethionine 
                 
                   3.9 
                 
                 0.0002 
                 2.39 
                 0.8164 
                 
                   4.65 
                 
                 2.61E−06 
               
               
                 S-methylcysteine 
                 
                   0.81 
                 
                 0.0002 
                 
                   0.8 
                 
                 0.0405 
                 
                   0.87 
                 
                 0.0489 
               
               
                 valylglycine 
                 
                   0.87 
                 
                 0.0002 
                 
                   0.73 
                 
                 2.17E−05 
                 1 
                 0.3709 
               
               
                 tyrosyltyrosine 
                 
                   2.04 
                 
                 0.0002 
                 1.87 
                 0.1295 
                 
                   2.16 
                 
                 0.0011 
               
               
                 alanyltryptophan 
                 
                   1.72 
                 
                 0.0002 
                 
                   2.45 
                 
                 6.65E−05 
                 
                   1.46 
                 
                 0.0587 
               
               
                 oleate (18:1n9) 
                 
                   1.49 
                 
                 0.0003 
                 
                   1.47 
                 
                 0.0601 
                 
                   1.55 
                 
                 0.0003 
               
               
                 2-ethylhexanoate 
                 
                   0.93 
                 
                 0.0003 
                 1.23 
                 0.9113 
                 
                   0.71 
                 
                 1.57E−06 
               
               
                 2-docosapentaenoylglycerophosphoethanolamine 
                 
                   1.71 
                 
                 0.0003 
                 1.35 
                 0.4746 
                 
                   1.82 
                 
                 0.0051 
               
               
                 thymidine 
                 
                   0.75 
                 
                 0.0003 
                 
                   0.64 
                 
                 0.0015 
                 
                   0.79 
                 
                 0.0341 
               
               
                 1-oleoylglycerol (1-monoolein) 
                 
                   1.65 
                 
                 0.0004 
                 1.41 
                 0.2749 
                 
                   1.79 
                 
                 0.0002 
               
               
                 adenosine 5′-monophosphate (AMP) 
                 
                   1.9 
                 
                 0.0005 
                 
                   2.28 
                 
                 0.0005 
                 
                   1.82 
                 
                 0.0135 
               
               
                 choline phosphate 
                 
                   1.31 
                 
                 0.0005 
                 
                   1.47 
                 
                 0.0003 
                 
                   1.25 
                 
                 0.0482 
               
               
                 4-hydroxybutyrate (GHB) 
                 
                   3.12 
                 
                 0.0005 
                 1.92 
                 0.6215 
                 
                   3.69 
                 
                 1.70E−06 
               
               
                 2-oleoylglycerophosphoserine 
                 
                   0.96 
                 
                 0.0005 
                 
                   0.93 
                 
                 0.0122 
                 1.05 
                 0.2395 
               
               
                 leucylglycine 
                 
                   2.53 
                 
                 0.0005 
                 1.65 
                 0.5448 
                 
                   2.95 
                 
                 0.0002 
               
               
                 valyltyrosine 
                 
                   3.12 
                 
                 0.0005 
                 2.25 
                 0.6048 
                 
                   3.51 
                 
                 8.19E−05 
               
               
                 valylserine 
                 
                   1.96 
                 
                 0.0005 
                 1.08 
                 0.83 
                 
                   2.5 
                 
                 3.84E−05 
               
               
                 valylarginine 
                 
                   1.72 
                 
                 0.0005 
                 
                   1.96 
                 
                 0.0482 
                 
                   1.65 
                 
                 0.003 
               
               
                 nicotinamide 
                 
                   0.86 
                 
                 0.0008 
                 
                   0.88 
                 
                 0.0674 
                 
                   0.9 
                 
                 0.0856 
               
               
                 leucylmethionine 
                 
                   1.09 
                 
                 0.0008 
                 
                   0.75 
                 
                 0.0001 
                 1.36 
                 0.338 
               
               
                 isoleucyltryptophan 
                 
                   3.04 
                 
                 0.0008 
                 1.44 
                 0.5864 
                 
                   3.93 
                 
                 8.60E−06 
               
               
                 valylhistidine 
                 
                   0.82 
                 
                 0.0009 
                 
                   0.54 
                 
                 0.0003 
                 1.04 
                 0.2933 
               
               
                 arginylmethionine 
                 
                   1.8 
                 
                 0.0009 
                 
                   2.24 
                 
                 0.0454 
                 
                   1.62 
                 
                 0.0155 
               
               
                 2-arachidonoylglycerophosphoethanolamine 
                 
                   0.88 
                 
                 0.0011 
                 
                   0.81 
                 
                 0.0182 
                 0.99 
                 0.2724 
               
               
                 alanylmethionine 
                 
                   2.32 
                 
                 0.0012 
                 1.86 
                 0.1669 
                 
                   2.51 
                 
                 0.0023 
               
               
                 threonylvaline 
                 
                   1.79 
                 
                 0.0012 
                 1.84 
                 0.1523 
                 
                   1.71 
                 
                 0.0085 
               
               
                 6-keto prostaglandin F1alpha 
                 
                   0.65 
                 
                 0.0015 
                 
                   0.53 
                 
                 0.0263 
                 
                   0.72 
                 
                 0.0468 
               
               
                 leucyltyrosine 
                 
                   1.97 
                 
                 0.0015 
                 1.76 
                 0.7723 
                 
                   1.92 
                 
                 0.0036 
               
               
                 7-beta-hydroxycholesterol 
                 
                   1.71 
                 
                 0.0016 
                 1.27 
                 0.3887 
                 
                   2.01 
                 
                 0.0043 
               
               
                 glycylmethionine 
                 
                   1.7 
                 
                 0.0016 
                 1.45 
                 0.3622 
                 
                   1.86 
                 
                 0.0006 
               
               
                 pyrophosphate (PPi) 
                 
                   0.72 
                 
                 0.0018 
                 
                   0.64 
                 
                 0.0162 
                 
                   0.7 
                 
                 0.0274 
               
               
                 aspartylphenylalanine 
                 
                   1.82 
                 
                 0.0019 
                 1.45 
                 0.6813 
                 
                   2.03 
                 
                 4.59E−05 
               
               
                 16-hydroxypalmitate 
                 
                   0.74 
                 
                 0.0019 
                 
                   0.83 
                 
                 0.0121 
                 
                   0.66 
                 
                 0.0316 
               
               
                 1-linoleoylglycerophosphocholine 
                 
                   0.64 
                 
                 0.0025 
                 
                   0.37 
                 
                 0.0001 
                 0.9 
                 0.5971 
               
               
                 valylglutamate 
                 
                   1.84 
                 
                 0.003 
                 1.43 
                 0.8909 
                 
                   2.1 
                 
                 4.15E−05 
               
               
                 cystine 
                 
                   1.58 
                 
                 0.003 
                 
                   1.89 
                 
                 0.0601 
                 
                   1.46 
                 
                 0.0657 
               
               
                 phosphoethanolamine 
                 
                   0.92 
                 
                 0.0032 
                 
                   0.92 
                 
                 0.0974 
                 
                   0.95 
                 
                 0.0686 
               
               
                 N-acetyltryptophan 
                 
                   0.1 
                 
                 0.0035 
                 0.09 
                 0.1115 
                 
                   0.1 
                 
                 0.023 
               
               
                 3-hydroxydecanoate 
                 
                   0.76 
                 
                 0.0036 
                 
                   0.77 
                 
                 0.0443 
                 
                   0.77 
                 
                 0.0623 
               
               
                 betaine 
                 
                   0.79 
                 
                 0.0036 
                 0.72 
                 0.19 
                 
                   0.85 
                 
                 0.0241 
               
               
                 leucylasparagine 
                 
                   2.07 
                 
                 0.0036 
                 1.6 
                 0.9498 
                 
                   2.27 
                 
                 0.0012 
               
               
                 cytidine 5′-diphosphocholine 
                 
                   1.85 
                 
                 0.0037 
                 1.52 
                 0.6134 
                 
                   1.98 
                 
                 0.0014 
               
               
                 leucylphenylalanine 
                 
                   2.15 
                 
                 0.0038 
                 1.59 
                 0.9033 
                 
                   2.37 
                 
                 0.0008 
               
               
                 tryptophylglutamate 
                 
                   1.56 
                 
                 0.0042 
                 1.62 
                 0.2478 
                 
                   1.58 
                 
                 0.0029 
               
               
                 2-phosphoglycerate 
                 
                   0.61 
                 
                 0.0054 
                 0.73 
                 0.1842 
                 
                   0.54 
                 
                 0.0129 
               
               
                 6′-sialyllactose 
                 
                   2.62 
                 
                 0.007 
                 2.49 
                 0.1936 
                 
                   2.85 
                 
                 0.0038 
               
               
                 margarate (17:0) 
                 
                   1.15 
                 
                 0.0076 
                 
                   1.16 
                 
                 0.0824 
                 
                   1.14 
                 
                 0.0527 
               
               
                 glycerate 
                 
                   0.85 
                 
                 0.0076 
                 
                   0.86 
                 
                 0.0664 
                 
                   0.86 
                 
                 0.0993 
               
               
                 isoleucylhistidine 
                 
                   0.7 
                 
                 0.0077 
                 0.7 
                 0.1031 
                 0.81 
                 0.3691 
               
               
                 alpha-glutamyltyrosine 
                 
                   2.04 
                 
                 0.0079 
                 1.68 
                 0.78 
                 
                   2.28 
                 
                 0.0011 
               
               
                 tryptophylasparagine 
                 
                   2.15 
                 
                 0.0083 
                 1.7 
                 0.4846 
                 
                   2.34 
                 
                 0.0006 
               
               
                 arginylvaline 
                 
                   1.3 
                 
                 0.0099 
                 1.47 
                 0.1562 
                 
                   1.23 
                 
                 0.0646 
               
               
                 adenylosuccinate 
                 
                   0.81 
                 
                 0.0103 
                 
                   0.6 
                 
                 0.002 
                 1.11 
                 0.7343 
               
               
                 myristate (14:0) 
                 
                   0.94 
                 
                 0.0107 
                 1.05 
                 0.5054 
                 
                   0.88 
                 
                 0.0017 
               
               
                 lysylmethionine 
                 
                   1.28 
                 
                 0.0107 
                 1.46 
                 0.8904 
                 
                   1.22 
                 
                 0.0035 
               
               
                 1-linoleoylglycerol (1-monolinolein) 
                 
                   1.67 
                 
                 0.0125 
                 1.6 
                 0.2315 
                 
                   1.67 
                 
                 0.0181 
               
               
                 1-arachidonylglycerol 
                 
                   0.74 
                 
                 0.0132 
                 0.86 
                 0.6146 
                 
                   0.72 
                 
                 0.0457 
               
               
                 guanine 
                 
                   0.89 
                 
                 0.0136 
                 0.48 
                 0.5964 
                 
                   1.15 
                 
                 0.0572 
               
               
                 glycerol 2-phosphate 
                 
                   1.59 
                 
                 0.0137 
                 1.4 
                 0.2948 
                 
                   1.79 
                 
                 0.0048 
               
               
                 2′-deoxyinosine 
                 
                   1.32 
                 
                 0.0144 
                 1.05 
                 0.7128 
                 
                   1.42 
                 
                 0.0052 
               
               
                 palmitate (16:0) 
                 
                   1.13 
                 
                 0.0168 
                 
                   1.18 
                 
                 0.0478 
                 1.11 
                 0.1342 
               
               
                 prostaglandin A2 
                 
                   0.65 
                 
                 0.0188 
                 0.51 
                 0.112 
                 0.71 
                 0.1511 
               
               
                 isoleucylarginine 
                 
                   1.02 
                 
                 0.0194 
                 
                   1.05 
                 
                 0.002 
                 1.02 
                 0.9057 
               
               
                 phenylalanyltryptophan 
                 
                   1.52 
                 
                 0.0203 
                 1.53 
                 0.5818 
                 
                   1.47 
                 
                 0.0491 
               
               
                 homocysteine 
                 
                   1 
                 
                 0.0228 
                 
                   0.42 
                 
                 0.0004 
                 1.49 
                 0.4194 
               
               
                 1,3-dihydroxyacetone 
                 
                   1.37 
                 
                 0.024 
                 1.03 
                 0.7914 
                 
                   1.48 
                 
                 0.0102 
               
               
                 1-arachidonoylglycerophosphocholine 
                 
                   0.8 
                 
                 0.0269 
                 
                   0.49 
                 
                 0.0002 
                 1.05 
                 0.9462 
               
               
                 aspartylvaline 
                 
                   1.4 
                 
                 0.0269 
                 
                   0.72 
                 
                 0.0008 
                 1.74 
                 0.6929 
               
               
                 2-oleoylglycerophosphocholine 
                 
                   0.85 
                 
                 0.0275 
                 
                   0.48 
                 
                 0.0008 
                 1.16 
                 0.9341 
               
               
                 threonylmethionine 
                 
                   1.81 
                 
                 0.0281 
                 1.3 
                 0.7264 
                 
                   2.07 
                 
                 0.0025 
               
               
                 dihydrocholesterol 
                 
                   1.46 
                 
                 0.0314 
                 1.12 
                 0.2523 
                 
                   1.9 
                 
                 0.0001 
               
               
                 valylasparagine 
                 
                   1.63 
                 
                 0.0314 
                 0.84 
                 0.1212 
                 
                   2.13 
                 
                 0.0015 
               
               
                 uridine 
                 
                   0.89 
                 
                 0.0331 
                 
                   0.8 
                 
                 0.0181 
                 0.96 
                 0.5118 
               
               
                 2-palmitoylglycerophosphocholine 
                 
                   0.66 
                 
                 0.0362 
                 
                   0.37 
                 
                 0.0007 
                 0.89 
                 0.7683 
               
               
                 7-alpha-hydroxycholesterol 
                 
                   2.52 
                 
                 0.0367 
                 1.53 
                 0.9998 
                 
                   2.73 
                 
                 0.0665 
               
               
                 cholesterol 
                 
                   1.16 
                 
                 0.0369 
                 1.07 
                 0.3459 
                 
                   1.26 
                 
                 0.0146 
               
               
                 isoleucylisoleucine 
                 
                   2.26 
                 
                 0.0383 
                 1.89 
                 0.8332 
                 
                   2.43 
                 
                 0.0087 
               
               
                 alpha-glutamyltryptophan 
                 
                   1.8 
                 
                 0.0389 
                 1.36 
                 0.6571 
                 
                   2.05 
                 
                 0.0044 
               
               
                 isoleucylserine 
                 
                   1.94 
                 
                 0.0408 
                 1.38 
                 0.8156 
                 
                   2.28 
                 
                 0.0046 
               
               
                 bilirubin (E,E) 
                 
                   1.23 
                 
                 0.0433 
                 
                   1.17 
                 
                 0.0457 
                 1.02 
                 0.7542 
               
               
                 stearoylcarnitine 
                 
                   1.2 
                 
                 0.0435 
                 0.95 
                 0.9679 
                 
                   1.48 
                 
                 0.0366 
               
               
                 1,2-propanediol 
                 
                   0.87 
                 
                 0.0507 
                 0.95 
                 0.946 
                 
                   0.85 
                 
                 0.0454 
               
               
                 2-docosahexaenoylglycerophosphocholine 
                 
                   0.87 
                 
                 0.0575 
                 
                   0.58 
                 
                 0.0069 
                 1.04 
                 0.6503 
               
               
                 prostaglandin E2 
                 
                   0.53 
                 
                 0.0624 
                 0.29 
                 0.2867 
                 0.83 
                 0.2277 
               
               
                 methionylaspartate 
                 
                   1.7 
                 
                 0.0633 
                 1.66 
                 0.3022 
                 
                   1.88 
                 
                 0.0767 
               
               
                 isoleucylalanine 
                 
                   2.01 
                 
                 0.0751 
                 1.44 
                 0.5482 
                 
                   2.32 
                 
                 0.0015 
               
               
                 N-acetylglucosamine 
                 
                   0.66 
                 
                 0.0835 
                 
                   0.57 
                 
                 0.0957 
                 0.68 
                 0.2922 
               
               
                 triethyleneglycol 
                 
                   0.9 
                 
                 0.0988 
                 
                   0.82 
                 
                 0.0476 
                 1.06 
                 0.696 
               
               
                 threonylglutamate 
                 
                   1.11 
                 
                 0.0999 
                 
                   0.88 
                 
                 0.0274 
                 1.25 
                 0.882 
               
               
                 valylalanine 
                 1.78 
                 0.1209 
                 1.36 
                 0.4229 
                 
                   1.99 
                 
                 0.0049 
               
               
                 hypotaurine 
                 1.69 
                 0.1214 
                 
                   1.87 
                 
                 0.0574 
                 1.77 
                 0.144 
               
               
                 2′-deoxyadenosine 3′-monophosphate 
                 1.21 
                 0.1295 
                 1.05 
                 0.9603 
                 
                   1.33 
                 
                 0.0266 
               
               
                 palmitoyl sphingomyelin 
                 0.92 
                 0.1296 
                 0.86 
                 0.1301 
                 0.99 
                 0.7402 
               
               
                 argininosuccinate 
                 0.53 
                 0.1327 
                 
                   0.47 
                 
                 0.0623 
                 0.56 
                 0.6963 
               
               
                 adrenate (22:4n6) 
                 1.12 
                 0.1383 
                 0.99 
                 0.7539 
                 
                   1.21 
                 
                 0.0211 
               
               
                 alanylalanine 
                 1.1 
                 0.1551 
                 
                   1.05 
                 
                 0.0105 
                 1.15 
                 0.8715 
               
               
                 2′-deoxycytidine 3′-monophosphate 
                 1.21 
                 0.1915 
                 1.01 
                 0.933 
                 1.2 
                 0.6439 
               
               
                 S-adenosylmethionine (SAM) 
                 1.24 
                 0.196 
                 
                   0.83 
                 
                 0.0027 
                 
                   1.48 
                 
                 0.0004 
               
               
                 alanylthreonine 
                 1.66 
                 0.201 
                 1.74 
                 0.5377 
                 
                   1.72 
                 
                 0.014 
               
               
                 tyrosyllysine 
                 1.62 
                 0.2136 
                 0.81 
                 0.1455 
                 
                   2.33 
                 
                 0.0318 
               
               
                 valylglutamine 
                 1.66 
                 0.2152 
                 1.11 
                 0.1806 
                 
                   2.01 
                 
                 0.0048 
               
               
                 phytosphingosine 
                 0.82 
                 0.2359 
                 0.69 
                 0.1964 
                 0.96 
                 0.8095 
               
               
                 cortisol 
                 0.74 
                 0.2361 
                 0.51 
                 0.8553 
                 0.95 
                 0.5266 
               
               
                 valyllysine 
                 1.12 
                 0.2369 
                 
                   0.74 
                 
                 0.0346 
                 1.37 
                 0.5939 
               
               
                 serylvaline 
                 1.59 
                 0.2378 
                 1.29 
                 0.3069 
                 
                   1.74 
                 
                 0.0141 
               
               
                 leucylarginine 
                 1.56 
                 0.2687 
                 1.43 
                 0.7131 
                 
                   1.59 
                 
                 0.0396 
               
               
                 2-arachidonoylglycerophosphocholine 
                 1.3 
                 0.2775 
                 
                   0.73 
                 
                 0.0671 
                 
                   1.79 
                 
                 0.019 
               
               
                 glycyllysine 
                 1.13 
                 0.282 
                 1.14 
                 0.6421 
                 1.25 
                 0.266 
               
               
                 galactose 
                 1.5 
                 0.2857 
                 1.4 
                 0.6402 
                 
                   1.5 
                 
                 0.0284 
               
               
                 valylvaline 
                 1.92 
                 0.3058 
                 1.22 
                 0.2967 
                 
                   2.3 
                 
                 0.0219 
               
               
                 nicotinamide adenine dinucleotide 
                 1.45 
                 0.3061 
                 1.57 
                 0.5098 
                 1.53 
                 0.3233 
               
               
                 reduced (NADH) 
               
               
                 agmatine 
                 1.53 
                 0.3279 
                 0.83 
                 0.2243 
                 
                   2.31 
                 
                 0.0026 
               
               
                 leucyltryptophan 
                 1.18 
                 0.3339 
                 1.06 
                 0.3349 
                 
                   1.24 
                 
                 0.0976 
               
               
                 ribose 
                 1.19 
                 0.3602 
                 
                   0.72 
                 
                 0.0034 
                 
                   1.53 
                 
                 0.0555 
               
               
                 alpha-glutamylglutamate 
                 1.55 
                 0.3695 
                 1.17 
                 0.5033 
                 
                   1.8 
                 
                 0.075 
               
               
                 prolylmethionine 
                 1.78 
                 0.3832 
                 1.39 
                 0.1804 
                 
                   2.09 
                 
                 0.0024 
               
               
                 2-palmitoylglycerol (2-monopalmitin) 
                 1 
                 0.4149 
                 
                   0.87 
                 
                 0.0578 
                 1.15 
                 0.2072 
               
               
                 dodecanedioate 
                 0.92 
                 0.4214 
                 1.03 
                 0.8457 
                 
                   0.82 
                 
                 0.0947 
               
               
                 valylisoleucine 
                 2.09 
                 0.4309 
                 1.38 
                 0.1845 
                 
                   2.43 
                 
                 0.0355 
               
               
                 2′-deoxyguanosine 
                 1.18 
                 0.4593 
                 0.93 
                 0.1993 
                 
                   1.35 
                 
                 0.0602 
               
               
                 2-docosapentaenoylglycerophosphocholine 
                 1.1 
                 0.4792 
                 
                   0.63 
                 
                 0.0546 
                 
                   1.44 
                 
                 0.0556 
               
               
                 glycylleucine 
                 1.13 
                 0.486 
                 
                   1.12 
                 
                 0.0573 
                 1.2 
                 0.2792 
               
               
                 serylisoleucine 
                 1.25 
                 0.5075 
                 1.23 
                 0.1074 
                 1.33 
                 0.2853 
               
               
                 N-acetylornithine 
                 1.11 
                 0.5223 
                 1.2 
                 0.2014 
                 1.13 
                 0.4737 
               
               
                 isoleucylvaline 
                 1.8 
                 0.523 
                 
                   1.21 
                 
                 0.009 
                 
                   2.13 
                 
                 0.0923 
               
               
                 arabonate 
                 1.07 
                 0.5252 
                 
                   1.21 
                 
                 0.0977 
                 1.04 
                 0.9216 
               
               
                 ornithine 
                 1.17 
                 0.5853 
                 
                   1.58 
                 
                 0.0488 
                 1.07 
                 0.2307 
               
               
                 glycyltryptophan 
                 1.4 
                 0.5951 
                 1.22 
                 0.3179 
                 
                   1.6 
                 
                 0.059 
               
               
                 testosterone 
                 1.01 
                 0.6287 
                 
                   1.27 
                 
                 0.0247 
                 0.89 
                 0.3475 
               
               
                 methionylphenylalanine 
                 1.47 
                 0.6522 
                 
                   1.23 
                 
                 0.0263 
                 1.3 
                 0.236 
               
               
                 alanylglycine 
                 1.26 
                 0.7033 
                 0.96 
                 0.1068 
                 
                   1.45 
                 
                 0.0723 
               
               
                 alanylvaline 
                 1.4 
                 0.7425 
                 1.21 
                 0.1474 
                 1.54 
                 0.1896 
               
               
                 isoleucylphenylalanine 
                 2.97 
                 0.7426 
                 1.88 
                 0.4284 
                 3.45 
                 0.1202 
               
               
                 docosapentaenoate (n3 DPA; 22:5n3) 
                 1.09 
                 0.7743 
                 1.03 
                 0.6054 
                 1.14 
                 0.6734 
               
               
                 valylaspartate 
                 1.38 
                 0.7778 
                 
                   1.05 
                 
                 0.0819 
                 1.63 
                 0.1175 
               
               
                 2-linoleoylglycerophosphocholine 
                 1.11 
                 0.8078 
                 
                   0.66 
                 
                 0.0131 
                 
                   1.58 
                 
                 0.0463 
               
               
                 piperine 
                 1.08 
                 0.8111 
                 1.1 
                 0.9512 
                 1.05 
                 0.8957 
               
               
                 13-HODE + 9-HODE 
                 1.15 
                 0.8212 
                 1.3 
                 0.9076 
                 1.04 
                 0.9013 
               
               
                 alanylisoleucine 
                 1.53 
                 0.8533 
                 
                   1.14 
                 
                 0.0337 
                 
                   1.8 
                 
                 0.0789 
               
               
                 lysyllysine 
                 1.17 
                 0.8843 
                 1 
                 0.1283 
                 1.25 
                 0.175 
               
               
                 dihomo-linolenate (20:3n3 or n6) 
                 1.08 
                 0.9478 
                 
                   0.86 
                 
                 0.0567 
                 
                   1.25 
                 
                 0.0966 
               
               
                 2-eicosatrienoylglycerophosphocholine 
                 1.21 
                 0.9714 
                 
                   0.55 
                 
                 0.0036 
                 
                   1.87 
                 
                 0.0338 
               
               
                 phenylalanylarginine 
                 1.21 
                 0.9854 
                 1.7 
                 0.2294 
                 1.05 
                 0.627 
               
               
                 nicotinamide riboside 
                 1.18 
                 0.9877 
                 0.82 
                 0.1453 
                 
                   1.65 
                 
                 0.0561 
               
               
                 2-docosahexaenoylglycerophosphoethanolamine 
                 1.1 
                 0.9879 
                 0.89 
                 0.2814 
                 1.18 
                 0.8106 
               
               
                 isoleucylglutamate 
                 1.3 
                 0.9945 
                 
                   0.94 
                 
                 0.0357 
                 
                   1.53 
                 
                 0.0811 
               
               
                 creatinine 
                 
                   0.33 
                 
                 p &lt; 0.0001 
                 
                   0.38 
                 
                 1.00E−15 
                 
                   0.32 
                 
                 p &lt; 0.0001 
               
               
                 N-acetylneuraminate 
                 
                   2.45 
                 
                 p &lt; 0.0001 
                 
                   3.09 
                 
                 9.66E−12 
                 
                   2.34 
                 
                 6.31E−13 
               
               
                 4-hydroxyhippurate 
                 
                   0.09 
                 
                 p &lt; 0.0001 
                 
                   0.16 
                 
                 9.72E−12 
                 
                   0.08 
                 
                 p &lt; 0.0001 
               
               
                 malonylcarnitine 
                 
                   0.36 
                 
                 p &lt; 0.0001 
                 
                   0.27 
                 
                 9.78E−11 
                 
                   0.4 
                 
                 p &lt; 0.0001 
               
               
                 3-methylglutarylcarnitine (C6) 
                 
                   0.51 
                 
                 p &lt; 0.0001 
                 
                   0.72 
                 
                 3.19E−10 
                 
                   0.25 
                 
                 p &lt; 0.0001 
               
               
                 tryptophan betaine 
                 
                   2.84 
                 
                 p &lt; 0.0001 
                 
                   2.47 
                 
                 7.85E−08 
                 
                   3.21 
                 
                 2.00E−14 
               
               
                 2-hydroxyglutarate 
                 
                   6.14 
                 
                 p &lt; 0.0001 
                 
                   4.68 
                 
                 0.0002 
                 
                   7.38 
                 
                 p &lt; 0.0001 
               
               
                 chiro-inositol 
                 
                   0.36 
                 
                 4.19E−11 
                 
                   0.42 
                 
                 0.0001 
                 
                   0.37 
                 
                 1.30E−05 
               
               
                 glycolithocholate sulfate 
                 
                   0.69 
                 
                 2.99E−06 
                 0.91 
                 0.6539 
                 
                   0.59 
                 
                 6.79E−07 
               
               
                 pregnen-diol disulfate 
                 
                   0.65 
                 
                 2.93E−05 
                 0.92 
                 0.1813 
                 
                   0.54 
                 
                 2.15E−05 
               
               
                 C-glycosyltryptophan 
                 
                   0.8 
                 
                 0.0004 
                 0.96 
                 0.3785 
                 
                   0.74 
                 
                 0.0021 
               
               
                 glycocholenate sulfate 
                 
                   0.88 
                 
                 0.0024 
                 
                   0.88 
                 
                 0.0484 
                 
                   0.86 
                 
                 0.0125 
               
               
                 succinylcarnitine 
                 
                   0.91 
                 
                 0.0029 
                 
                   0.91 
                 
                 0.0796 
                 
                   0.93 
                 
                 0.0681 
               
               
                 4-androsten-3beta,17beta-diol disulfate 1 
                 
                   0.82 
                 
                 0.0488 
                 1.11 
                 0.5082 
                 
                   0.7 
                 
                 0.0234 
               
               
                 glycerol 
                 
                   1 
                 
                 0.0677 
                 0.95 
                 0.1488 
                 1.06 
                 0.7738 
               
               
                 1,5-anhydroglucitol (1,5-AG) 
                 0.98 
                 0.1785 
                 1.07 
                 0.2849 
                 
                   0.94 
                 
                 0.0714 
               
               
                 4-methyl-2-oxopentanoate 
                 1.1 
                 0.3792 
                 1.04 
                 0.9335 
                 1.13 
                 0.3022 
               
               
                 glutarate (pentanedioate) 
                 1.2 
                 0.6189 
                 0.92 
                 0.1615 
                 1.31 
                 0.7364 
               
               
                 2-hydroxybutyrate (AHB) 
                 1.05 
                 0.7168 
                 
                   1.17 
                 
                 0.0306 
                 0.96 
                 0.2883 
               
               
                 tryptophan 
                 
                   0.31 
                 
                 p &lt; 0.0001 
                 
                   0.29 
                 
                 5.90E−14 
                 
                   0.33 
                 
                 p &lt; 0.0001 
               
               
                 beta-alanine 
                 
                   4.27 
                 
                 p &lt; 0.0001 
                 
                   5.68 
                 
                 2.32E−13 
                 
                   4.09 
                 
                 1.42E−10 
               
               
                 glutamate 
                 
                   1.5 
                 
                 p &lt; 0.0001 
                 
                   1.45 
                 
                 2.78E−06 
                 
                   1.57 
                 
                 1.53E−13 
               
               
                 histidine 
                 
                   0.49 
                 
                 p &lt; 0.0001 
                 
                   0.51 
                 
                 1.62E−09 
                 
                   0.5 
                 
                 9.00E−15 
               
               
                 leucine 
                 
                   0.59 
                 
                 p &lt; 0.0001 
                 
                   0.55 
                 
                 1.11E−10 
                 
                   0.62 
                 
                 4.23E−10 
               
               
                 phenylalanine 
                 
                   0.59 
                 
                 p &lt; 0.0001 
                 
                   0.55 
                 
                 6.65E−10 
                 
                   0.63 
                 
                 1.77E−09 
               
               
                 4-hydroxyphenylacetate 
                 
                   0.31 
                 
                 p &lt; 0.0001 
                 
                   0.32 
                 
                 4.92E−11 
                 
                   0.31 
                 
                 p &lt; 0.0001 
               
               
                 fructose 
                 
                   4.9 
                 
                 p &lt; 0.0001 
                 
                   3.72 
                 
                 0.0001 
                 
                   5.32 
                 
                 p &lt; 0.0001 
               
               
                 gluconate 
                 
                   0.3 
                 
                 p &lt; 0.0001 
                 
                   0.33 
                 
                 8.03E−09 
                 
                   0.3 
                 
                 6.31E−12 
               
               
                 trans-urocanate 
                 
                   0.5 
                 
                 p &lt; 0.0001 
                 
                   0.59 
                 
                 1.15E−05 
                 
                   0.45 
                 
                 p &lt; 0.0001 
               
               
                 isoleucine 
                 
                   0.55 
                 
                 p &lt; 0.0001 
                 
                   0.5 
                 
                 1.50E−11 
                 
                   0.59 
                 
                 8.50E−12 
               
               
                 threonine 
                 
                   0.39 
                 
                 p &lt; 0.0001 
                 
                   0.36 
                 
                 4.23E−10 
                 
                   0.42 
                 
                 1.90E−11 
               
               
                 tyrosine 
                 
                   0.51 
                 
                 p &lt; 0.0001 
                 
                   0.47 
                 
                 8.54E−12 
                 
                   0.54 
                 
                 1.86E−13 
               
               
                 methionine 
                 
                   0.49 
                 
                 p &lt; 0.0001 
                 
                   0.44 
                 
                 2.98E−12 
                 
                   0.52 
                 
                 1.21E−12 
               
               
                 malate 
                 
                   0.48 
                 
                 p &lt; 0.0001 
                 
                   0.46 
                 
                 1.65E−07 
                 
                   0.52 
                 
                 1.02E−09 
               
               
                 gamma-aminobutyrate (GABA) 
                 
                   0.26 
                 
                 p &lt; 0.0001 
                 
                   0.27 
                 
                 1.12E−08 
                 
                   0.26 
                 
                 1.05E−13 
               
               
                 pantothenate 
                 
                   0.21 
                 
                 p &lt; 0.0001 
                 
                   0.21 
                 
                 p &lt; 0.0001 
                 
                   0.23 
                 
                 p &lt; 0.0001 
               
               
                 sarcosine (N-Methylglycine) 
                 
                   2.78 
                 
                 p &lt; 0.0001 
                 
                   2.23 
                 
                 1.93E−08 
                 
                   2.98 
                 
                 7.13E−12 
               
               
                 5,6-dihydrouracil 
                 
                   2.51 
                 
                 p &lt; 0.0001 
                 
                   2.11 
                 
                 2.75E−05 
                 
                   2.85 
                 
                 1.96E−12 
               
               
                 citrate 
                 
                   3.32 
                 
                 p &lt; 0.0001 
                 
                   14.84 
                 
                 p &lt; 0.0001 
                 
                   1.83 
                 
                 2.47E−08 
               
               
                 vanillylmandelate (VMA) 
                 
                   0.09 
                 
                 p &lt; 0.0001 
                 
                   0.12 
                 
                 p &lt; 0.0001 
                 
                   0.09 
                 
                 p &lt; 0.0001 
               
               
                 fumarate 
                 
                   0.29 
                 
                 p &lt; 0.0001 
                 
                   0.24 
                 
                 3.58E−13 
                 
                   0.32 
                 
                 1.00E−15 
               
               
                 serine 
                 
                   0.34 
                 
                 p &lt; 0.0001 
                 
                   0.31 
                 
                 1.01E−11 
                 
                   0.36 
                 
                 4.00E−14 
               
               
                 valine 
                 
                   0.54 
                 
                 p &lt; 0.0001 
                 
                   0.52 
                 
                 3.58E−10 
                 
                   0.57 
                 
                 3.58E−13 
               
               
                 cortisone 
                 
                   0.27 
                 
                 p &lt; 0.0001 
                 
                   0.23 
                 
                 3.39E−07 
                 
                   0.28 
                 
                 1.05E−10 
               
               
                 riboflavin (Vitamin B2) 
                 
                   0.42 
                 
                 p &lt; 0.0001 
                 
                   0.4 
                 
                 4.86E−09 
                 
                   0.45 
                 
                 1.57E−13 
               
               
                 proline 
                 
                   0.5 
                 
                 p &lt; 0.0001 
                 
                   0.46 
                 
                 3.31E−13 
                 
                   0.54 
                 
                 4.90E−14 
               
               
                 hypoxanthine 
                 
                   0.59 
                 
                 p &lt; 0.0001 
                 
                   0.54 
                 
                 5.24E−09 
                 
                   0.63 
                 
                 5.15E−13 
               
               
                 xanthine 
                 
                   0.66 
                 
                 p &lt; 0.0001 
                 
                   0.54 
                 
                 1.00E−11 
                 
                   0.74 
                 
                 5.78E−08 
               
               
                 cis-aconitate 
                 
                   2.18 
                 
                 p &lt; 0.0001 
                 
                   4.78 
                 
                 6.28E−12 
                 
                   1.48 
                 
                 2.24E−05 
               
               
                 xanthosine 
                 
                   0.53 
                 
                 p &lt; 0.0001 
                 
                   0.42 
                 
                 3.31E−11 
                 
                   0.58 
                 
                 1.59E−11 
               
               
                 kynurenine 
                 
                   7.89 
                 
                 p &lt; 0.0001 
                 
                   8.74 
                 
                 2.50E−14 
                 
                   7.74 
                 
                 p &lt; 0.0001 
               
               
                 mannitol 
                 
                   0.26 
                 
                 p &lt; 0.0001 
                 
                   0.29 
                 
                 9.48E−07 
                 
                   0.22 
                 
                 5.68E−12 
               
               
                 glucuronate 
                 
                   0.3 
                 
                 p &lt; 0.0001 
                 
                   0.25 
                 
                 6.43E−09 
                 
                   0.34 
                 
                 1.58E−13 
               
               
                 choline 
                 
                   0.66 
                 
                 p &lt; 0.0001 
                 
                   0.79 
                 
                 1.22E−05 
                 
                   0.6 
                 
                 p &lt; 0.0001 
               
               
                 N1-methyladenosine 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.35 
                 
                 6.36E−13 
                 
                   0.26 
                 
                 p &lt; 0.0001 
               
               
                 3-methylhistidine 
                 
                   0.55 
                 
                 p &lt; 0.0001 
                 
                   0.63 
                 
                 3.93E−08 
                 
                   0.51 
                 
                 1.92E−11 
               
               
                 glycolate (hydroxyacetate) 
                 
                   0.71 
                 
                 p &lt; 0.0001 
                 
                   0.72 
                 
                 2.73E−05 
                 
                   0.71 
                 
                 1.78E−11 
               
               
                 anserine 
                 
                   0.27 
                 
                 p &lt; 0.0001 
                 
                   0.22 
                 
                 1.16E−05 
                 
                   0.34 
                 
                 2.95E−09 
               
               
                 hippurate 
                 
                   0.1 
                 
                 p &lt; 0.0001 
                 
                   0.11 
                 
                 p &lt; 0.0001 
                 
                   0.09 
                 
                 p &lt; 0.0001 
               
               
                 aspartate 
                 
                   0.46 
                 
                 p &lt; 0.0001 
                 
                   0.54 
                 
                 2.62E−06 
                 
                   0.45 
                 
                 1.78E−12 
               
               
                 myo-inositol 
                 
                   0.32 
                 
                 p &lt; 0.0001 
                 
                   0.28 
                 
                 2.83E−10 
                 
                   0.4 
                 
                 9.50E−13 
               
               
                 glucose 
                 
                   4.18 
                 
                 p &lt; 0.0001 
                 
                   3.19 
                 
                 6.35E−09 
                 
                   4.48 
                 
                 p &lt; 0.0001 
               
               
                 adipate 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.25 
                 
                 5.62E−10 
                 
                   0.34 
                 
                 1.14E−10 
               
               
                 2-hydroxyisobutyrate 
                 
                   0.41 
                 
                 p &lt; 0.0001 
                 
                   0.46 
                 
                 3.10E−09 
                 
                   0.41 
                 
                 p &lt; 0.0001 
               
               
                 citramalate 
                 
                   0.19 
                 
                 p &lt; 0.0001 
                 
                   0.15 
                 
                 1.90E−14 
                 
                   0.22 
                 
                 p &lt; 0.0001 
               
               
                 N-acetylaspartate (NAA) 
                 
                   0.09 
                 
                 p &lt; 0.0001 
                 
                   0.07 
                 
                 p &lt; 0.0001 
                 
                   0.11 
                 
                 p &lt; 0.0001 
               
               
                 indoleacetate 
                 
                   0.2 
                 
                 p &lt; 0.0001 
                 
                   0.2 
                 
                 9.45E−13 
                 
                   0.2 
                 
                 p &lt; 0.0001 
               
               
                 pyridoxate 
                 
                   0.29 
                 
                 p &lt; 0.0001 
                 
                   0.31 
                 
                 3.20E−14 
                 
                   0.27 
                 
                 p &lt; 0.0001 
               
               
                 androsterone sulfate 
                 
                   0.59 
                 
                 p &lt; 0.0001 
                 
                   0.76 
                 
                 0.0007 
                 
                   0.52 
                 
                 1.94E−13 
               
               
                 N1-methylguanosine 
                 
                   0.19 
                 
                 p &lt; 0.0001 
                 
                   0.18 
                 
                 p &lt; 0.0001 
                 
                   0.2 
                 
                 p &lt; 0.0001 
               
               
                 acetylcarnitine 
                 
                   2.77 
                 
                 p &lt; 0.0001 
                 
                   2.62 
                 
                 1.37E−08 
                 
                   2.92 
                 
                 p &lt; 0.0001 
               
               
                 1-methylimidazoleacetate 
                 
                   0.58 
                 
                 p &lt; 0.0001 
                 
                   0.77 
                 
                 0.0024 
                 
                   0.49 
                 
                 2.00E−15 
               
               
                 scyllo-inositol 
                 
                   0.23 
                 
                 p &lt; 0.0001 
                 
                   0.16 
                 
                 4.70E−14 
                 
                   0.33 
                 
                 p &lt; 0.0001 
               
               
                 trigonelline (N′-methylnicotinate) 
                 
                   0.39 
                 
                 p &lt; 0.0001 
                 
                   0.33 
                 
                 4.58E−08 
                 
                   0.41 
                 
                 3.40E−14 
               
               
                 phenol sulfate 
                 
                   0.51 
                 
                 p &lt; 0.0001 
                 
                   0.78 
                 
                 0.0078 
                 
                   0.44 
                 
                 p &lt; 0.0001 
               
               
                 pyroglutamine 
                 
                   3.61 
                 
                 p &lt; 0.0001 
                 
                   3.18 
                 
                 1.23E−05 
                 
                   3.98 
                 
                 2.00E−15 
               
               
                 pseudouridine 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.26 
                 
                 p &lt; 0.0001 
                 
                   0.3 
                 
                 p &lt; 0.0001 
               
               
                 N-acetylglutamine 
                 
                   6.41 
                 
                 p &lt; 0.0001 
                 
                   7.39 
                 
                 5.88E−11 
                 
                   6.11 
                 
                 6.76E−13 
               
               
                 isovalerylcarnitine 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.22 
                 
                 1.40E−14 
                 
                   0.33 
                 
                 1.10E−13 
               
               
                 phenylacetylglutamine 
                 
                   0.1 
                 
                 p &lt; 0.0001 
                 
                   0.12 
                 
                 p &lt; 0.0001 
                 
                   0.1 
                 
                 p &lt; 0.0001 
               
               
                 pro-hydroxy-pro 
                 
                   0.43 
                 
                 p &lt; 0.0001 
                 
                   0.37 
                 
                 1.44E−10 
                 
                   0.46 
                 
                 p &lt; 0.0001 
               
               
                 N2-methylguanosine 
                 
                   0.26 
                 
                 p &lt; 0.0001 
                 
                   0.19 
                 
                 p &lt; 0.0001 
                 
                   0.28 
                 
                 p &lt; 0.0001 
               
               
                 N2,N2-dimethylguanosine 
                 
                   0.19 
                 
                 p &lt; 0.0001 
                 
                   0.22 
                 
                 p &lt; 0.0001 
                 
                   0.17 
                 
                 p &lt; 0.0001 
               
               
                 N6-carbamoylthreonyladenosine 
                 
                   0.37 
                 
                 p &lt; 0.0001 
                 
                   0.36 
                 
                 p &lt; 0.0001 
                 
                   0.37 
                 
                 p &lt; 0.0001 
               
               
                 2-methylbutyrylcarnitine (C5) 
                 
                   0.35 
                 
                 p &lt; 0.0001 
                 
                   0.28 
                 
                 6.10E−14 
                 
                   0.41 
                 
                 p &lt; 0.0001 
               
               
                 N-acetyl-aspartyl-glutamate (NAAG) 
                 
                   0.18 
                 
                 p &lt; 0.0001 
                 
                   0.19 
                 
                 p &lt; 0.0001 
                 
                   0.19 
                 
                 p &lt; 0.0001 
               
               
                 threitol 
                 
                   0.57 
                 
                 p &lt; 0.0001 
                 
                   0.3 
                 
                 7.22E−10 
                 
                   0.69 
                 
                 1.64E−12 
               
               
                 p-cresol sulfate 
                 
                   0.55 
                 
                 p &lt; 0.0001 
                 
                   0.73 
                 
                 0.0063 
                 
                   0.49 
                 
                 1.50E−14 
               
               
                 N6-acetyllysine 
                 
                   0.22 
                 
                 p &lt; 0.0001 
                 
                   0.22 
                 
                 2.00E−15 
                 
                   0.22 
                 
                 p &lt; 0.0001 
               
               
                 dimethylarginine (SDMA + ADMA) 
                 
                   0.28 
                 
                 p &lt; 0.0001 
                 
                   0.31 
                 
                 6.23E−12 
                 
                   0.26 
                 
                 p &lt; 0.0001 
               
               
                 glycylproline 
                 
                   1.7 
                 
                 1.00E−15 
                 
                   1.57 
                 
                 5.31E−05 
                 
                   1.84 
                 
                 3.80E−12 
               
               
                 glutarylcarnitine (C5) 
                 
                   0.46 
                 
                 1.00E−15 
                 
                   0.44 
                 
                 2.09E−07 
                 
                   0.46 
                 
                 4.92E−09 
               
               
                 catechol sulfate 
                 
                   0.57 
                 
                 1.20E−14 
                 
                   0.57 
                 
                 0.0001 
                 
                   0.56 
                 
                 6.36E−10 
               
               
                 glutamine 
                 
                   1.37 
                 
                 1.30E−14 
                 
                   1.44 
                 
                 1.62E−07 
                 
                   1.35 
                 
                 2.32E−07 
               
               
                 isobutyrylcarnitine 
                 
                   0.66 
                 
                 2.80E−14 
                 
                   0.67 
                 
                 4.59E−05 
                 
                   0.71 
                 
                 1.79E−07 
               
               
                 gamma-glutamylisoleucine 
                 
                   0.52 
                 
                 3.10E−14 
                 
                   0.59 
                 
                 0.0031 
                 
                   0.47 
                 
                 6.86E−11 
               
               
                 octanoylcarnitine 
                 
                   2.14 
                 
                 3.50E−14 
                 
                   1.91 
                 
                 5.49E−05 
                 
                   2.24 
                 
                 5.96E−09 
               
               
                 gulono-1,4-lactone 
                 
                   0.48 
                 
                 3.90E−14 
                 
                   0.56 
                 
                 0.008 
                 
                   0.48 
                 
                 4.78E−10 
               
               
                 urate 
                 
                   0.74 
                 
                 2.01E−13 
                 
                   0.89 
                 
                 0.0108 
                 
                   0.64 
                 
                 2.49E−13 
               
               
                 2-aminoadipate 
                 
                   4.63 
                 
                 3.51E−13 
                 
                   5.01 
                 
                 1.79E−08 
                 
                   4.56 
                 
                 1.64E−06 
               
               
                 guanidinoacetate 
                 
                   0.46 
                 
                 4.55E−13 
                 
                   0.41 
                 
                 3.18E−05 
                 
                   0.5 
                 
                 1.81E−07 
               
               
                 quinate 
                 
                   0.43 
                 
                 4.73E−13 
                 
                   0.54 
                 
                 0.0033 
                 
                   0.42 
                 
                 3.62E−08 
               
               
                 lysine 
                 
                   0.64 
                 
                 1.08E−12 
                 
                   0.63 
                 
                 1.99E−05 
                 
                   0.66 
                 
                 3.82E−07 
               
               
                 5-aminovalerate 
                 
                   1.82 
                 
                 3.24E−12 
                 
                   1.42 
                 
                 0.0066 
                 
                   2.22 
                 
                 4.74E−11 
               
               
                 3-aminoisobutyrate 
                 
                   3.86 
                 
                 3.38E−12 
                 
                   4.95 
                 
                 1.21E−08 
                 
                   3.91 
                 
                 4.92E−07 
               
               
                 sorbitol 
                 
                   6.4 
                 
                 3.78E−12 
                 
                   7.27 
                 
                 1.60E−05 
                 
                   6.74 
                 
                 8.12E−08 
               
               
                 S-adenosylhomocysteine (SAH) 
                 
                   2.09 
                 
                 4.41E−12 
                 
                   1.44 
                 
                 0.0838 
                 
                   2.58 
                 
                 6.79E−13 
               
               
                 tartarate 
                 
                   0.08 
                 
                 1.24E−11 
                 
                   0.3 
                 
                 0.0007 
                 
                   0.07 
                 
                 4.50E−08 
               
               
                 creatine 
                 
                   2.09 
                 
                 5.21E−11 
                 
                   1.67 
                 
                 0.0005 
                 
                   2.57 
                 
                 9.74E−10 
               
               
                 2-isopropylmalate 
                 
                   0.58 
                 
                 8.52E−11 
                 
                   0.61 
                 
                 1.73E−05 
                 
                   0.58 
                 
                 3.15E−05 
               
               
                 gamma-glutamylphenylalanine 
                 
                   0.73 
                 
                 1.58E−10 
                 0.89 
                 0.1345 
                 
                   0.67 
                 
                 2.95E−08 
               
               
                 N-acetylarginine 
                 
                   4.49 
                 
                 1.70E−10 
                 
                   4.01 
                 
                 0.0001 
                 
                   4.89 
                 
                 1.55E−06 
               
               
                 uracil 
                 
                   0.66 
                 
                 1.86E−10 
                 
                   0.63 
                 
                 1.86E−05 
                 
                   0.7 
                 
                 6.75E−05 
               
               
                 N-6-trimethyllysine 
                 
                   0.63 
                 
                 2.64E−10 
                 
                   0.67 
                 
                 0.0003 
                 
                   0.62 
                 
                 1.65E−05 
               
               
                 homostachydrine 
                 
                   1.57 
                 
                 2.82E−10 
                 
                   1.48 
                 
                 0.0002 
                 
                   1.6 
                 
                 2.57E−07 
               
               
                 xylulose 
                 
                   1.69 
                 
                 5.34E−10 
                 
                   1.41 
                 
                 0.0047 
                 
                   1.81 
                 
                 1.30E−07 
               
               
                 xylose 
                 
                   0.21 
                 
                 3.60E−09 
                 
                   0.23 
                 
                 0.0563 
                 
                   0.2 
                 
                 1.37E−07 
               
               
                 3-indoxyl sulfate 
                 
                   0.47 
                 
                 4.38E−09 
                 
                   0.69 
                 
                 0.0691 
                 
                   0.37 
                 
                 1.06E−07 
               
               
                 adenosine 
                 
                   0.65 
                 
                 6.10E−09 
                 
                   0.62 
                 
                 0.0019 
                 
                   0.69 
                 
                 2.75E−05 
               
               
                 hexanoylcarnitine 
                 
                   1.51 
                 
                 2.94E−08 
                 1.32 
                 0.1342 
                 
                   1.75 
                 
                 4.14E−09 
               
               
                 5-oxoproline 
                 
                   0.84 
                 
                 4.46E−08 
                 1.3 
                 0.1643 
                 
                   0.62 
                 
                 4.09E−13 
               
               
                 stachydrine 
                 
                   1.3 
                 
                 9.15E−08 
                 
                   1.28 
                 
                 0.0008 
                 
                   1.32 
                 
                 0.0002 
               
               
                 alanine 
                 
                   0.74 
                 
                 1.01E−07 
                 
                   0.68 
                 
                 0.0002 
                 
                   0.79 
                 
                 0.0014 
               
               
                 lactate 
                 
                   1.48 
                 
                 2.22E−07 
                 
                   1.41 
                 
                 0.0103 
                 
                   1.58 
                 
                 6.17E−06 
               
               
                 N-acetylleucine 
                 
                   2.03 
                 
                 8.18E−07 
                 1.47 
                 0.1471 
                 
                   2.44 
                 
                 3.12E−06 
               
               
                 glycerophosphorylcholine (GPC) 
                 
                   1.57 
                 
                 4.83E−06 
                 1.3 
                 0.318 
                 
                   1.84 
                 
                 2.39E−09 
               
               
                 cholate 
                 
                   0.66 
                 
                 7.93E−06 
                 0.8 
                 0.1036 
                 
                   0.57 
                 
                 3.43E−05 
               
               
                 N-acetylphenylalanine 
                 
                   0.78 
                 
                 9.93E−06 
                 
                   0.57 
                 
                 1.26E−05 
                 1.05 
                 0.1404 
               
               
                 succinate 
                 
                   1.97 
                 
                 1.11E−05 
                 1.45 
                 0.2597 
                 
                   2.31 
                 
                 5.95E−06 
               
               
                 mannose 
                 
                   2.1 
                 
                 1.60E−05 
                 1.25 
                 0.9842 
                 
                   2.56 
                 
                 9.59E−07 
               
               
                 benzoate 
                 
                   0.87 
                 
                 2.88E−05 
                 1.14 
                 0.8585 
                 
                   0.7 
                 
                 1.36E−07 
               
               
                 N-acetylasparagine 
                 
                   2.25 
                 
                 5.84E−05 
                 
                   2.11 
                 
                 0.0279 
                 
                   2.38 
                 
                 0.0017 
               
               
                 propionylcarnitine 
                 
                   0.88 
                 
                 7.81E−05 
                 
                   0.74 
                 
                 0.0007 
                 
                   0.97 
                 
                 0.0755 
               
               
                 2-hydroxyhippurate (salicylurate) 
                 
                   0.58 
                 
                 0.0002 
                 0.87 
                 0.1239 
                 
                   0.47 
                 
                 0.0014 
               
               
                 2-aminobutyrate 
                 
                   1.34 
                 
                 0.0004 
                 
                   1.46 
                 
                 0.0003 
                 
                   1.33 
                 
                 0.0404 
               
               
                 glycine 
                 
                   0.84 
                 
                 0.0006 
                 0.89 
                 0.1623 
                 
                   0.86 
                 
                 0.0186 
               
               
                 N-acetylthreonine 
                 
                   1.3 
                 
                 0.0006 
                 
                   1.41 
                 
                 0.0028 
                 
                   1.24 
                 
                 0.0253 
               
               
                 N-acetylisoleucine 
                 
                   1.29 
                 
                 0.0011 
                 1.15 
                 0.2296 
                 
                   1.35 
                 
                 0.0044 
               
               
                 glycerol 3-phosphate (G3P) 
                 
                   0.84 
                 
                 0.0012 
                 
                   0.68 
                 
                 0.028 
                 1.02 
                 0.1327 
               
               
                 allo-threonine 
                 
                   0.57 
                 
                 0.0013 
                 0.75 
                 0.322 
                 
                   0.48 
                 
                 0.001 
               
               
                 carnitine 
                 
                   1.27 
                 
                 0.0022 
                 1.17 
                 0.3274 
                 
                   1.39 
                 
                 0.0002 
               
               
                 theobromine 
                 
                   0.79 
                 
                 0.0027 
                 0.83 
                 0.2223 
                 
                   0.78 
                 
                 0.0186 
               
               
                 fucose 
                 
                   0.81 
                 
                 0.0032 
                 
                   0.87 
                 
                 0.0266 
                 0.8 
                 0.1222 
               
               
                 quinolinate 
                 
                   2.04 
                 
                 0.0042 
                 
                   2.58 
                 
                 0.0024 
                 1.9 
                 0.3388 
               
               
                 ribitol 
                 
                   1.37 
                 
                 0.0085 
                 1.58 
                 0.1303 
                 1.45 
                 0.2585 
               
               
                 azelate (nonanedioate) 
                 
                   1.16 
                 
                 0.0117 
                 1.17 
                 0.276 
                 
                   1.17 
                 
                 0.0122 
               
               
                 threonate 
                 
                   1.78 
                 
                 0.0151 
                 
                   2.92 
                 
                 0.0003 
                 1.21 
                 0.4008 
               
               
                 3-carboxy-4-methyl-5-propyl-2- 
                 
                   1.3 
                 
                 0.0164 
                 
                   1.62 
                 
                 9.06E−06 
                 1.06 
                 0.9562 
               
               
                 furanpropanoate (CMPF) 
               
               
                 5-methylthioadenosine (MTA) 
                 
                   1.67 
                 
                 0.0177 
                 
                   0.86 
                 
                 0.0367 
                 
                   2.21 
                 
                 7.90E−06 
               
               
                 glucarate (saccharate) 
                 
                   1.34 
                 
                 0.0218 
                 1.44 
                 0.3828 
                 
                   1.31 
                 
                 0.0478 
               
               
                 nicotinate 
                 
                   1.1 
                 
                 0.0485 
                 1.07 
                 0.6339 
                 
                   1.14 
                 
                 0.0091 
               
               
                 3-dehydrocarnitine 
                 
                   0.98 
                 
                 0.062 
                 0.93 
                 0.1582 
                 1.07 
                 0.8919 
               
               
                 thymine 
                 
                   0.79 
                 
                 0.0702 
                 
                   0.83 
                 
                 0.0277 
                 0.75 
                 0.5818 
               
               
                 erythronate 
                 
                   0.89 
                 
                 0.0766 
                 0.99 
                 0.7247 
                 0.89 
                 0.4353 
               
               
                 3-ureidopropionate 
                 
                   1.33 
                 
                 0.0839 
                 1.34 
                 0.1297 
                 1.36 
                 0.2074 
               
               
                 N-acetylvaline 
                 
                   0.97 
                 
                 0.0864 
                 
                   0.78 
                 
                 0.057 
                 1.06 
                 0.5605 
               
               
                 3-hydroxybutyrate (BHBA) 
                 
                   0.94 
                 
                 0.0937 
                 1.04 
                 0.698 
                 0.89 
                 0.1488 
               
               
                 gamma-glutamylleucine 
                 
                   0.94 
                 
                 0.0998 
                 
                   1.33 
                 
                 0.0031 
                 
                   0.75 
                 
                 0.0003 
               
               
                 indolelactate 
                 0.83 
                 0.1075 
                 1.17 
                 0.5598 
                 
                   0.72 
                 
                 0.0227 
               
               
                 pipecolate 
                 1.29 
                 0.1524 
                 1.11 
                 0.7949 
                 1.29 
                 0.5894 
               
               
                 alpha-hydroxyisovalerate 
                 1.1 
                 0.2137 
                 1.14 
                 0.1512 
                 1.12 
                 0.4197 
               
               
                 gamma-glutamylvaline 
                 0.98 
                 0.2204 
                 1.17 
                 0.434 
                 
                   0.86 
                 
                 0.0388 
               
               
                 ascorbate (Vitamin C) 
                 1.12 
                 0.2491 
                 0.95 
                 0.1257 
                 1.29 
                 0.418 
               
               
                 3-methyl-2-oxovalerate 
                 0.9 
                 0.2641 
                 0.85 
                 0.8026 
                 0.91 
                 0.3935 
               
               
                 beta-hydroxypyruvate 
                 1.04 
                 0.3506 
                 0.9 
                 0.1368 
                 1.1 
                 0.1346 
               
               
                 N2-acetyllysine 
                 2.31 
                 0.3516 
                 2.07 
                 0.6481 
                 2.48 
                 0.6123 
               
               
                 taurine 
                 1.08 
                 0.3532 
                 0.94 
                 0.3709 
                 1.22 
                 0.719 
               
               
                 N-acetyltyrosine 
                 1.06 
                 0.3873 
                 
                   0.82 
                 
                 0.0102 
                 1.28 
                 0.3139 
               
               
                 N-acetylglycine 
                 1.13 
                 0.4728 
                 1.01 
                 0.428 
                 1.2 
                 0.1732 
               
               
                 4-guanidinobutanoate 
                 1.2 
                 0.4889 
                 1.19 
                 0.4321 
                 1.2 
                 0.7021 
               
               
                 adenine 
                 1.57 
                 0.6044 
                 
                   0.67 
                 
                 0.0002 
                 
                   2.34 
                 
                 0.0216 
               
               
                 dimethylglycine 
                 1.07 
                 0.711 
                 0.87 
                 0.656 
                 1.2 
                 0.1971 
               
               
                 cysteine 
                 1.46 
                 0.7909 
                 1.27 
                 0.271 
                 1.69 
                 0.2777 
               
               
                 xylonate 
                 0.9 
                 0.7933 
                 1.15 
                 0.129 
                 0.83 
                 0.6313 
               
               
                   
               
             
          
         
       
     
         [0145]    The biomarkers were used to create a statistical model to classify the samples. Using Random Forest analysis, the biomarkers were used in a mathematical model to classify samples as Normal tissue or as Tumor (cancer). Samples from patient-matched kidney tumor and normal tissue from 140 subjects were used in this analysis. 
         [0146]    Random Forest results show that the samples were classified with 99% prediction accuracy. The Confusion Matrix presented in Table 5 shows the number of samples predicted for each classification and the actual in each group (Tumor or Normal). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from tumor tissue or normal tissue). The OOB error from this Random Forest was approximately 1%, and the model estimated that, when used on a new set of subjects, the identity of normal subjects could be predicted correctly 98% of the time and kidney cancer subjects could be predicted 100% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Results of Random Forest: Kidney Tumor vs. Normal 
               
             
          
           
               
                   
                   
                   
                 Predicted Group 
                 Class 
               
             
          
           
               
                   
                   
                   
                 Normal 
                 Tumor 
                 Error 
               
               
                   
                   
               
               
                   
                 Actual 
                 Normal 
                 137 
                   3 
                 0.0214 
               
               
                   
                 Group 
                 Tumor 
                   1 
                 139 
                 0.0071 
               
             
          
           
               
                   
                   
                 Predictive accuracy = 99% 
               
               
                   
                   
               
             
          
         
       
     
         [0147]    Based on the OOB Error rate of 1%, the Random Forest model that was created predicted the tumor status of a sample with about 99% accuracy based on the levels of the biomarkers measured in samples from the subject. Exemplary biomarkers for distinguishing the groups are N-acetylaspartate (NAA), maltose, N-acetyl-aspartyl-glutamate (NAAG), 1-palmitoylglycerophosphoethanolamine, phenylacetylglutamine, glucose 6-phosphate (G6P), 1-oleoylglycerophosphoethanolamine, pseudouridine, maltotriose, N6-acetyllysine, 2-oleoylglycerophosphoethanolamine, glucose, eicosenoate (20:1n9 or 1n11), fructose-6-phosphate, 1-palmitoylglycerophosphoinositol, maltotetraose, N1-methylguanosine, 2-palmitoylglycerophosphoethanolamine, dimethylarginine (ADMA+SDMA), N1-methyladenosine, pantothenate, malonylcarnitine, arachidonate (20:4n6), 1-palmitoylplasmenylethanolamine, hippurate, 1-stearoylglycerophosphoethanolamine, kynurenine, alpha-tocopherol, fructose 1-phosphate, and 1-stearoylglycerophosphoinositol. 
         [0148]    The Random Forest analysis demonstrated that by using the biomarkers, tumor samples were distinguished from Normal samples with 99% sensitivity, 98% specificity, 98% PPV and 99% NPV. 
         [0149]    The biomarkers were used to create a statistical model to classify the early stage (T1) samples. Using Random Forest analysis, the biomarkers were used in a mathematical model to classify samples as Normal or as tumor. Samples from patient-matched kidney tumor and normal tissue from 43 subjects with Stage 1 (T1) kidney cancer were used in this analysis. 
         [0150]    Random Forest results show that the samples were classified with 99% prediction accuracy. The Confusion Matrix presented in Table 6 shows the number of samples predicted for each classification and the actual in each group (T1 Tumor or T1 Normal). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from tumor tissue or normal tissue). The OOB error from this Random Forest was approximately 1%, and the model estimated that, when used on a new set of subjects, the identity of normal subjects could be predicted correctly 98% of the time and kidney cancer subjects could be predicted 100% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Results of Random Forest: Kidney T1 Tumor vs. T1 Normal 
               
             
          
           
               
                   
                   
                   
                 Predicted Group 
                 Class 
               
             
          
           
               
                   
                   
                   
                 Normal 
                 Tumor 
                 Error 
               
               
                   
                   
               
               
                   
                 Actual 
                 Normal 
                 42 
                  1 
                 0.0233 
               
               
                   
                 Group 
                 Tumor 
                  0 
                 43 
                 0      
               
             
          
           
               
                   
                   
                 Predictive accuracy = 99% 
               
               
                   
                   
               
             
          
         
       
     
         [0151]    Based on the OOB Error rate of 1%, the Random Forest model that was created predicted the tumor status of a sample with about 99% accuracy based on the levels of the biomarkers measured in samples from the subjects. Exemplary biomarkers for distinguishing the groups are N-acetylaspartate (NAA), 1-oleoyl-GPE (18:1), N-acetyl-aspartyl-glutamate (NAAG), 1-palmitoyl-GPE (16:0), maltose, 2-oleoyl-GPE (18:1), eicosenoate (20:1n9 or 1n11), 1-palmitoyl-GPI (16:0), 2-palmitoyl-GPE (16:0), 1-stearoyl-GPI (18:0), N2-methylguanosine, phenylacetylglutamine, N-acetylneuraminate, beta-alanine, malonylcarnitine, fructose 6-phosphate, gamma-glutamylglutamate, FAD, pseudouridine, 1-methylguanisine, 1-stearoyl-GPE (18:0), citrate, pantothenate (Vitamin B5), 1-palmitoylplasmenylethanolamine, arachidonate (20:4n6), N6-acetyllysine, 1-oleoyl-GPI (18:1), 2-methylbutyroylcarnitine (C5), fructose 1-phosphate, alpha-tocopherol. 
         [0152]    The Random Forest analysis demonstrated that by using the biomarkers, tumor samples were distinguished from Normal samples with 100% sensitivity, 98% specificity, 98% PPV and 100% NPV. 
         [0153]    The biomarkers were used to create a statistical model to classify the samples. Using Random Forest analysis, the biomarkers were used in a mathematical model to classify samples as Normal or as tumor. Samples from patient-matched kidney tumor and normal tissue from 80 subjects with Stage 3 (T3) kidney cancer were used in this analysis. 
         [0154]    Random Forest results show that the samples were classified with 98% prediction accuracy. The Confusion Matrix presented in Table 7 shows the number of samples predicted for each classification and the actual in each group (T3 Tumor or T3 Normal). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from tumor tissue or normal tissue). The OOB error from this Random Forest was approximately 2%, and the model estimated that, when used on a new set of subjects, the identity of normal subjects could be predicted correctly 96% of the time and kidney cancer subjects could be predicted 99% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Results of Random Forest: Kidney T3 Tumor vs. T3 Normal 
               
             
          
           
               
                   
                   
                 Predicted Group 
                 Class 
               
             
          
           
               
                   
                   
                 Normal 
                 Tumor 
                 Error 
               
               
                   
               
               
                 Actual 
                 Normal 
                 77 
                  3 
                 0.0375 
               
               
                 Group 
                 Tumor 
                  1 
                 79 
                 0.0125 
               
             
          
           
               
                   
                 Predictive accuracy = 98% 
               
               
                   
               
             
          
         
       
     
         [0155]    Based on the OOB Error rate of 2%, the Random Forest model that was created predicted the tumor status of a sample with about 98% accuracy based on the levels of the biomarkers measured in samples from the subject. Exemplary biomarkers for distinguishing the groups are maltose, N-acetylaspartate (NAA), N-acetyl-aspartyl-glutamate (NAAG), glucose 6-phosphate (G6P), maltotetraose, phenylacetylglutamine, maltotriose, pseudouridine, 1-palmitoylglycerophosphoethanolamine, N1-methylguanosine, methyl-alpha-glucopyranoside, fructose-6-phosphate, 1-oleoylglycerophosphoethanolamine, N6-acetyllysine, dimethylarginine (ADMA+SDMA), 1-palmitoylglycerophosphoinositol, hippurate, N1-methyladenosine, mannose-6-phosphate, eicosenoate (20:1n9 or 11), glucose, pantothenate, 2-oleoylglycerophosphoethanolamine, alpha-tocopherol, 2-hydroxyglutarate, 2-palmitoylglycerophosphoethanolamine, arabitol, malonylcarnitine, arachidonate (20:4n6), and ergothioneine. 
         [0156]    The Random Forest analysis demonstrated that by using the biomarkers, tumor samples were distinguished from Normal samples with 99% sensitivity, 96% specificity, 96% PPV and 99% NPV. 
       Example 4 
     Tissue Biomarkers for Staging Kidney Cancer 
       [0157]    Kidney cancer staging provides an indication of how far the kidney tumor has spread beyond the kidney. The tumor stage is used to select treatment options and to estimate a patient&#39;s prognosis. Kidney tumor stages range from T1 (tumor 7 cm or less in size and limited to kidney, least advanced) to T4 (tumor invades beyond Gerota&#39;s fascia, most advanced). 
         [0158]    To identify biomarkers of kidney cancer stage, metabolomic analysis was carried out on tissue samples from 56 subjects with Low stage RCC (T1, T2) and 84 subjects with High stage RCC (T3,T4). After the levels of metabolites were determined, the data were analyzed using Welch&#39;s two-sample t-test to identify biomarkers that differed between low stage kidney cancer compared to high stage kidney cancer. The biomarkers are listed in Table 8. 
         [0159]    Table 8 includes, for each biomarker, the biochemical name of the biomarker, the fold change (FC) of the biomarker in high stage kidney cancer compared to low stage kidney cancer (T3,T4 Tumor/T1,T2 Tumor) and the p-value determined in the statistical analysis of the data concerning the biomarkers. Columns 4 and 5 of Table 8 include the identifier for that biomarker compound in the Kyoto Encyclopedia of Genes and Genomes (KEGG), if available; and the identifier for that biomarker compound in the Human Metabolome Database (HMDB), if available. Bold values indicate a fold of change with a p-value of &lt;0.1. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Tissue Biomarkers for Kidney Cancer Staging 
               
             
          
           
               
                   
                 T3-T4-TUMOR 
                   
                   
               
               
                   
                 T1-T2-TUMOR 
                   
                   
               
             
          
           
               
                 Biochemical Name 
                 FC 
                 p-value 
                 KEGG 
                 HMDB 
               
               
                   
               
             
          
           
               
                 laurate (12:0) 
                 0.66 
                 1.78E−07 
                 C02679 
                 HMDB00638 
               
               
                 pelargonate (9:0) 
                 0.72 
                 1.16E−06 
                 C01601 
                 HMDB00847 
               
               
                 homocysteine 
                 2.45 
                 7.32E−06  
                 C00155 
                 HMDB00742 
               
               
                 arginine 
                 1.35 
                 4.62E−05 
                 C00062 
                 HMDB00517 
               
               
                 ribose 
                 1.76 
                 5.02E−05 
                 C00121 
                 HMDB00283 
               
               
                 2-ethylhexanoate 
                 0.56 
                 9.99E−05 
                   
                   
               
               
                 inositol 1-phosphate (I1P) 
                 0.61 
                 0.0004 
                   
                 HMDB00213 
               
               
                 guanosine 5′-monophosphate (5′-GMP)  
                 0.59 
                 0.0073 
                   
                   
               
               
                 4-hydroxybutyrate (GHB) 
                 2.59 
                 6.60E−06 
                 C00989 
                 HMDB00710 
               
               
                 lysylmethionine 
                 2.27 
                 9.77E−08 
                   
                   
               
               
                 glutathione, reduced (GSH) 
                 10.33 
                 4.58E−06  
                 C00051 
                 HMDB00125 
               
               
                 cytidine 5′-diphosphocholine 
                 2.03 
                 3.74E−05 
                   
                   
               
               
                 glycylisoleucine 
                 1.75 
                 4.20E−05 
                   
                   
               
               
                 isoleucyltryptophan 
                 2.98 
                 6.36E−05 
                   
                   
               
               
                 aspartylphenylalanine 
                 1.78 
                 6.91E−05 
                   
                 HMDB00706 
               
               
                 S-adenosylmethionine (SAM) 
                 1.55 
                 9.03E−05 
                   
                   
               
               
                 valerylcarnitine 
                 1.69 
                 9.85E−05 
                   
                 HMDB13128 
               
               
                 galactose 
                 1.93 
                 0.0001 
                 C01582 
                 HMDB00143 
               
               
                 glucose 1-phosphate 
                 0.51 
                 0.0001 
                 C00103 
                 HMDB01586 
               
               
                 alanylglycine 
                 1.82 
                 0.0001 
                   
                 HMDB06899 
               
               
                 alanylisoleucine 
                 2.18 
                 0.0001 
                   
                   
               
               
                 isoleucylmethionine 
                 2.66 
                 0.0001 
                   
                   
               
               
                 aspartylleucine 
                 1.79 
                 0.0001 
                   
                   
               
               
                 methionylalanine 
                 2.79 
                 0.0001 
                   
                   
               
               
                 glycylthreonine 
                 1.72 
                 0.0001 
                   
                   
               
               
                 asparagine 
                 1.6 
                 0.0002 
                 C00152 
                 HMDB00168 
               
               
                 isoleucylglycine 
                 1.62 
                 0.0002 
                   
                   
               
               
                 caprate (10:0) 
                 0.81 
                 0.0003 
                 C01571 
                 HMDB00511 
               
               
                 tryptophylasparagine 
                 2.1 
                 0.0003 
                   
                   
               
               
                 2′-deoxyinosine 
                 1.93 
                 0.0004 
                 C05512 
                 HMDB00071 
               
               
                 homoserine 
                 1.87 
                 0.0004 
                 C00263 
                 HMDB00719 
               
               
                 nicotinamide 
                 1.3 
                 0.0005 
                 C00153 
                 HMDB01406 
               
               
                 alanylglutamate 
                 1.83 
                 0.0005 
                   
                   
               
               
                 tyrosylalanine 
                 1.68 
                 0.0005 
                   
                   
               
               
                 serylisoleucine 
                 1.62 
                 0.0005 
                   
                   
               
               
                 cytosine-2′,3′-cyclic monophosphate 
                 1.72 
                 0.0006  
                 C02354 
                 HMDB11691 
               
               
                 isoleucylhistidine 
                 1.46 
                 0.0006 
                   
                   
               
               
                 aspartyltryptophan 
                 1.63 
                 0.0006 
                   
                   
               
               
                 valylglycine 
                 1.81 
                 0.0007 
                   
                   
               
               
                 xylitol 
                 1.61 
                 0.0007 
                 C00379 
                 HMDB00568 
               
               
                 prolylmethionine 
                 1.77 
                 0.0007 
                   
                   
               
               
                 myristate (14:0) 
                 0.84 
                 0.0009 
                 C06424 
                 HMDB00806 
               
               
                 butyrylcarnitine 
                 1.39 
                 0.0009 
                   
                   
               
               
                 aspartate-glutamate 
                 1.66 
                 0.0009 
                   
                   
               
               
                 phenylalanylserine 
                 1.87 
                 0.0009 
                   
                   
               
               
                 isoleucylvaline 
                 2.04 
                 0.0009 
                   
                   
               
               
                 tyrosylglycine 
                 1.38 
                 0.0009 
                   
                   
               
               
                 histidyltryptophan 
                 1.94 
                 0.0009 
                   
                   
               
               
                 lysyltyrosine 
                 3.27 
                 0.0009 
                   
                   
               
               
                 glycyltryptophan 
                 1.82 
                 0.001 
                   
                   
               
               
                 threonylmethionine 
                 1.91 
                 0.0012 
                   
                   
               
               
                 glycylvaline 
                 1.47 
                 0.0013 
                   
                   
               
               
                 leucyltryptophan 
                 1.53 
                 0.0013 
                   
                   
               
               
                 isoleucylalanine 
                 2.01 
                 0.0014 
                   
                   
               
               
                 valylglutamate 
                 1.6 
                 0.0015 
                   
                   
               
               
                 leucylserine 
                 2.01 
                 0.0023 
                   
                   
               
               
                 methionylglycine 
                 2.14 
                 0.0024 
                   
                   
               
               
                 aspartylvaline 
                 3.04 
                 0.0024 
                   
                   
               
               
                 caprylate (8:0) 
                 0.77 
                 0.0028 
                 C06423 
                 HMDB00482 
               
               
                 methionylleucine 
                 2.13 
                 0.0028 
                   
                   
               
               
                 leucylphenylalanine 
                 1.79 
                 0.0029 
                   
                   
               
               
                 isoleucylglutamate 
                 1.79 
                 0.0029 
                   
                   
               
               
                 isoleucylphenylalanine 
                 2.28 
                 0.0031 
                   
                   
               
               
                 valylphenylalanine 
                 2.26 
                 0.0031 
                   
                   
               
               
                 3-hydroxyhippurate 
                 2.45 
                 0.0032 
                   
                 HMDB06116 
               
               
                 phenylalanylalanine 
                 1.77 
                 0.0036 
                   
                   
               
               
                 valylvaline 
                 1.98 
                 0.0037 
                   
                   
               
               
                 alanylvaline 
                 1.7 
                 0.0038 
                   
                   
               
               
                 2-eicosatrienoylglycerophosphocholine 
                 2.04 
                 0.0039 
                   
                   
               
               
                 phenylalanylaspartate 
                 1.64 
                 0.0039 
                   
                   
               
               
                 2′-deoxyguanosine 
                 1.66 
                 0.0044 
                 C00330 
                 HMDB00085 
               
               
                 tyrosylvaline 
                 1.61 
                 0.0044 
                   
                   
               
               
                 mannose-6-phosphate 
                 1.33 
                 0.0045  
                 C00275 
                 HMDB01078 
               
               
                 methionylasparagine 
                 1.63 
                 0.0046 
                   
                   
               
               
                 tryptophylglutamate 
                 1.42 
                 0.0047 
                   
                   
               
               
                 glycylleucine 
                 1.39 
                 0.0048 
                 C02155 
                 HMDB00759 
               
               
                 alanylphenylalanine 
                 2.21 
                 0.0048 
                   
                   
               
               
                 caproate (6:0) 
                 0.83 
                 0.0053 
                 C01585 
                 HMDB00535 
               
               
                 lysylleucine 
                 1.7 
                 0.0054 
                   
                   
               
               
                 valyltyrosine 
                 1.9 
                 0.0059 
                   
                   
               
               
                 2-arachidonoylglycerophosphoethanolamine 
                 1.28 
                 0.0068 
                   
                   
               
               
                 serylleucine 
                 1.92 
                 0.0068 
                   
                   
               
               
                 valylalanine 
                 1.83 
                 0.0068 
                   
                   
               
               
                 histidyltyrosine 
                 1.46 
                 0.0073 
                   
                   
               
               
                 agmatine 
                 2.06 
                 0.0074 
                 C00179 
                 HMDB01432 
               
               
                 phenylalanylglutamate 
                 2.13 
                 0.0076 
                   
                   
               
               
                 alanylleucine 
                 2.25 
                 0.0077 
                   
                   
               
               
                 N-acetylmethionine 
                 1.4 
                 0.0079 
                 C02712 
                 HMDB11745 
               
               
                 citrulline 
                 0.8 
                 0.0079 
                 C00327 
                 HMDB00904 
               
               
                 valylaspartate 
                 1.72 
                 0.0079 
                   
                   
               
               
                 valylasparagine 
                 2.13 
                 0.0079 
                 C00252 
                 HMDB02923 
               
               
                 tyrosylleucine 
                 1.79 
                 0.0086 
                   
                   
               
               
                 cysteinylglycine 
                 4.01 
                 0.0089 
                 C01419 
                 HMDB00078 
               
               
                 valylmethionine 
                 2.26 
                 0.009 
                   
                   
               
               
                 phenylalanylglycine 
                 1.94 
                 0.0092 
                   
                   
               
               
                 spermidine 
                 1.26 
                 0.0097 
                 C00315 
                 HMDB01257 
               
               
                 phenylalanylvaline 
                 1.74 
                 0.0099 
                   
                   
               
               
                 threonylphenylalanine 
                 1.73 
                 0.01 
                   
                   
               
               
                 leucyltyrosine 
                 1.57 
                 0.0102 
                   
                   
               
               
                 N-acetylglucosamine 6-phosphate 
                 1.35 
                 0.0103 
                 C00357 
                 HMDB02817 
               
               
                 phenylalanyltyrosine 
                 1.54 
                 0.0116 
                   
                   
               
               
                 histidylleucine 
                 1.46 
                 0.0117 
                   
                   
               
               
                 glycylmethionine 
                 1.56 
                 0.0118 
                   
                   
               
               
                 leucylmethionine 
                 1.81 
                 0.0127 
                   
                   
               
               
                 valylhistidine 
                 1.92 
                 0.0128 
                   
                   
               
               
                 3′-dephosphocoenzyme A 
                 1.41 
                 0.013 
                 C00882 
                 HMDB01373 
               
               
                 leucylglycine 
                 2.19 
                 0.013 
                   
                   
               
               
                 2-palmitoleoylglycerophosphocholine 
                 1.42 
                 0.0131 
                   
                   
               
               
                 isoleucylarginine 
                 1.31 
                 0.0131 
                   
                   
               
               
                 gamma-glutamylcysteine 
                 1.32 
                 0.0132 
                 C00669 
                 HMDB01049 
               
               
                 valylisoleucine 
                 1.91 
                 0.0133 
                   
                   
               
               
                 valyllysine 
                 1.9 
                 0.0142 
                   
                   
               
               
                 serylvaline 
                 1.49 
                 0.0144 
                   
                   
               
               
                 isoleucyltyrosine 
                 1.81 
                 0.0147 
                   
                   
               
               
                 threonylglutamate 
                 1.64 
                 0.0151 
                   
                   
               
               
                 uridine monophosphate (5′ or 3′) 
                 0.7 
                 0.0154 
                   
                   
               
               
                 glycyltyrosine 
                 1.31 
                 0.0155 
                   
                   
               
               
                 dihydrocholesterol 
                 1.17 
                 0.0157 
                   
                 HMDB00908 
               
               
                 3-(4-hydroxyphenyl)lactate 
                 1.42 
                 0.0164 
                 C03672 
                 HMDB00755 
               
               
                 histidylmethionine 
                 1.65 
                 0.0169 
                   
                   
               
               
                 phosphate 
                 1.22 
                 0.0175 
                 C00009 
                 HMDB01429 
               
               
                 alpha-glutamyltyrosine 
                 1.55 
                 0.0175 
                   
                   
               
               
                 histidylphenylalanine 
                 1.55 
                 0.0182 
                   
                   
               
               
                 leucylglutamate 
                 1.86 
                 0.0183 
                   
                   
               
               
                 valylglutamine 
                 1.69 
                 0.0191 
                   
                   
               
               
                 glycylphenylalanine 
                 1.52 
                 0.0202 
                   
                   
               
               
                 1,3-dihydroxyacetone 
                 1.39 
                 0.0203 
                 C00184 
                 HMDB01882 
               
               
                 alanylthreonine 
                 1.48 
                 0.0203 
                   
                   
               
               
                 leucylarginine 
                 1.51 
                 0.021 
                   
                   
               
               
                 putrescine 
                 1.17 
                 0.0211 
                 C00134 
                 HMDB01414 
               
               
                 cytidine 
                 1.35 
                 0.0214 
                 C00475 
                 HMDB00089 
               
               
                 trans-4-hydroxyproline 
                 2.46 
                 0.0214 
                 C01157 
                 HMDB00725 
               
               
                 tyrosylglutamine 
                 1.44 
                 0.0215 
                   
                   
               
               
                 glucose-6-phosphate (G6P) 
                 1.29 
                 0.0217 
                 C00668 
                 HMDB01401 
               
               
                 2-oleoylglycerophosphoserine 
                 1.13 
                 0.0248 
                   
                   
               
               
                 alpha-glutamyltryptophan 
                 1.68 
                 0.0248 
                   
                   
               
               
                 testosterone 
                 0.8 
                 0.0249 
                 C00535 
                 HMDB00234 
               
               
                 1-heptadecanoylglycerophosphoethanolamine 
                 1.93 
                 0.0252 
                   
                   
               
               
                 leucylalanine 
                 1.81 
                 0.0252 
                   
                   
               
               
                 VGAHAGEYGAEALER 
                 0.92 
                 0.0253 
                   
                   
               
               
                 adenosine 2′-monophosphate (2′-AMP) 
                 1.22 
                 0.0257 
                 C00946 
                 HMDB11617 
               
               
                 valylserine 
                 1.98 
                 0.0261 
                   
                   
               
               
                 cystine 
                 0.86 
                 0.0264 
                 C00491 
                 HMDB00192 
               
               
                 arginylleucine 
                 1.76 
                 0.0264 
                   
                   
               
               
                 bilirubin (E,E) 
                 0.7 
                 0.0268 
                   
                   
               
               
                 myristoleate (14:1n5) 
                 0.89 
                 0.0275 
                 C08322 
                 HMDB02000 
               
               
                 threonylleucine 
                 1.71 
                 0.0285 
                   
                   
               
               
                 phenylalanylarginine 
                 1.97 
                 0.0291 
                   
                   
               
               
                 guanine 
                 0.54 
                 0.0294 
                 C00242 
                 HMDB00132 
               
               
                 isoleucylserine 
                 1.8 
                 0.0299 
                   
                   
               
               
                 Isobar: fructose 1,6-diphosphate, glucose 1,6- 
                 0.73 
                 0.0314 
                   
                   
               
               
                 diphosphate, myo-inositol 1,4 or 
                   
                   
                   
                   
               
               
                 1,3-diphosphate 
                   
                   
                   
                   
               
               
                 leucylleucine 
                 1.62 
                 0.032 
                 C11332 
                   
               
               
                 phenylalanylproline 
                 1.55 
                 0.0323 
                   
                   
               
               
                 2-linoleoylglycerophosphocholine 
                 1.4 
                 0.0333 
                   
                   
               
               
                 16-hydroxypalmitate 
                 0.86 
                 0.0336 
                 C18218 
                   
               
               
                 lysyllysine 
                 1.31 
                 0.0347 
                   
                   
               
               
                 N-acetylalanine 
                 1.19 
                 0.0365 
                 C02847 
                 HMDB00766 
               
               
                 phenylalanyltryptophan 
                 1.36 
                 0.0376 
                   
                   
               
               
                 7-alpha-hydroxy-3-oxo-4-cholestenoate  
                 1.65 
                 0.038 
                 C17337 
                 HMDB12458 
               
               
                 (7-Hoca) 
                   
                   
                   
                   
               
               
                 arginylvaline 
                 1.25 
                 0.038 
                   
                   
               
               
                 alanylmethionine 
                 1.89 
                 0.0387 
                   
                   
               
               
                 valyltryptophan 
                 1.7 
                 0.0388 
                   
                   
               
               
                 6′-sialyllactose 
                 1.49 
                 0.039 
                 G00265 
                 HMDB06569 
               
               
                 threonylvaline 
                 1.66 
                 0.0406 
                   
                   
               
               
                 serylphenyalanine 
                 1.55 
                 0.0408 
                   
                   
               
               
                 2-arachidonoylglycerophosphocholine 
                 1.56 
                 0.0411 
                   
                   
               
               
                 bilirubin (Z,Z) 
                 0.59 
                 0.0419 
                 C00486 
                 HMDB00054 
               
               
                 ribulose 
                 1.32 
                 0.042 
                 C00309 
                 HMDB00621 
               
               
                   
                   
                   
                   
                 HMDB03371 
               
               
                 alanylalanine 
                 1.27 
                 0.0423 
                 C00993 
                 HMDB03459 
               
               
                 heme 
                 0.64 
                 0.0424 
                   
                   
               
               
                 valylleucine 
                 2.26 
                 0.0428 
                   
                   
               
               
                 2′-deoxyadenosine 3′-monophosphate 
                 1.36 
                 0.0436 
                   
                   
               
               
                 2-palmitoylglycerol (2-monopalmitin) 
                 1.21 
                 0.0462 
                   
                   
               
               
                 dihomo-linolenate (20:3n3 or n6) 
                 1.27 
                 0.0462 
                 C03242 
                 HMDB02925 
               
               
                 ophthalmate 
                 1.42 
                 0.0464 
                   
                 HMDB05765 
               
               
                 3-hydroxyoctanoate 
                 1.18 
                 0.049 
                   
                 HMDB01954 
               
               
                 leucylasparagine 
                 1.59 
                 0.0517 
                   
                   
               
               
                 arginylmethionine 
                 1.44 
                 0.0519 
                   
                   
               
               
                 2-docosapentaenoylglycerophosphocholine 
                 1.44 
                 0.0532 
                   
                   
               
               
                 deoxycarnitine 
                 1.15 
                 0.0544 
                 C01181 
                 HMDB01161 
               
               
                 docosatrienoate (22:3n3) 
                 1.34 
                 0.0566 
                 C16534 
                 HMDB02823 
               
               
                 2-hydroxypalmitate 
                 1.67 
                 0.0595 
                   
                   
               
               
                 sedoheptulose-7-phosphate 
                 1.25 
                 0.0636 
                 C05382 
                 HMDB01068 
               
               
                 1,2-propanediol 
                 1.22 
                 0.0637 
                 C00583 
                 HMDB01881 
               
               
                 glutathione, oxidized (GSSG) 
                 2.04 
                 0.0688 
                 C00127 
                 HMDB03337 
               
               
                 urea 
                 1.26 
                 0.0728 
                 C00086 
                 HMDB00294 
               
               
                 alanyltyrosine 
                 1.45 
                 0.074 
                   
                   
               
               
                 glycylglycine 
                 1.44 
                 0.0789 
                 C02037 
                 HMDB11733 
               
               
                 N-acetylserine 
                 1.27 
                 0.0838 
                   
                 HMDB02931 
               
               
                 arginyltyrosine 
                 1.4 
                 0.0923 
                   
                   
               
               
                 maltohexaose 
                 0.75 
                 0.0928 
                 C01936 
                 HMDB12253 
               
               
                 phenylalanylleucine 
                 1.66 
                 0.0928 
                   
                   
               
               
                 arabonate 
                 1.31 
                 0.0929 
                   
                 HMDB00539 
               
               
                 thymidine 
                 1.16 
                 0.0931 
                 C00214 
                 HMDB00273 
               
               
                 alpha-glutamylglutamate 
                 1.61 
                 0.0934 
                 C01425 
                   
               
               
                 gamma-glutamylglutamate 
                 0.76 
                 0.0951 
                   
                   
               
               
                 tyrosyllysine 
                 2.17 
                 0.0973 
                   
                   
               
               
                 2-docosapentaenoylglycerophosphoethanolamine 
                 0.78 
                 0.1003 
                   
                   
               
               
                 2-linoleoylglycerophosphoethanolamine 
                 1.2 
                 0.1008 
                   
                   
               
               
                 N-acetylornithine 
                 0.94 
                 0.1037 
                 C00437 
                 HMDB03357 
               
               
                 6-phosphogluconate 
                 1.46 
                 0.1065 
                 C00345 
                 HMDB01316 
               
               
                 fructose-6-phosphate 
                 1.17 
                 0.1075 
                 C05345 
                 HMDB00124 
               
               
                 tyrosyltyrosine 
                 1.39 
                 0.1082 
                   
                   
               
               
                 phosphoethanolamine 
                 1.14 
                 0.1088 
                 C00346 
                 HMDB00224 
               
               
                 arginylphenylalanine 
                 1.5 
                 0.1107 
                   
                   
               
               
                 2-oleoylglycerophosphocholine 
                 1.51 
                 0.1137 
                   
                   
               
               
                 maltotetraose 
                 0.69 
                 0.1147 
                 C02052 
                 HMDB01296 
               
               
                 4-hydroxyglutamate 
                 1.66 
                 0.1166 
                 C03079 
                 HMDB01344 
               
               
                 N-acetyltryptophan 
                 2.91 
                 0.1178 
                 C03137 
                   
               
               
                 spermine 
                 2.08 
                 0.1336 
                 C00750 
                 HMDB01256 
               
               
                 dodecanedioate 
                 0.83 
                 0.1358 
                 C02678 
                 HMDB00623 
               
               
                 2-stearoylglycerophosphoethanolamine 
                 1.13 
                 0.1375 
                   
                   
               
               
                 gamma-tocopherol 
                 0.8 
                 0.1403 
                 C02483 
                 HMDB01492 
               
               
                 phenylalanylphenylalanine 
                 1.49 
                 0.1446 
                   
                   
               
               
                 methionylglutamate 
                 1.39 
                 0.1564 
                   
                   
               
               
                 choline phosphate 
                 0.9 
                 0.1585 
                   
                   
               
               
                 2-oleoylglycerol (2-monoolein) 
                 1.24 
                 0.164 
                   
                   
               
               
                 tyrosylhistidine 
                 1.38 
                 0.1653 
                   
                   
               
               
                 7-alpha-hydroxycholesterol 
                 1.75 
                 0.167 
                 C03594 
                 HMDB01496 
               
               
                 methionylaspartate 
                 1.56 
                 0.1679 
                   
                   
               
               
                 1-palmitoleoylglycerophosphocholine 
                 1.33 
                 0.1718 
                   
                   
               
               
                 adrenate (22:4n6) 
                 1.12 
                 0.1861 
                 C16527 
                 HMDB02226 
               
               
                 pyridoxal 
                 1.14 
                 0.1869 
                 C00250 
                 HMDB01545 
               
               
                 1-stearoylglycerophosphoinositol 
                 1.28 
                 0.1869 
                   
                   
               
               
                 1-oleoylglycerophosphocholine 
                 1.4 
                 0.1898 
                   
                   
               
               
                 beta-tocopherol 
                 0.79 
                 0.1941 
                 C14152 
                 HMDB06335 
               
               
                 tryptophylleucine 
                 1.38 
                 0.2027 
                   
                   
               
               
                 isoleucylisoleucine 
                 1.51 
                 0.2093 
                   
                   
               
               
                 1-palmitoylglycerophosphoinositol 
                 1.14 
                 0.2119 
                   
                   
               
               
                 uridine 
                 1.1 
                 0.2138 
                 C00299 
                 HMDB00296 
               
               
                 15-methylpalmitate (isobar with 2- 
                 0.93 
                 0.2288 
                   
                   
               
               
                 methylpalmitate) 
                   
                   
                   
                   
               
               
                 tyrosylphenylalanine 
                 1.12 
                 0.2336 
                   
                   
               
               
                 N-methylglutamate 
                 1.81 
                 0.2357 
                 C01046 
                   
               
               
                 leucylhistidine 
                 1.37 
                 0.2423 
                   
                   
               
               
                 cytidine-3′-monophosphate (3′-CMP) 
                 1.19 
                 0.2435 
                 C05822 
                   
               
               
                 maltotriose 
                 0.85 
                 0.2474 
                 C01835 
                 HMDB01262 
               
               
                 1-arachidonoylglycerophosphocholine 
                 1.3 
                 0.2594 
                 C05208 
                   
               
               
                 linolenate [alpha or gamma; (18:3n3 or 6)] 
                 0.91 
                 0.2599 
                 C06427 
                 HMDB01388 
               
               
                 2-docosahexaenoylglycerophosphoethanolamine 
                 0.8 
                 0.2601 
                   
                   
               
               
                 nicotinamide ribonucleotide (NMN) 
                 0.86 
                 0.265 
                 C00455 
                 HMDB00229 
               
               
                 dihomo-linoleate (20:2n6) 
                 1.07 
                 0.2651 
                 C16525 
                   
               
               
                 stearate (18:0) 
                 0.94 
                 0.269 
                 C01530 
                 HMDB00827 
               
               
                 linoleate (18:2n6) 
                 0.92 
                 0.2714 
                 C01595 
                 HMDB00673 
               
               
                 pyrophosphate (PPi) 
                 0.86 
                 0.2716 
                 C00013 
                 HMDB00250 
               
               
                 1-stearoylglycerol (1-monostearin) 
                 0.89 
                 0.273 
                 D01947 
                   
               
               
                 flavin adenine dinucleotide (FAD) 
                 1.1 
                 0.2752 
                 C00016 
                 HMDB01248 
               
               
                 13-HODE +9-HODE 
                 0.73 
                 0.2837 
                   
                   
               
               
                 adenosine 3′-monophosphate (3′-AMP) 
                 1.21 
                 0.284 
                 C01367 
                 HMDB03540 
               
               
                 3-phosphoglycerate 
                 0.97 
                 0.2876 
                 C00597 
                 HMDB00807 
               
               
                 erucate (22:1n9) 
                 0.86 
                 0.293 
                 C08316 
                 HMDB02068 
               
               
                 cytidine 5′-monophosphate (5′-CMP) 
                 1.14 
                 0.2937 
                 C00055  
                 HMDB00095 
               
               
                 S-methylcysteine 
                 1.13 
                 0.3022 
                   
                 HMDB02108 
               
               
                 glycerate 
                 1.17 
                 0.3074 
                 C00258  
                 HMDB00139 
               
               
                 oleoylcarnitine 
                 1.04 
                 0.3201 
                   
                 HMDB05065 
               
               
                 5-methyluridine (ribothymidine) 
                 1.01 
                 0.3202 
                   
                 HMDB00884 
               
               
                 1-myristoylglycerophosphoethanolamine 
                 1 
                 0.3202 
                   
                 HMDB11500 
               
               
                 methionylphenylalanine 
                 0.97 
                 0.3209 
                   
                   
               
               
                 adenosine 5′-monophosphate (AMP) 
                 0.85 
                 0.3289 
                 C00020 
                 HMDB00045 
               
               
                 2-oleoylglycerophosphoethanolamine 
                 1.19 
                 0.335 
                   
                   
               
               
                 glycerol 2-phosphate 
                 1.17 
                 0.3378 
                 C02979  
                 HMDB02520 
               
               
                 2′-deoxycytidine 3′-monophosphate 
                 1.32 
                 0.3429 
                   
                   
               
               
                 ethanolamine 
                 1.12 
                 0.3446 
                 C00189  
                 HMDB00149 
               
               
                 undecanedioate 
                 1.05 
                 0.3449 
                   
                 HMDB00888 
               
               
                 phenylalanylmethionine 
                 1.41 
                 0.3499 
                   
                   
               
               
                 prolylglycine 
                 1.22 
                 0.3521 
                   
                   
               
               
                 methyl-alpha-glucopyranoside 
                 0.92 
                 0.359 
                 C02603 
                   
               
               
                 1-myristoylglycerophosphocho line 
                 1.27 
                 0.3722 
                   
                 HMDB10379 
               
               
                 ergothioneine 
                 1.11 
                 0.3762 
                 C05570  
                 HMDB03045 
               
               
                 arachidate (20:0) 
                 0.95 
                 0.3782 
                 C06425  
                 HMDB02212 
               
               
                 2-palmitoylglycerophosphocholine 
                 1.28 
                 0.3785 
                   
                   
               
               
                 2-linoleoylglycerol (2-monolinolein) 
                 0.91 
                 0.3788 
                   
                 HMDB11538 
               
               
                 palmitate (16:0) 
                 0.95 
                 0.3812 
                 C00249  
                 HMDB00220 
               
               
                 methylphosphate 
                 0.97 
                 0.3818 
                   
                   
               
               
                 margarate (17:0) 
                 0.94 
                 0.3828 
                   
                 HMDB02259 
               
               
                 alanyltryptophan 
                 0.99 
                 0.3891 
                   
                   
               
               
                 Ac-Ser-Asp-Lys-Pro-OH 
                 1.02 
                 0.3919 
                   
                   
               
               
                 glycyllysine 
                 1.43 
                 0.3928 
                   
                   
               
               
                 valylarginine 
                 1.02 
                 0.4048 
                   
                   
               
               
                 3,4-dihydroxyphenethyleneglycol 
                 1.07 
                 0.4052 
                 C05576  
                 HMDB00318 
               
               
                 5-oxoETE 
                 0.88 
                 0.4116 
                 C14732  
                 HMDB10217 
               
               
                 docosapentaenoate (n6 DPA; 22:5n6) 
                 1.16 
                 0.4121 
                 C06429  
                 HMDB13123 
               
               
                 5-HETE 
                 0.8 
                 0.4208 
                   
                   
               
               
                 stearoylcarnitine 
                 1.33 
                 0.4226 
                   
                 HMDB00848 
               
               
                 cholesterol 
                 1.08 
                 0.4227 
                 C00187  
                 HMDB00067 
               
               
                 1-pentadecanoylglycerophosphocholine 
                 1.28 
                 0.4281 
                   
                   
               
               
                 glycerophosphoethanolamine 
                 1.41 
                 0.4285 
                 C01233  
                 HMDB00114 
               
               
                 1-oleoylglycerophosphoethanolamine 
                 1.27 
                 0.4334 
                   
                 HMDB11506 
               
               
                 1-linoleoylglycerophosphocholine 
                 1.15 
                 0.4349 
                 C04100 
                   
               
               
                 1-palmitoylplasmenylethanolamine 
                 1.06 
                 0.4451 
                   
                   
               
               
                 imidazole propionate 
                 1.48 
                 0.4462 
                   
                 HMDB02271 
               
               
                 maltopentaose 
                 0.77 
                 0.4504 
                 C06218  
                 HMDB12254 
               
               
                 triethyleneglycol 
                 1.09 
                 0.4541 
                   
                   
               
               
                 1-palmitoylglycerophosphocholine 
                 1.03 
                 0.4648 
                   
                   
               
               
                 Isobar: ribulose 5-phosphate, xylulose  
                 1.08 
                 0.4651 
                   
                   
               
               
                 5-phosphate 
                   
                   
                   
                   
               
               
                 1-stearoylglycerophosphoethanolamine 
                 1.09 
                 0.4718 
                   
                 HMDB11130 
               
               
                 inosine 
                 1.04 
                 0.4725 
                   
                   
               
               
                 nicotinamide adenine dinucleotide reduced 
                 0.88 
                 0.4747 
                 C00004 
                 HMDB01487 
               
               
                 (NADH) 
                   
                   
                   
                   
               
               
                 sphinganine 
                 1.17 
                 0.4777 
                 C00836 
                 HMDB00269 
               
               
                 phytosphingosine 
                 1.15 
                 0.4789 
                 C12144 
                 HMDB04610 
               
               
                 cysteine-glutathione disulfide 
                 1.61 
                 0.4798 
                   
                 HMDB00656 
               
               
                 alpha-tocopherol 
                 0.92 
                 0.4869 
                 C02477 
                 HMDB01893 
               
               
                 cis-vaccenate (18:1n7) 
                 0.98 
                 0.4893 
                 C08367 
                   
               
               
                 arabitol 
                 1.17 
                 0.4953 
                 C00474 
                 HMDB01851 
               
               
                 palmitoleate (16:1n7) 
                 0.93 
                 0.5007 
                 C08362 
                 HMDB03229 
               
               
                 1-arachidonoylglycerophosphoinositol 
                 0.99 
                 0.5024 
                   
                   
               
               
                 betaine 
                 0.93 
                 0.5137 
                   
                 HMDB00043 
               
               
                 palmitoylcarnitine 
                 1.08 
                 0.5141 
                   
                   
               
               
                 7-beta-hydroxycholesterol 
                 1.3 
                 0.5168 
                 C03594 
                 HMDB06119 
               
               
                 stearidonate (18:4n3) 
                 0.95 
                 0.5205 
                 C16300 
                 HMDB06547 
               
               
                 argininosuccinate 
                 1.31 
                 0.5259 
                 C03406 
                 HMDB00052 
               
               
                 1-arachidonoylglycerophosphoethanolamine  
                 1.02 
                 0.5265 
                   
                 HMDB11517 
               
               
                 docosadienoate (22:2n6) 
                 0.99 
                 0.5352 
                 C16533 
                   
               
               
                 ornithine 
                 1.32 
                 0.5601 
                 C00077 
                 HMDB03374 
               
               
                 glutamate, gamma-methyl ester 
                 1.12 
                 0.5676 
                   
                   
               
               
                 cinnamoylglycine 
                 0.99 
                 0.5701 
                   
                   
               
               
                 adenylosuccinate 
                 0.87 
                 0.5734 
                 C03794 
                 HMDB00536 
               
               
                 2-myristoylglycerophosphocholine 
                 1 
                 0.5844 
                   
                   
               
               
                 arachidonate (20:4n6) 
                 0.98 
                 0.5993 
                 C00219 
                 HMDB01043 
               
               
                 2-palmitoylglycerophosphoethanolamine 
                 1.24 
                 0.6045 
                   
                   
               
               
                 1-stearoylglycerophosphocholine 
                 1.15 
                 0.6215 
                   
                   
               
               
                 1-palmitoleoylglycerophosphoethanolamine 
                 0.97 
                 0.6247 
                   
                   
               
               
                 5-methyltetrahydrofolate (5MeTHF) 
                 0.99 
                 0.6345 
                 C00440 
                 HMDB01396 
               
               
                 2-phosphoglycerate 
                 1.04 
                 0.6516 
                 C00631 
                 HMDB03391 
               
               
                 gamma-glutamylglutamine 
                 1.53 
                 0.6572 
                   
                 HMDB11738 
               
               
                 N1-Methyl-2-pyridone-5-carboxamide 
                 1.04 
                 0.6632 
                 C05842 
                 HMDB04193 
               
               
                 saccharopine 
                 1.34 
                 0.664 
                 C00449 
                 HMDB00279 
               
               
                 1-arachidonylglycerol 
                 0.96 
                 0.6669 
                 C13857 
                 HMDB11572 
               
               
                 phosphoenolpyruvate (PEP) 
                 1.1 
                 0.6688 
                 C00074 
                 HMDB00263 
               
               
                 6-keto prostaglandin Flalpha 
                 1.25 
                 0.6797 
                 C05961 
                 HMDB02886 
               
               
                 1-docosahexaenoylglycerophosphocholine 
                 1.07 
                 0.6855 
                   
                   
               
               
                 nicotinamide adenine dinucleotide (NAD+)  
                 1.29 
                 0.6861 
                 C00003 
                 HMDB00902 
               
               
                 maltose 
                 1.06 
                 0.691 
                 C00208 
                 HMDB00163 
               
               
                 pentadecanoate (15:0) 
                 1 
                 0.6963 
                 C16537 
                 HMDB00826 
               
               
                 oleate (18:1n9) 
                 0.9 
                 0.7 
                 C00712 
                 HMDB00207 
               
               
                 2-docosahexaenoylglycerophosphocholine 
                 1.08 
                 0.7031 
                   
                   
               
               
                 palmitoyl sphingomyelin 
                 0.97 
                 0.7068 
                   
                   
               
               
                 eicosenoate (20:1n9 or 11) 
                 0.91 
                 0.7232 
                   
                 HMDB02231 
               
               
                 piperine 
                 0.95 
                 0.7288 
                 C03882 
                   
               
               
                 nervonate (24:1n9) 
                 0.98 
                 0.7451 
                 C08323 
                 HMDB02368 
               
               
                 hypotaurine 
                 1.01 
                 0.7604 
                 C00519 
                 HMDB00965 
               
               
                 1-palmitoylglycerophosphoethanolamine 
                 1.19 
                 0.7781 
                   
                 HMDB11503 
               
               
                 sphingosine 
                 1.28 
                 0.7939 
                 C00319 
                 HMDB00252 
               
               
                 1-oleoylglycerol (1-monoolein) 
                 1.03 
                 0.7969 
                   
                 HMDB11567 
               
               
                 prostaglandin A2 
                 1.07 
                 0.7971 
                 C05953 
                 HMDB02752 
               
               
                 1-oleoylglycerophosphoserine 
                 1.03 
                 0.8021 
                   
                   
               
               
                 fructose 1-phosphate 
                 0.83 
                 0.8127 
                 C01094 
                 HMDB01076 
               
               
                 1-linoleoylglycerophosphoethanolamine 
                 0.99 
                 0.8379 
                   
                 HMDB11507 
               
               
                 prostaglandin E2 
                 1.43 
                 0.8423 
                 C00584 
                 HMDB01220 
               
               
                 1-palmitoylglycerol (1-monopalmitin) 
                 0.94 
                 0.8438 
                   
                   
               
               
                 N-acetylglucosamine 
                 1.36 
                 0.8453 
                 C00140 
                 HMDB00215 
               
               
                 sorbitol 6-phosphate 
                 0.92 
                 0.8477 
                 C01096 
                 HMDB05831 
               
               
                 1-heptadecanoylglycerophosphocholine 
                 1.12 
                 0.8515 
                   
                 HMDB12108 
               
               
                 pregnanediol-3-glucuronide 
                 1 
                 0.856 
                   
                   
               
               
                 guanosine 
                 1 
                 0.8626 
                 C00387 
                 HMDB00133 
               
               
                 3-hydroxydecanoate 
                 1.02 
                 0.863 
                   
                 HMDB02203 
               
               
                 10-heptadecenoate (17:1n7) 
                 0.98 
                 0.8818 
                   
                   
               
               
                 laurylcarnitine 
                 1.07 
                 0.8844 
                   
                 HMDB02250 
               
               
                 myristoylcarnitine 
                 1.06 
                 0.8978 
                   
                   
               
               
                 squalene 
                 0.88 
                 0.9086 
                 C00751 
                 HMDB00256 
               
               
                 cortisol 
                 0.92 
                 0.9148 
                 C00735 
                 HMDB00063 
               
               
                 1-oleoylglycerophosphoinositol 
                 1.02 
                 0.9196 
                   
                   
               
               
                 docosapentaenoate (n3 DPA; 22:5n3) 
                 0.93 
                 0.922 
                 C16513 
                 HMDB01976 
               
               
                 2-stearoylglycerophosphocholine 
                 1.13 
                 0.9348 
                   
                   
               
               
                 histamine 
                 1.08 
                 0.9451 
                 C00388 
                 HMDB00870 
               
               
                 nicotinamide riboside 
                 1.07 
                 0.9464 
                   
                   
               
               
                 L-urobilin 
                 1.04 
                 0.9504 
                 C05793 
                 HMDB04159 
               
               
                 1-linoleoylglycerol (1-monolinolein) 
                 1.02 
                 0.9733 
                   
                   
               
               
                 docosahexaenoate (DHA; 22:6n3) 
                 0.99 
                 0.9812 
                 C06429 
                 HMDB02183 
               
               
                 10-nonadecenoate (19:1n9) 
                 0.95 
                 0.9859 
                   
                   
               
               
                 eicosapentaenoate (EPA; 20:5n3) 
                 0.92 
                 0.9922 
                 C06428 
                 HMDB01999 
               
               
                 2-hydroxyglutarate 
                 1.36 
                 0.0009 
                 C02630 
                 HMDB00606 
               
               
                 succinylcarnitine 
                 1.62 
                 0.0017 
                   
                   
               
               
                 malonylcarnitine 
                 1.35 
                 0.0101 
                   
                 HMDB02095 
               
               
                 glycerol 
                 1.27 
                 0.0272 
                 C00116 
                 HMDB00131 
               
               
                 glutarate (pentanedioate) 
                 1.54 
                 0.0403 
                 C00489 
                 HMDB00661 
               
               
                 glycocholenate sulfate 
                 1.04 
                 0.0433 
                   
                   
               
               
                 C-glycosyltryptophan 
                 1.12 
                 0.0734 
                   
                   
               
               
                 3-methylglutarylcarnitine (C6) 
                 0.15 
                 0.0823 
                   
                 HMDB00552 
               
               
                 pregnen-diol disulfate 
                 1.28 
                 0.0989 
                 C05484 
                 HMDB04025 
               
               
                 4-androsten-3beta,17beta-diol disulfate 1 
                 1.32 
                 0.1059 
                   
                 HMDB03818 
               
               
                 2-hydroxybutyrate (AHB) 
                 0.91 
                 0.1272 
                 C05984 
                 HMDB00008 
               
               
                 creatinine 
                 1.18 
                 0.2356 
                 C00791 
                 HMDB00562 
               
               
                 chiro-inositol 
                 1.46 
                 0.298 
                   
                   
               
               
                 tryptophan betaine 
                 1.39 
                 0.3182 
                 C09213 
                   
               
               
                 1,5-anhydroglucitol (1,5-AG) 
                 0.91 
                 0.3416 
                 C07326 
                 HMDB02712 
               
               
                 4-hydroxyhippurate 
                 0.75 
                 0.591 
                   
                   
               
               
                 4-methyl-2-oxopentanoate 
                 1.12 
                 0.6942 
                 C00233 
                 HMDB00695 
               
               
                 glycolithocholate sulfate 
                 1.02 
                 0.9038 
                 C11301 
                 HMDB02639 
               
               
                 N-acetylneuraminate 
                 1.02 
                 0.9189 
                 C00270 
                 HMDB00230 
               
               
                 isoleucine 
                 1.43 
                 3.31E−07 
                 C00407 
                 HMDB00172 
               
               
                 choline 
                 0.62 
                 4.64E−07 
                   
                   
               
               
                 tyrosine 
                 1.41 
                 1.32E−06 
                 C00082  
                 HMDB00158 
               
               
                 gamma-glutamylleucine 
                 0.65 
                 1.70E-06 
                   
                 HMDB11171 
               
               
                 benzoate 
                 0.57 
                 1.90E−06 
                 C00180 
                 HMDB01870 
               
               
                 xanthine 
                 1.34 
                 3.64E−06 
                 C00385 
                 HMDB00292 
               
               
                 5-methylthioadenosine (MTA) 
                 2.14 
                 4.97E−06 
                 C00170  
                 HMDB01173 
               
               
                 N2-methylguanosine 
                 1.91 
                 5.19E−06 
                   
                 HMDB05862 
               
               
                 fucose 
                 1.88 
                 5.38E−06 
                   
                 HMDB00174 
               
               
                 phenylalanine 
                 1.4 
                 5.63E−06 
                 C00079 
                 HMDB00159 
               
               
                 S-adenosylhomocysteine (SAH) 
                 1.72 
                 5.66E−06 
                 C00021  
                 HMDB00939 
               
               
                 leucine 
                 1.38 
                 6.36E−06 
                 C00123  
                 HMDB00687 
               
               
                 5-oxoproline 
                 0.56 
                 1.46E−05 
                 C01879  
                 HMDB00267 
               
               
                 citrate 
                 0.55 
                 1.51E−05 
                 C00158 
                 HMDB00094 
               
               
                 N6-carbamoylthreonyladenosine 
                 1.44 
                 1.93E−05 
                   
                   
               
               
                 methionine 
                 1.39 
                 2.72E−05 
                 C00073 
                 HMDB00696 
               
               
                 adenine 
                 2.62 
                 2.88E−05 
                 C00147  
                 HMDB00034 
               
               
                 2-methylbutyrylcarnitine (C5) 
                 1.64 
                 3.58E−05 
                   
                 HMDB00378 
               
               
                 xanthosine 
                 1.63 
                 3.79E−05 
                 C01762  
                 HMDB00299 
               
               
                 pantothenate 
                 1.45 
                 4.30E−05 
                 C00864  
                 HMDB00210 
               
               
                 gamma-glutamylvaline 
                 0.63 
                 7.26E−05 
                   
                 HMDB11172 
               
               
                 valine 
                 1.28 
                 7.35E−05 
                 C00183 
                 HMDB00883 
               
               
                 glycylproline 
                 1.42 
                 7.75E−05 
                   
                 HMDB00721 
               
               
                 mannose 
                 1.98 
                 0.0001 
                 C00159  
                 HMDB00169 
               
               
                 proline 
                 1.32 
                 0.0001 
                 C00148  
                 HMDB00162 
               
               
                 uracil 
                 1.66 
                 0.0002 
                 C00106 
                 HMDB00300 
               
               
                 threonine 
                 1.52 
                 0.0002 
                 C00188  
                 HMDB00167 
               
               
                 cis-aconitate 
                 0.67 
                 0.0002 
                 C00417  
                 HMDB00072 
               
               
                 propionylcarnitine 
                 1.56 
                 0.0002 
                 C03017 
                 HMDB00824 
               
               
                 lactate 
                 1.5 
                 0.0003 
                 C00186 
                 HMDB00190 
               
               
                 mannitol 
                 0.33 
                 0.0003 
                 C00392  
                 HMDB00765 
               
               
                 hexanoylcarnitine 
                 1.54 
                 0.0003 
                 C01585  
                 HMDB00705 
               
               
                 gamma-glutamylphenylalanine 
                 0.79 
                 0.0004 
                   
                 HMDB00594 
               
               
                 fructose 
                 1.56 
                 0.0005 
                 C00095  
                 HMDB00660 
               
               
                 cortisone 
                 1.5 
                 0.0006 
                 C00762  
                 HMDB02802 
               
               
                 hypoxanthine 
                 1.28 
                 0.0008 
                 C00262 
                 HMDB00157 
               
               
                 serine 
                 1.46 
                 0.0009  
                 C00065  
                 HMDB03406 
               
               
                 alanine 
                 1.47 
                 0.001 
                 C00041  
                 HMDB00161 
               
               
                 threonate 
                 0.59 
                 0.001 
                 C01620 
                 HMDB00943 
               
               
                 acetylcarnitine 
                 1.31 
                 0.0015 
                 C02571  
                 HMDB00201 
               
               
                 pyroglutamine 
                 1.63 
                 0.002 
                   
                   
               
               
                 erythronate 
                 1.38 
                 0.002 
                   
                 HMDB00613 
               
               
                 2-isopropylmalate 
                 1.57 
                 0.0024  
                 C02504  
                 HMDB00402 
               
               
                 gamma-glutamylisoleucine 
                 0.71 
                 0.0026 
                   
                 HMDB11170 
               
               
                 5,6-dihydrouracil 
                 2.14 
                 0.0027  
                 C00429  
                 HMDB00076 
               
               
                 cysteine 
                 1.81 
                 0.003 
                 C00097  
                 HMDB00574 
               
               
                 thymine 
                 1.92 
                 0.0045 
                 C00178 
                 HMDB00262 
               
               
                 pseudouridine 
                 1.3 
                 0.005 
                 C02067  
                 HMDB00767 
               
               
                 glucarate (saccharate) 
                 1.51 
                 0.0055 
                 C00818 
                 HMDB00663 
               
               
                 xylose 
                 1.78 
                 0.0065  
                 C00181 
                 HMDB00098 
               
               
                 glycolate (hydroxyacetate) 
                 0.9 
                 0.0077  
                 C00160 
                 HMDB00115 
               
               
                 creatine 
                 1.58 
                 0.008 
                 C00300  
                 HMDB00064 
               
               
                 histidine 
                 1.23 
                 0.0082 
                 C00135  
                 HMDB00177 
               
               
                 3-carboxy-4-methy1-5-propy1-2- 
                 0.58 
                 0.0085 
                   
                   
               
               
                 furanpropanoate (CMPF) 
                   
                   
                   
                   
               
               
                 ascorbate (Vitamin C) 
                 1.54 
                 0.0095 
                 C00072 
                 HMDB00044 
               
               
                 pro-hydroxy-pro 
                 1.3 
                 0.0129 
                   
                 HMDB06695 
               
               
                 succinate 
                 1.47 
                 0.013 
                 C00042 
                 HMDB00254 
               
               
                 riboflavin (Vitamin B2) 
                 1.27 
                 0.0147  
                 C00255  
                 HMDB00244 
               
               
                 taurine 
                 1.42 
                 0.0221 
                 C00245  
                 HMDB00251 
               
               
                 trigonelline (N′-methylnicotinate) 
                 1.61 
                 0.0229 
                   
                 HMDB00875 
               
               
                 glucose 
                 1.42 
                 0.025 
                 C00031 
                 HMDB00122 
               
               
                 3-ureidopropionate 
                 2.04 
                 0.0267 
                 C02642  
                 HMDB00026 
               
               
                 quinate 
                 1.63 
                 0.0299 
                 C00296 
                 HMDB03072 
               
               
                 lysine 
                 1.2 
                 0.0307  
                 C00047 
                 HMDB00182 
               
               
                 urate 
                 0.83 
                 0.0321 
                 C00366 
                 HMDB00289 
               
               
                 N-acetyltyrosine 
                 1.33 
                 0.0409 
                   
                 HMDB00866 
               
               
                 Nl-methylguanosine 
                 1.37 
                 0.0417 
                   
                 HMDB01563 
               
               
                 glucuronate 
                 1.46 
                 0.0453  
                 C00191  
                 HMDB00127 
               
               
                 N-acetylglycine 
                 1.26 
                 0.0502 
                   
                 HMDB00532 
               
               
                 3-dehydrocarnitine 
                 1.23 
                 0.0536 
                   
                   
               
               
                 tryptophan 
                 1.51 
                 0.0574 
                 C00078 
                 HMDB00929 
               
               
                 N-6-trimethyllysine 
                 1.16 
                 0.0679  
                 C03793 
                 HMDB01325 
               
               
                 2-hydroxyisobutyrate 
                 0.88 
                 0.0691 
                   
                 HMDB00729 
               
               
                 1-methylimidazoleacetate 
                 0.81 
                 0.0694 
                 C05828 
                 HMDB02820 
               
               
                 ribitol 
                 1.22 
                 0.0757  
                 C00474 
                 HMDB00508 
               
               
                 isovalerylcarnitine 
                 1.53 
                 0.0775 
                   
                 HMDB00688 
               
               
                 fumarate 
                 1.19 
                 0.0809  
                 C00122 
                 HMDB00134 
               
               
                 sarcosine (N-Methylglycine) 
                 1.63 
                 0.0881  
                 C00213 
                 HMDB00271 
               
               
                 N-acetylthreonine 
                 1.27 
                 0.0945 
                 C01118 
                   
               
               
                 2-hydroxyhippurate (salicylurate) 
                 1.1 
                 0.0949 
                 C07588  
                 HMDB00840 
               
               
                 dimethylglycine 
                 1.2 
                 0.0986  
                 C01026  
                 HMDB00092 
               
               
                 xylonate 
                 1.3 
                 0.1114 
                 C05411 
                   
               
               
                 malate 
                 1.24 
                 0.1181  
                 C00149  
                 HMDB00156 
               
               
                 alpha-hydroxyisovalerate 
                 1.3 
                 0.1218 
                   
                 HMDB00407 
               
               
                 adenosine 
                 0.85 
                 0.1231  
                 C00212  
                 HMDB00050 
               
               
                 beta-hydroxypyruvate 
                 1.11 
                 0.1278 
                 C00168  
                 HMDB01352 
               
               
                 isobutyrylcarnitine 
                 1.28 
                 0.1327 
                   
                   
               
               
                 N-acetylvaline 
                 1.38 
                 0.1481 
                   
                 HMDB11757 
               
               
                 stachydrine 
                 1.52 
                 0.161 
                 C10172  
                 HMDB04827 
               
               
                 nicotinate 
                 1.07 
                 0.169 
                 C00253 
                 HMDB01488 
               
               
                 N-acetylleucine 
                 1.47 
                 0.1865 
                 C02710 
                 HMDB11756 
               
               
                 tartarate 
                 1.56 
                 0.2007  
                 C00898  
                 HMDB00956 
               
               
                 N6-acetyllysine 
                 1.15 
                 0.2018 
                 C02727 
                 HMDB00206 
               
               
                 citramalate 
                 1.46 
                 0.2034  
                 C00815 
                 HMDB00426 
               
               
                 glycine 
                 1.16 
                 0.2096 
                 C00037 
                 HMDB00123 
               
               
                 homostachydrine 
                 1.57 
                 0.2144 
                 C08283 
                   
               
               
                 xylulose 
                 1.11 
                 0.2212 
                 C00310 
                 HMDB00654 
               
               
                 gulono-1,4-lactone 
                 1.24 
                 0.2265 
                 C01040  
                 HMDB03466 
               
               
                 2-aminobutyrate 
                 0.95 
                 0.2316 
                 C02261 
                 HMDB00650 
               
               
                 phenylacetylglutamine 
                 1.3 
                 0.2334  
                 C04148 
                 HMDB06344 
               
               
                 threitol 
                 2.91 
                 0.2425 
                 C16884  
                 HMDB04136 
               
               
                 kynurenine 
                 1.21 
                 0.2444 
                 C00328  
                 HMDB00684 
               
               
                 scyllo-inositol 
                 1.54 
                 0.2585  
                 C06153 
                 HMDB06088 
               
               
                 N-acetylisoleucine 
                 1.21 
                 0.2697 
                   
                   
               
               
                 guanidinoacetate 
                 1.57 
                 0.2807  
                 C00581 
                 HMDB00128 
               
               
                 dimethylarginine (SDMA + ADMA) 
                 1.09 
                 0.3281 
                 C03626 
                 HMDB01539 
               
               
                   
                   
                   
                   
                 HMDB03334 
               
               
                 gluconate 
                 1.06 
                 0.3381 
                 C00257  
                 HMDB00625 
               
               
                 5-aminovalerate 
                 1.22 
                 0.361 
                 C00431  
                 HMDB03355 
               
               
                 3-indoxyl sulfate 
                 0.87 
                 0.3619 
                   
                 HMDB00682 
               
               
                 pyridoxate 
                 1.16 
                 0.3722  
                 C00847  
                 HMDB00017 
               
               
                 cholate 
                 0.9 
                 0.3809 
                 C00695  
                 HMDB00619 
               
               
                 sorbitol 
                 0.83 
                 0.3962 
                 C00794  
                 HMDB00247 
               
               
                 myo-inositol 
                 1.27 
                 0.399 
                 C00137 
                 HMDB00211 
               
               
                 androsterone sulfate 
                 0.89 
                 0.4224 
                 C00523  
                 HMDB02759 
               
               
                 quinolinate 
                 1.8 
                 0.4244  
                 C03722 
                 HMDB00232 
               
               
                 allo-threonine 
                 1.16 
                 0.4274  
                 C05519  
                 HMDB04041 
               
               
                 N-acetylasparagine 
                 1.25 
                 0.4508 
                   
                 HMDB06028 
               
               
                 gamma-aminobutyrate (GABA) 
                 1.2 
                 0.4516 
                 C00334  
                 HMDB00112 
               
               
                 4-guanidinobutanoate 
                 1.14 
                 0.4601 
                 C01035  
                 HMDB03464 
               
               
                 adipate 
                 0.59 
                 0.4795 
                 C06104 
                 HMDB00448 
               
               
                 NI-methyladenosine 
                 0.99 
                 0.5092  
                 C02494 
                 HMDB03331 
               
               
                 N2,N2-dimethylguanosine 
                 1.04 
                 0.513 
                   
                 HMDB04824 
               
               
                 glycerophosphorylcholine (GPC) 
                 0.99 
                 0.5162  
                 C00670 
                 HMDB00086 
               
               
                 2-aminoadipate 
                 1.01 
                 0.5453 
                 C00956 
                 HMDB00510 
               
               
                 N-acetylglutamine 
                 1.19 
                 0.5703 
                 C02716 
                 HMDB06029 
               
               
                 vanillylmandelate (VMA) 
                 1.22 
                 0.5885 
                 C05584 
                 HMDB00291 
               
               
                 glutarylcarnitine (C5) 
                 1.11 
                 0.6188 
                   
                 HMDB13130 
               
               
                 indolelactate 
                 1.18 
                 0.6342 
                 C02043 
                 HMDB00671 
               
               
                 phenol sulfate 
                 1 
                 0.6594  
                 C02180 
                   
               
               
                 N-acetyl-aspartyl-glutamate (NAAG) 
                 0.9 
                 0.665 
                 C12270 
                 HMDB01067 
               
               
                 3-methyl-2-oxovalerate 
                 1.14 
                 0.681 
                 C00671 
                 HMDB03736 
               
               
                 pipecolate 
                 1.26 
                 0.6886 
                 C00408 
                 HMDB00070 
               
               
                 3-hydroxybutyrate (BHBA) 
                 1.02 
                 0.6983 
                 C01089 
                 HMDB00357 
               
               
                 N-acetylphenylalanine 
                 1.19 
                 0.7124 
                 C03519 
                 HMDB00512 
               
               
                 azelate (nonanedioate) 
                 0.99 
                 0.7187  
                 C08261 
                 HMDB00784 
               
               
                 theobromine 
                 0.99 
                 0.7441  
                 C07480 
                 HMDB02825 
               
               
                 glutamine 
                 1.02 
                 0.7453  
                 C00064 
                 HMDB00641 
               
               
                 N2-acetyllysine 
                 1.32 
                 0.7466 
                 C12989 
                 HMDB00446 
               
               
                 indoleacetate 
                 0.92 
                 0.7704 
                 C00954 
                 HMDB00197 
               
               
                 3-methylhistidine 
                 0.97 
                 0.7855 
                 C01152 
                 HMDB00479 
               
               
                 N-acetylarginine 
                 1.45 
                 0.7887  
                 C02562 
                 HMDB04620 
               
               
                 octanoylcarnitine 
                 1.18 
                 0.796 
                   
                   
               
               
                 3-aminoisobutyrate 
                 1.21 
                 0.8027 
                 C05145 
                 HMDB03911 
               
               
                 trans-urocanate 
                 1 
                 0.8589  
                 C00785 
                 HMDB00301 
               
               
                 catechol sulfate 
                 0.79 
                 0.8966 
                 C00090 
                   
               
               
                 4-hydroxyphenylacetate 
                 1.01 
                 0.8992 
                 C00642 
                 HMDB00020 
               
               
                 p-cresol sulfate 
                 1.05 
                 0.9092 
                 C01468 
                   
               
               
                 glycerol 3-phosphate (G3P) 
                 1.03 
                 0.9262  
                 C00093 
                 HMDB00126 
               
               
                 hippurate 
                 0.8 
                 0.9285  
                 C01586 
                 HMDB00714 
               
               
                 anserine 
                 0.97 
                 0.9341  
                 C01262 
                 HMDB00194 
               
               
                 aspartate 
                 1.03 
                 0.9454  
                 C00049 
                 HMDB00191 
               
               
                 N-acetylaspartate (NAA) 
                 0.97 
                 0.9552  
                 C01042 
                 HMDB00812 
               
               
                 carnitine 
                 1.01 
                 0.9555 
                   
                   
               
               
                 beta-alanine 
                 1.15 
                 0.9745  
                 C00099 
                 HMDB00056 
               
               
                 glutamate 
                 0.99 
                 0.9867  
                 C00025 
                 HMDB03339 
               
               
                   
               
             
          
         
       
     
         [0160]    The biomarkers were used to create a statistical model to classify the subjects. The biomarkers were evaluated using Random Forest analysis to classify subjects as having low stage or high stage kidney cancer. Samples from 56 subjects with Low stage RCC (T1, T2) and 84 subjects with High stage RCC (T3,T4) were used in this analysis. 
         [0161]    Random Forest results show that the samples were classified with 72% prediction accuracy. The Confusion Matrix presented in Table 9 shows the number of samples predicted for each classification and the actual in each group (Low Stage or High Stage). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from a subject with low stage RCC or high stage RCC). The OOB error from this Random Forest was approximately 28%, and the model estimated that, when used on a new set of subjects, the identity of low stage RCC subjects could be predicted correctly 68% of the time and high stage RCC subjects could be predicted 75% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Results of Random Forest: Low Stage vs. High Stage RCC 
               
             
          
           
               
                   
                   
                 Predicted Group 
                   
               
             
          
           
               
                   
                   
                 Low 
                 High 
                 Class 
               
               
                   
                   
                 Stage 
                 Stage 
                 Error 
               
               
                   
               
               
                 Actual 
                 Low 
                 38 
                 18 
                 0.3214 
               
               
                 Group 
                 Stage 
                   
                   
                   
               
               
                   
                 High 
                 21 
                 63 
                 0.25   
               
               
                   
                 Stage 
                   
                   
                   
               
             
          
           
               
                   
                 Predictive accuracy = 72% 
               
               
                   
               
             
          
         
       
     
         [0162]    Based on the OOB Error rate of 28%, the Random Forest model that was created predicted whether a sample was from an individual with low stage or high stage kidney cancer with about 72% accuracy based on the levels of the biomarkers measured in samples from the subject. Exemplary biomarkers for distinguishing the groups are choline, pelargonate (9:0), arginine, gamma-glutamylleucine, xanthine, tyrosine, 5-oxoproline, inositol-1-phosphate (11P), N2-methylguanosine, isoleucine, 2-ethylhexanoate, leucine, adenine, 5-methylthioadenosine (MTA), laurate (12:0), phenylalanine, mannose, uracil, xanthosine, erythritol, guanosine-5-monophosphate-5 (GMP), homocysteine, lactate, 4-hydroxybutyrate (GHB), ribose, fucose, S-adenosylhomocysteine (SAH), mannitol, hypoxanthine, and threonine. 
         [0163]    The Random Forest analysis demonstrated that by using the biomarkers, low stage kidney cancer subjects were distinguished from high stage kidney cancer subjects with 75% sensitivity, 68% specificity, 78% PPV and 64% NPV. 
       Example 5 
     Tissue Biomarkers for Kidney Cancer Aggressiveness 
       [0164]    Tumors from subjects with kidney cancer were assessed for aggressiveness based on three criteria: tumor stage, tumor grade, and tumor metastatic potential. To identify biomarkers of kidney cancer aggressiveness, metabolomic analysis was carried out on tissue samples from 140 subjects with kidney cancer. Tumor stage, grade and metastatic potential were reported for each subject. After the levels of metabolites were determined, the data were analyzed using a mixed model that consists of fixed effects and a random effect. Fisher&#39;s method was then used combine the aggressiveness criteria of tumor stage, tumor grade and tumor metastatic potential to identify biomarkers that are associated with kidney cancer aggressiveness. The 50 biomarkers most highly associated with kidney cancer aggressiveness are listed in Table 10. 
         [0165]    Table 10 includes, for each biomarker, the biochemical name of the biomarker, the internal identifier for that biomarker compound in the in-house chemical library of authentic standards (CompID), the p-value determined in the statistical analysis of the data concerning the biomarkers, and whether the biomarker is positively or negatively associated with aggressiveness. A positive association means that as kidney cancer aggressiveness increases, the level of the biomarker increases (i.e., the biomarker is higher in more aggressive cancer); a negative association means that as kidney cancer aggressiveness increases, the level of the biomarker decreases (i.e., the biomarker is lower in more aggressive cancer). 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Tissue Biomarkers for Kidney Cancer Aggressiveness 
               
             
          
           
               
                   
                   
                   
                 Aggressiveness 
               
               
                 Biochemical Name 
                 CompID 
                 P-value 
                 Association 
               
               
                   
               
             
          
           
               
                 pelargonate (9:0) 
                 12035 
                 1.75E−13 
                 negative 
               
               
                 laurate (12:0) 
                 1645 
                 5.59E−12 
                 negative 
               
               
                 homocysteine 
                 40266 
                 1.63E−09 
                 positive 
               
               
                 2′-deoxyinosine 
                 15076 
                 2.48E−09 
                 positive 
               
               
                 S-adenosylmethionine (SAM) 
                 15915 
                 2.49E−09 
                 positive 
               
               
                 glycylthreonine 
                 42050 
                 3.72E−09 
                 positive 
               
               
                 aspartylphenylalanine 
                 22175 
                 4.05E−09 
                 positive 
               
               
                 phenylalanylglycine 
                 41370 
                 4.63E−09 
                 positive 
               
               
                 cytidine 5′-diphosphocholine 
                 34418 
                 2.02E−08 
                 positive 
               
               
                 alanylglycine 
                 37075 
                 3.69E−08 
                 positive 
               
               
                 lysylmethionine 
                 41943 
                 4.41E−08 
                 positive 
               
               
                 glycylisoleucine 
                 36659 
                 4.87E−08 
                 positive 
               
               
                 ribose 
                 12080 
                 5.25E−08 
                 positive 
               
               
                 aspartylleucine 
                 40068 
                 5.66E−08 
                 positive 
               
               
                 2-ethylhexanoate 
                 1554 
                 6.27E−08 
                 negative 
               
               
                 asparagine 
                 11398 
                 7.16E−08 
                 positive 
               
               
                 homoserine 
                 23642 
                 9.90E−08 
                 positive 
               
               
                 2′-deoxyguanosine 
                 1411 
                 2.69E−07 
                 positive 
               
               
                 valerylcarnitine 
                 34406 
                 3.06E−07 
                 positive 
               
               
                 4-hydroxybutyrate (GHB) 
                 34585 
                 5.40E−07 
                 positive 
               
               
                 caprate (10:0) 
                 1642 
                 7.22E−07 
                 negative 
               
               
                 galactose 
                 12055 
                 8.03E−07 
                 positive 
               
               
                 heme 
                 41754 
                 1.06E−06 
                 negative 
               
               
                 butyrylcarnitine 
                 32412 
                 1.07E−06 
                 positive 
               
               
                 choline 
                 15506 
                 p &lt; 0.000001 
                 negative 
               
               
                 isoleucine 
                 1125 
                 2.20E−13 
                 positive 
               
               
                 mannitol 
                 15335 
                 7.67E−13 
                 negative 
               
               
                 fucose 
                 15821 
                 2.92E−11 
                 positive 
               
               
                 tyrosine 
                 1299 
                 2.03E−10 
                 positive 
               
               
                 xanthine 
                 3147 
                 5.42E−10 
                 positive 
               
               
                 5-oxoproline 
                 1494 
                 1.34E−09 
                 negative 
               
               
                 5-methylthioadenosine (MTA) 
                 1419 
                 1.59E−09 
                 positive 
               
               
                 phenylalanine 
                 64 
                 2.02E−09 
                 positive 
               
               
                 leucine 
                 60 
                 2.08E−09 
                 positive 
               
               
                 threonate 
                 27738 
                 2.16E−09 
                 negative 
               
               
                 gamma-glutamylleucine 
                 18369 
                 4.43E−09 
                 negative 
               
               
                 benzoate 
                 15778 
                 6.98E−09 
                 negative 
               
               
                 proline 
                 1898 
                 8.66E−09 
                 positive 
               
               
                 methionine 
                 1302 
                 1.44E−08 
                 positive 
               
               
                 glycylproline 
                 22171 
                 2.31E−08 
                 positive 
               
               
                 N2-methylguanosine 
                 35133 
                 2.77E−08 
                 positive 
               
               
                 adenine 
                 554 
                 4.62E−08 
                 positive 
               
               
                 2-methylbutyroylcarnitine 
                 35431 
                 5.90E−08 
                 positive 
               
               
                 S-adenosylhomocysteine 
                 15948 
                 6.07E−08 
                 positive 
               
               
                 (SAH) 
                   
                   
                   
               
               
                 citrate 
                 1564 
                 6.61E−08 
                 negative 
               
               
                 xanthosine 
                 15136 
                 1.43E−07 
                 positive 
               
               
                 5,6-dihydrouracil 
                 1559 
                 3.42E−07 
                 positive 
               
               
                 threonine 
                 1284 
                 5.28E−07 
                 positive 
               
               
                 valine 
                 1649 
                 5.84E−07 
                 positive 
               
               
                 pantothenate 
                 1508 
                 7.64E−07 
                 positive 
               
               
                   
               
             
          
         
       
     
       VII. Example 6 
     Urine Biomarkers for Renal Cell Carcinoma 
       [0166]    To identify biomarkers of renal cell carcinoma, urine samples collected 
         [0167]    from subjects with: 1) RCC, 2) prostate cancer (PCA), 3) bladder cancer (BCA) and 4) normal subjects were analyzed metabolomically. After the levels of metabolites were determined, biomarkers of RCC were identified using one-way ANOVA contrasts. Biomarkers of RCC were identified as metabolites that differed between 1) RCC and normal subjects, 2) RCC and PCA subjects, and/or 3) RCC and BCA subjects. The biomarkers are listed in Table 11. 
         [0168]    Table 11 includes, for each biomarker, the biochemical name of the biomarker, the fold change (FC) of the biomarker in 1) RCC compared to Normal, 2) RCC compared to BCA, 3) RCC compared to PCA, and the p-value determined in the statistical analysis of the data concerning the biomarkers. In column 8 of Table 11, the identifier for that biomarker compound in the Human Metabolome Database (HMDB), if available, is listed. Bold values indicate a fold of change with a p-value of &lt;0.1. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Urine biomarkers for kidney cancer 
               
             
          
           
               
                   
                 RCC/Norm 
                 RCC/BCA 
                 RCC/PCA 
                   
               
             
          
           
               
                 Biochemical Name 
                 FC 
                 P-value 
                 FC 
                 P-value 
                 FC 
                 P-value 
                 HMDB 
               
               
                   
               
             
          
           
               
                 3-hydroxyhippurate 
                 
                   0.32 
                 
                 7.35E−11 
                 0.79 
                 0.8623 
                 1.91 
                 0.6142 
                 HMDB06116 
               
               
                 methyl indole-3-acetate 
                 
                   5.91 
                 
                 7.93E−12 
                 
                   4.36 
                 
                 4.23E−09 
                 1.82 
                 0.3269 
               
               
                 2,3-dihydroxyisovalerate 
                 
                   0.14 
                 
                 9.50E−11 
                 0.52 
                 0.1943 
                 0.78 
                 0.4462 
               
               
                 cinnamoylglycine 
                 
                   0.39 
                 
                 1.31E−08 
                 0.8 
                 0.2802 
                 1.18 
                 0.1474 
               
               
                 galactose 
                 
                   0.45 
                 
                 4.18E−08 
                 
                   0.67 
                 
                 0.0026 
                 
                   0.89 
                 
                 0.0022 
                 HMDB00143 
               
               
                 4-hydroxy-2-oxoglutaric acid 
                 
                   4.71 
                 
                 5.90E−08 
                 
                   1.76 
                 
                 0.0349 
                 0.99 
                 0.2168 
                 HMDB02070 
               
               
                 gluconate 
                 
                   12.15 
                 
                 1.05E−07 
                 1.1 
                 0.6536 
                 
                   0.49 
                 
                 7.27E−12 
                 HMDB00625 
               
               
                 1,2-propanediol 
                 
                   3.15 
                 
                 1.86E−07 
                 0.59 
                 0.5991 
                 
                   0.14 
                 
                 5.08E−05 
                 HMDB01881 
               
               
                 2-oxindole-3-acetate 
                 
                   0.42 
                 
                 2.33E−07 
                 0.91 
                 0.3503 
                 
                   2.16 
                 
                 0.0005 
               
               
                 alpha-CEHC glucuronide 
                 
                   0.37 
                 
                 6.71E−07 
                 0.79 
                 0.8128 
                 
                   1.41 
                 
                 0.0215 
               
               
                 ethanolamine 
                 
                   0.57 
                 
                 9.18E−07 
                 
                   0.87 
                 
                 0.0147 
                 1.02 
                 0.1873 
                 HMDB00149 
               
               
                 phenylpropionylglycine 
                 
                   0.42 
                 
                 9.40E−07 
                 0.84 
                 0.5281 
                 0.86 
                 0.7559 
                 HMDB00860 
               
               
                 2,3-butanediol 
                 
                   0.26 
                 
                 1.72E−06 
                 
                   0.6 
                 
                 0.0055 
                 
                   0.63 
                 
                 0.0068 
                 HMDB03156 
               
               
                 adenosine 5′-monophosphate 
                 
                   3.23 
                 
                 4.40E−06 
                 
                   0.15 
                 
                 0.0019 
                 
                   0.59 
                 
                 0.0005 
                 HMDB00045 
               
               
                 (AMP) 
               
               
                 N6-methyladenosine 
                 
                   2.49 
                 
                 5.48E−06 
                 
                   1.48 
                 
                 0.0046 
                 1.18 
                 0.5508 
                 HMDB04044 
               
               
                 caffeate 
                 
                   0.39 
                 
                 9.78E−05 
                 
                   0.47 
                 
                 0.0019 
                 0.98 
                 0.3662 
                 HMDB01964 
               
               
                 1-(3-aminopropyl)-2- 
                 
                   1.6 
                 
                 0.0003 
                 1 
                 0.5363 
                 
                   1.78 
                 
                 9.44E−05 
               
               
                 pyrrolidone 
               
               
                 gamma-CEHC 
                 
                   1.67 
                 
                 0.0017 
                 
                   2.68 
                 
                 5.11E−06 
                 
                   1.64 
                 
                 0.0154 
                 HMDB01931 
               
               
                 21-hydroxypregnenolone 
                 
                   1.35 
                 
                 0.0067 
                 
                   1.7 
                 
                 0.0013 
                 1.26 
                 0.4325 
                 HMDB04026 
               
               
                 disulfate 
               
               
                 guanine 
                 1.02 
                 0.1408 
                 1.08 
                 0.7162 
                 
                   0.68 
                 
                 0.0001 
                 HMDB00132 
               
               
                 sulforaphane 
                 1.09 
                 0.2226 
                 
                   1.28 
                 
                 0.0849 
                 
                   1.52 
                 
                 0.0284 
                 HMDB05792 
               
               
                 imidazole propionate 
                 1.19 
                 0.2819 
                 
                   0.85 
                 
                 0.0028 
                 2 
                 0.2612 
                 HMDB02271 
               
               
                 12-dehydrocholate 
                 2.31 
                 0.2856 
                 
                   2.67 
                 
                 0.0266 
                 
                   4.26 
                 
                 0.0008 
                 HMDB00400 
               
               
                 3-sialyllactose 
                 1.34 
                 0.3463 
                 
                   1.5 
                 
                 0.0239 
                 
                   1.79 
                 
                 0.0013 
                 HMDB00825 
               
               
                 Isobar: glucuronate, 
                 0.85 
                 0.4657 
                 0.96 
                 0.6749 
                 
                   1.46 
                 
                 0.0002 
               
               
                 galacturonate, 5-keto-gluconate 
               
               
                 N-methyl proline 
                 0.77 
                 0.5755 
                 
                   0.48 
                 
                 0.0034 
                 0.84 
                 0.5548 
               
               
                 orotidine 
                 1.06 
                 0.7045 
                 0.67 
                 0.7869 
                 
                   1.73 
                 
                 0.0067 
                 HMDB00788 
               
               
                 palmitoyl sphingomyelin 
                 2.7 
                 0.839 
                 
                   0.26 
                 
                 0.0001 
                 2.3 
                 0.4001 
               
               
                 methyl-4-hydroxybenzoate 
                 
                   29.08 
                 
                 p &lt; 0.0001 
                 
                   3.87 
                 
                 3.94E−07 
                 
                   1.19 
                 
                 0.0499 
               
               
                 2,5-furandicarboxylic acid 
                 
                   0.39 
                 
                 5.05E−07 
                 0.69 
                 0.1772 
                 
                   2.16 
                 
                 0.0681 
                 HMDB04812 
               
               
                 arginine 
                 
                   0.23 
                 
                 8.65E−07 
                 
                   0.6 
                 
                 0.0463 
                 1.16 
                 0.5876 
                 HMDB00517 
               
               
                 homoserine 
                 
                   0.47 
                 
                 5.06E−06 
                 
                   0.51 
                 
                 0.0383 
                 0.89 
                 0.5568 
                 HMDB00719 
               
               
                 N-acetyltryptophan 
                 
                   0.43 
                 
                 5.93E−06 
                 0.89 
                 0.2169 
                 
                   1.74 
                 
                 0.0287 
               
               
                 cyclo(leu-pro) 
                 
                   0.52 
                 
                 1.15E−05 
                 
                   0.53 
                 
                 0.0025 
                 0.96 
                 0.5245 
               
               
                 2,4,6-trihydroxybenzoate 
                 
                   0.24 
                 
                 2.47E−05 
                 0.65 
                 0.4021 
                 1.29 
                 0.8021 
               
               
                 3-hydroxyproline 
                 
                   0.74 
                 
                 6.60E−05 
                 
                   0.92 
                 
                 0.0356 
                 1.04 
                 0.3894 
               
               
                 putrescine 
                 
                   0.4 
                 
                 7.27E−05 
                 
                   0.33 
                 
                 0.0854 
                 1.47 
                 0.202 
                 HMDB01414 
               
               
                 cortisol 
                 
                   2.21 
                 
                 8.35E−05 
                 0.85 
                 0.3051 
                 0.89 
                 0.1558 
                 HMDB00063 
               
               
                 N-acetylcysteine 
                 
                   0.45 
                 
                 8.79E−05 
                 0.68 
                 0.1831 
                 0.82 
                 0.5203 
                 HMDB01890 
               
               
                 pinitol 
                 
                   0.23 
                 
                 0.0001 
                 
                   0.28 
                 
                 0.0339 
                 1.14 
                 0.9708 
               
               
                 N-carbamoylsarcosine 
                 
                   0.72 
                 
                 0.0001 
                 0.84 
                 0.1691 
                 1.32 
                 0.2097 
               
               
                 2-methylhippurate 
                 
                   1.67 
                 
                 0.0001 
                 0.58 
                 0.8307 
                 1.14 
                 0.6518 
                 HMDB11723 
               
               
                 dihydroferulic acid 
                 
                   0.28 
                 
                 0.0002 
                 0.38 
                 0.1143 
                 0.72 
                 0.6212 
               
               
                 3-hydroxybenzoate 
                 
                   0.62 
                 
                 0.0002 
                 
                   0.79 
                 
                 0.0647 
                 1.14 
                 0.5684 
                 HMDB02466 
               
               
                 ethyl glucuronide 
                 
                   0.34 
                 
                 0.0003 
                 
                   1.43 
                 
                 0.0816 
                 1.71 
                 0.7613 
               
               
                 ciliatine (2- 
                 
                   0.37 
                 
                 0.0003 
                 0.19 
                 0.33 
                 0.56 
                 0.719 
                 HMDB11747 
               
               
                 aminoethylphosphonate) 
               
               
                 3-phosphoglycerate 
                 
                   0.68 
                 
                 0.0004 
                 0.65 
                 0.4871 
                 1.31 
                 0.4863 
                 HMDB00807 
               
               
                 inosine 
                 
                   1.69 
                 
                 0.0004 
                 
                   1.17 
                 
                 0.0139 
                 
                   1.38 
                 
                 0.0445 
               
               
                 3-methylglutaconate 
                 
                   0.69 
                 
                 0.0005 
                 0.87 
                 0.3421 
                 0.9 
                 0.2874 
                 HMDB00522 
               
               
                 alanylalanine 
                 
                   0.59 
                 
                 0.0008 
                 0.8 
                 0.3922 
                 0.8 
                 0.6212 
                 HMDB03459 
               
               
                 5-methyltetrahydrofolate 
                 
                   0.35 
                 
                 0.001 
                 0.79 
                 0.5757 
                 0.63 
                 0.1217 
                 HMDB01396 
               
               
                 (5MeTHF) 
               
               
                 galactinol 
                 
                   0.48 
                 
                 0.0012 
                 1.02 
                 0.9326 
                 1.37 
                 0.1909 
                 HMDB05826 
               
               
                 trans-aconitate 
                 
                   0.73 
                 
                 0.0012 
                 0.95 
                 0.4419 
                 0.95 
                 0.3384 
                 HMDB00958 
               
               
                 dopamine 
                 
                   0.53 
                 
                 0.0017 
                 0.93 
                 0.5238 
                 1.18 
                 0.4495 
                 HMDB00073 
               
               
                 guanidine 
                 
                   0.6 
                 
                 0.0024 
                 1.2 
                 0.3713 
                 1.08 
                 0.9767 
                 HMDB01842 
               
               
                 3-hydroxymandelate 
                 
                   0.32 
                 
                 0.0032 
                 1.49 
                 0.3071 
                 2.88 
                 0.9955 
                 HMDB00750 
               
               
                 asparagine 
                 
                   0.68 
                 
                 0.0034 
                 0.81 
                 0.2918 
                 1.05 
                 0.1835 
                 HMDB00168 
               
               
                 2-phenylglycine 
                 
                   0.7 
                 
                 0.0034 
                 0.43 
                 0.19 
                 0.25 
                 0.7127 
                 HMDB02210 
               
               
                 S-methylcysteine 
                 
                   0.74 
                 
                 0.0036 
                 0.8 
                 0.1326 
                 0.79 
                 0.3376 
                 HMDB02108 
               
               
                 2-pyrrolidinone 
                 
                   0.64 
                 
                 0.0043 
                 1.12 
                 0.6896 
                 0.97 
                 0.5848 
                 HMDB02039 
               
               
                 N-acetylproline 
                 
                   0.68 
                 
                 0.0044 
                 0.97 
                 0.964 
                 1.08 
                 0.9559 
               
               
                 L-urobilin 
                 
                   1 
                 
                 0.0044 
                 1.31 
                 0.4793 
                 2 
                 0.6431 
                 HMDB04159 
               
               
                 abscisate 
                 
                   0.38 
                 
                 0.0054 
                 0.65 
                 0.4202 
                 1.08 
                 0.8488 
               
               
                 N-acetyl-beta-alanine 
                 
                   0.76 
                 
                 0.0054 
                 
                   0.8 
                 
                 0.0741 
                 
                   0.82 
                 
                 0.0814 
               
               
                 N-acetylserine 
                 
                   1.43 
                 
                 0.0054 
                 0.97 
                 0.9362 
                 
                   1.32 
                 
                 0.0554 
                 HMDB02931 
               
               
                 cystine 
                 
                   0.54 
                 
                 0.0059 
                 1.57 
                 0.4268 
                 0.95 
                 0.8388 
                 HMDB00192 
               
               
                 N-methylglutamate 
                 
                   0.68 
                 
                 0.0059 
                 0.7 
                 0.9942 
                 1.24 
                 0.1644 
               
               
                 arabonate 
                 
                   0.77 
                 
                 0.0066 
                 0.92 
                 0.4588 
                 1.05 
                 0.9858 
                 HMDB00539 
               
               
                 glycodeoxycholate 
                 
                   0.62 
                 
                 0.0075 
                 
                   0.56 
                 
                 0.0348 
                 1.44 
                 0.9653 
                 HMDB00631 
               
               
                 phosphoethanolamine 
                 
                   1.04 
                 
                 0.008 
                 1.24 
                 0.5162 
                 2.52 
                 0.2976 
                 HMDB00224 
               
               
                 5alpha-pregnan-3beta,20alpha- 
                 
                   2.24 
                 
                 0.0082 
                 
                   2.55 
                 
                 0.0051 
                 2.07 
                 0.1394 
               
               
                 diol disulfate 
               
               
                 alpha-tocopherol 
                 
                   4.01 
                 
                 0.0082 
                 
                   0.65 
                 
                 0.0484 
                 
                   3.03 
                 
                 0.0997 
                 HMDB01893 
               
               
                 N-carbamoylaspartate 
                 
                   0.38 
                 
                 0.0093 
                 0.88 
                 0.8658 
                 1.06 
                 0.4614 
                 HMDB00828 
               
               
                 aspartylaspartate 
                 
                   0.79 
                 
                 0.012 
                 1.35 
                 0.9659 
                 1.06 
                 0.6221 
               
               
                 2-octenedioate 
                 
                   0.7 
                 
                 0.0121 
                 0.92 
                 0.5898 
                 0.56 
                 0.3035 
                 HMDB00341 
               
               
                 2-(4-hydroxyphenyl)propionate 
                 
                   0.4 
                 
                 0.0125 
                 1.01 
                 0.4775 
                 4.01 
                 0.8379 
               
               
                 6-sialyl-N-acetyllactosamine 
                 
                   1.33 
                 
                 0.0138 
                 
                   1.4 
                 
                 0.0132 
                 
                   1.55 
                 
                 0.0005 
                 HMDB06584 
               
               
                 diglycerol 
                 
                   0.69 
                 
                 0.014 
                 0.75 
                 0.128 
                 1.16 
                 0.7456 
               
               
                 biotin 
                 
                   0.56 
                 
                 0.0157 
                 1.12 
                 0.549 
                 1.44 
                 0.4336 
                 HMDB00030 
               
               
                 pyridoxal 
                 
                   0.5 
                 
                 0.0167 
                 1.24 
                 0.2877 
                 
                   1.71 
                 
                 0.0158 
                 HMDB01545 
               
               
                 pyridoxine (Vitamin B6) 
                 
                   0.43 
                 
                 0.019 
                 1 
                 1 
                 1 
                 1 
                 HMDB02075 
               
               
                 daidzein 
                 
                   0.64 
                 
                 0.024 
                 0.71 
                 0.3 
                 0.94 
                 0.882 
                 HMDB03312 
               
               
                 pregnanediol-3-glucuronide 
                 
                   1.8 
                 
                 0.024 
                 
                   2 
                 
                 0.0328 
                 1.46 
                 0.939 
               
               
                 Isobar: dihydrocaffeate, 3,4- 
                 
                   0.74 
                 
                 0.0244 
                 0.72 
                 0.1813 
                 1.26 
                 0.9461 
               
               
                 dihydroxycinnamate 
               
               
                 guanosine 
                 
                   1.32 
                 
                 0.0282 
                 1.15 
                 0.1707 
                 
                   1.57 
                 
                 0.006 
                 HMDB00133 
               
               
                 3-hydroxyglutarate 
                 
                   0.78 
                 
                 0.0327 
                 1.11 
                 0.6713 
                 0.99 
                 0.3518 
                 HMDB00428 
               
               
                 N1-Methyl-2-pyridone-5- 
                 
                   0.75 
                 
                 0.0421 
                 0.82 
                 0.8673 
                 1.1 
                 0.2268 
                 HMDB04193 
               
               
                 carboxamide 
               
               
                 5alpha-androstan-3beta,17beta- 
                 
                   1.49 
                 
                 0.0491 
                 
                   1.69 
                 
                 0.0091 
                 0.97 
                 0.6298 
                 HMDB00493 
               
               
                 diol disulfate 
               
               
                 sinapate 
                 
                   0.5 
                 
                 0.0504 
                 0.79 
                 0.6032 
                 1.26 
                 0.6029 
               
               
                 2-oxo-1-pyrrolidinepropionate 
                 
                   1 
                 
                 0.0609 
                 0.92 
                 0.575 
                 
                   1.68 
                 
                 0.0135 
               
               
                 citraconate 
                 
                   0.67 
                 
                 0.062 
                 0.75 
                 0.1805 
                 
                   0.64 
                 
                 0.0883 
                 HMDB00634 
               
               
                 glucose 
                 
                   0.2 
                 
                 0.0626 
                 0.48 
                 0.4248 
                 1.36 
                 0.3522 
                 HMDB00122 
               
               
                 glucono-1,5-lactone 
                 
                   4.62 
                 
                 0.0656 
                 
                   0.54 
                 
                 0.0246 
                 
                   0.41 
                 
                 0.0003 
                 HMDB00150 
               
               
                 nicotinamide 
                 
                   0.61 
                 
                 0.0728 
                 0.48 
                 0.1121 
                 0.93 
                 0.8341 
                 HMDB01406 
               
               
                 arabitol 
                 
                   0.82 
                 
                 0.073 
                 0.98 
                 0.9546 
                 0.97 
                 0.7759 
                 HMDB01851 
               
               
                 prolylglycine 
                 
                   0.81 
                 
                 0.0767 
                 0.92 
                 0.608 
                 1.29 
                 0.5811 
               
               
                 3-(4-hydroxyphenyl)lactate 
                 
                   0.95 
                 
                 0.0789 
                 1.28 
                 0.9833 
                 
                   2.77 
                 
                 0.0561 
                 HMDB00755 
               
               
                 5alpha-pregnan-3alpha,20beta- 
                 
                   1.73 
                 
                 0.0804 
                 
                   1.83 
                 
                 0.024 
                 
                   2.1 
                 
                 0.0132 
               
               
                 diol disulfate 1 
               
               
                 sulforaphane-N-acetyl-cysteine 
                 
                   0.77 
                 
                 0.0822 
                 0.97 
                 0.8418 
                 0.97 
                 0.8452 
               
               
                 ethylmalonate 
                 
                   1.17 
                 
                 0.0844 
                 1.1 
                 0.3975 
                 0.99 
                 0.7187 
                 HMDB00622 
               
               
                 hydantoin-5-propionic acid 
                 
                   1.34 
                 
                 0.0964 
                 1.38 
                 0.1544 
                 1.37 
                 0.1151 
                 HMDB01212 
               
               
                 3-hydroxycinnamate (m- 
                 
                   0.58 
                 
                 0.0968 
                 0.89 
                 0.7784 
                 1.18 
                 0.6958 
                 HMDB01713 
               
               
                 coumarate) 
               
               
                 glucose-6-phosphate (G6P) 
                 1 
                 0.2504 
                 
                   0.59 
                 
                 0.0028 
                 1.42 
                 0.8295 
                 HMDB01401 
               
               
                 glutathione, reduced (GSH) 
                 0.92 
                 0.333 
                 
                   0.13 
                 
                 0.0003 
                 0.79 
                 0.5709 
                 HMDB00125 
               
               
                 prostaglandin E2 
                 0.98 
                 0.7664 
                 
                   0.71 
                 
                 0.0016 
                 0.83 
                 0.365 
                 HMDB01220 
               
               
                 biliverdin 
                 1 
                 1 
                 
                   0.83 
                 
                 0.0016 
                 0.98 
                 0.6548 
                 HMDB01008 
               
               
                 glycerol 
                 
                   12.19 
                 
                 1.70E−12 
                 
                   3.19 
                 
                 6.57E−06 
                 0.73 
                 0.5371 
                 HMDB00131 
               
               
                 pregnen-diol disulfate 
                 
                   1.74 
                 
                 3.82E−05 
                 
                   1.7 
                 
                 0.0165 
                 1.41 
                 0.7439 
                 HMDB04025 
               
               
                 4-androsten-3beta,17beta-diol 
                 
                   1.63 
                 
                 0.0007 
                 
                   1.69 
                 
                 0.0015 
                 1.09 
                 0.5963 
                 HMDB03818 
               
               
                 disulfate 1 
               
               
                 1,3-dimethylurate 
                 
                   0.64 
                 
                 0.0009 
                 
                   0.62 
                 
                 0.0195 
                 
                   0.84 
                 
                 0.0069 
                 HMDB01857 
               
               
                 2-hydroxybutyrate (AHB) 
                 
                   1.86 
                 
                 0.003 
                 0.63 
                 0.2777 
                 
                   0.28 
                 
                 0.0014 
                 HMDB00008 
               
               
                 4-androsten-3beta,17beta-diol 
                 
                   1.47 
                 
                 0.0038 
                 
                   1.81 
                 
                 0.0016 
                 1.1 
                 0.8567 
                 HMDB03818 
               
               
                 disulfate 2 
               
               
                 4-methyl-2-oxopentanoate 
                 
                   1.59 
                 
                 0.0066 
                 0.95 
                 0.6361 
                 0.75 
                 0.4842 
                 HMDB00695 
               
               
                 UDP-glucuronate 
                 
                   0.79 
                 
                 0.0262 
                 0.91 
                 0.6583 
                 1.18 
                 0.2571 
                 HMDB00935 
               
               
                 andro steroid monosulfate 2 
                 
                   1.96 
                 
                 0.0303 
                 
                   2.09 
                 
                 0.0528 
                 1.44 
                 0.6911 
                 HMDB02759 
               
               
                 C-glycosyltryptophan 
                 
                   1.29 
                 
                 0.0392 
                 
                   1.27 
                 
                 0.0251 
                 
                   1.33 
                 
                 0.0158 
               
               
                 andro steroid monosulfate 1 
                 
                   1.4 
                 
                 0.0411 
                 
                   1.37 
                 
                 0.0722 
                 0.92 
                 0.6729 
                 HMDB02759 
               
               
                 sucralose 
                 
                   0.46 
                 
                 0.0548 
                 1.13 
                 0.6182 
                 1.17 
                 0.6149 
               
               
                 glycocholenate sulfate 
                 
                   1.52 
                 
                 0.0589 
                 
                   1.74 
                 
                 0.0684 
                 1.27 
                 0.552 
               
               
                 2-hydroxyglutarate 
                 
                   1.66 
                 
                 0.067 
                 
                   1.72 
                 
                 0.0173 
                 1.31 
                 0.9778 
                 HMDB00606 
               
               
                 oxalate (ethanedioate) 
                 
                   2.03 
                 
                 0.0681 
                 0.96 
                 0.9104 
                 1.81 
                 0.1906 
                 HMDB02329 
               
               
                 methylglutaroylcarnitine 
                 
                   0.75 
                 
                 0.0965 
                 0.81 
                 0.3529 
                 0.97 
                 0.9447 
                 HMDB00552 
               
               
                 4-hydroxyhippurate 
                 1.26 
                 0.1096 
                 1.64 
                 0.163 
                 
                   2.56 
                 
                 0.0004 
               
               
                 catechol sulfate 
                 
                   0.3 
                 
                 p &lt; 0.0001 
                 
                   0.46 
                 
                 0.0011 
                 0.73 
                 0.2137 
               
               
                 N-(2-furoyl)glycine 
                 
                   0.15 
                 
                 9.50E−14 
                 
                   0.29 
                 
                 0.0003 
                 0.63 
                 0.203 
                 HMDB00439 
               
               
                 2-hydroxyhippurate 
                 
                   0.04 
                 
                 1.18E−12 
                 0.29 
                 0.4502 
                 0.97 
                 0.648 
                 HMDB00840 
               
               
                 (salicylurate) 
               
               
                 3-hydroxyphenylacetate 
                 
                   0.21 
                 
                 3.08E−12 
                 0.75 
                 0.7979 
                 0.66 
                 0.3209 
                 HMDB00440 
               
               
                 2-isopropylmalate 
                 
                   0.19 
                 
                 2.43E−11 
                 0.63 
                 0.2479 
                 1.35 
                 0.8165 
                 HMDB00402 
               
               
                 phenylacetylglycine 
                 
                   0.39 
                 
                 5.98E−10 
                 
                   0.68 
                 
                 0.0045 
                 
                   2.06 
                 
                 0.0436 
                 HMDB00821 
               
               
                 sorbose 
                 
                   0.22 
                 
                 2.34E−09 
                 
                   0.37 
                 
                 0.0572 
                 0.7 
                 0.5234 
                 HMDB01266 
               
               
                 sucrose 
                 
                   0.4 
                 
                 9.07E−09 
                 
                   0.88 
                 
                 0.0023 
                 1.63 
                 0.193 
                 HMDB00258 
               
               
                 3-hydroxypyridine 
                 
                   0.36 
                 
                 1.90E−08 
                 
                   0.5 
                 
                 0.0009 
                 1.01 
                 0.6845 
               
               
                 1,3,7-trimethylurate 
                 
                   0.33 
                 
                 6.47E−08 
                 
                   0.49 
                 
                 0.0017 
                 
                   0.94 
                 
                 0.0256 
                 HMDB02123 
               
               
                 hexanoylglycine 
                 
                   1.94 
                 
                 1.23E−07 
                 1.2 
                 0.1663 
                 
                   0.71 
                 
                 0.0342 
                 HMDB00701 
               
               
                 vanillate 
                 
                   0.31 
                 
                 2.49E−07 
                 
                   0.32 
                 
                 0.0079 
                 1.17 
                 0.778 
                 HMDB00484 
               
               
                 3,4-dihydroxyphenylacetate 
                 
                   0.45 
                 
                 5.32E−07 
                 0.97 
                 0.4211 
                 
                   0.89 
                 
                 0.0458 
                 HMDB01336 
               
               
                 tartarate 
                 
                   0.08 
                 
                 9.57E−07 
                 0.31 
                 0.5399 
                 0.79 
                 0.3541 
                 HMDB00956 
               
               
                 theobromine 
                 
                   0.4 
                 
                 1.39E−06 
                 
                   0.63 
                 
                 0.0275 
                 
                   0.78 
                 
                 0.0477 
                 HMDB02825 
               
               
                 adipate 
                 
                   5.03 
                 
                 1.71E−06 
                 1.11 
                 0.4498 
                 1.46 
                 0.6544 
                 HMDB00448 
               
               
                 riboflavin (Vitamin B2) 
                 
                   0.26 
                 
                 2.75E−06 
                 1.05 
                 0.189 
                 1.01 
                 0.346 
                 HMDB00244 
               
               
                 allo-threonine 
                 
                   0.63 
                 
                 3.90E−06 
                 
                   0.93 
                 
                 0.055 
                 0.85 
                 0.8116 
                 HMDB04041 
               
               
                 caffeine 
                 
                   0.23 
                 
                 3.96E−06 
                 
                   0.34 
                 
                 0.003 
                 0.74 
                 0.1958 
                 HMDB01847 
               
               
                 2-aminoadipate 
                 
                   0.62 
                 
                 5.33E−06 
                 
                   0.96 
                 
                 0.0542 
                 0.96 
                 0.5549 
                 HMDB00510 
               
               
                 5-aminovalerate 
                 
                   0.48 
                 
                 5.79E−06 
                 0.31 
                 0.1099 
                 1.01 
                 0.9767 
                 HMDB03355 
               
               
                 5-methylthioadenosine (MTA) 
                 
                   2.18 
                 
                 6.44E−06 
                 
                   2.04 
                 
                 0.0002 
                 1.33 
                 0.2644 
                 HMDB01173 
               
               
                 isobutyrylcarnitine 
                 
                   0.56 
                 
                 6.56E−06 
                 0.73 
                 0.3009 
                 0.84 
                 0.5299 
               
               
                 xanthurenate 
                 
                   0.68 
                 
                 9.84E−06 
                 1.17 
                 0.2871 
                 1.08 
                 0.5768 
                 HMDB00881 
               
               
                 scyllo-inositol 
                 
                   0.47 
                 
                 1.10E−05 
                 
                   0.59 
                 
                 0.0395 
                 0.87 
                 0.6725 
                 HMDB06088 
               
               
                 fructose 
                 
                   0.4 
                 
                 1.33E−05 
                 0.72 
                 0.7677 
                 1.17 
                 0.1565 
                 HMDB00660 
               
               
                 4-hydroxymandelate 
                 
                   0.56 
                 
                 1.34E−05 
                 0.78 
                 0.4183 
                 
                   0.82 
                 
                 0.0552 
                 HMDB00822 
               
               
                 p-cresol sulfate 
                 
                   0.6 
                 
                 1.51E−05 
                 1.23 
                 0.1282 
                 1.33 
                 0.1905 
               
               
                 nicotinate 
                 
                   0.49 
                 
                 2.82E−05 
                 
                   0.58 
                 
                 0.0062 
                 1.17 
                 0.9441 
                 HMDB01488 
               
               
                 tyramine 
                 
                   0.62 
                 
                 3.42E−05 
                 0.91 
                 0.9143 
                 0.86 
                 0.2212 
                 HMDB00306 
               
               
                 5-acetylamino-6-formylamino- 
                 
                   0.61 
                 
                 3.46E−05 
                 0.84 
                 0.1381 
                 
                   1.24 
                 
                 0.0472 
                 HMDB11105 
               
               
                 3-methyluracil 
               
               
                 3-(3-hydroxyphenyl)propionate 
                 
                   0.25 
                 
                 3.48E−05 
                 0.53 
                 0.3567 
                 1.6 
                 0.6808 
                 HMDB00375 
               
               
                 1-methylxanthine 
                 
                   0.46 
                 
                 3.79E−05 
                 
                   0.42 
                 
                 0.0247 
                 
                   0.63 
                 
                 0.0115 
               
               
                 trigonelline (N′- 
                 
                   0.67 
                 
                 4.67E−05 
                 
                   0.68 
                 
                 0.0012 
                 1.28 
                 0.4077 
                 HMDB00875 
               
               
                 methylnicotinate) 
               
               
                 3-methylxanthine 
                 
                   0.47 
                 
                 4.98E−05 
                 0.76 
                 0.1971 
                 0.86 
                 0.1676 
                 HMDB01886 
               
               
                 glucosamine 
                 
                   0.45 
                 
                 5.50E−05 
                 0.99 
                 0.2774 
                 1.35 
                 0.3249 
                 HMDB01514 
               
               
                 1,6-anhydroglucose 
                 
                   0.48 
                 
                 5.55E−05 
                 0.71 
                 0.1691 
                 1 
                 0.2081 
                 HMDB00640 
               
               
                 3-methylcrotonylglycine 
                 
                   0.65 
                 
                 5.67E−05 
                 1.1 
                 0.402 
                 1.56 
                 0.2008 
                 HMDB00459 
               
               
                 gulono-1,4-lactone 
                 
                   2.04 
                 
                 5.93E−05 
                 1.09 
                 0.2409 
                 
                   0.66 
                 
                 0.0003 
                 HMDB03466 
               
               
                 quinate 
                 
                   0.66 
                 
                 7.93E−05 
                 
                   0.81 
                 
                 0.0009 
                 
                   0.94 
                 
                 0.0002 
                 HMDB03072 
               
               
                 mesaconate (methylfumarate) 
                 
                   0.62 
                 
                 8.49E−05 
                 0.99 
                 0.3644 
                 1.08 
                 0.5564 
                 HMDB00749 
               
               
                 sebacate (decanedioate) 
                 
                   2.53 
                 
                 0.0001 
                 0.62 
                 0.1849 
                 0.51 
                 0.4858 
                 HMDB00792 
               
               
                 N-acetylphenylalanine 
                 
                   0.65 
                 
                 0.0001 
                 1.1 
                 0.7182 
                 
                   1.93 
                 
                 0.0012 
                 HMDB00512 
               
               
                 beta-alanine 
                 
                   0.32 
                 
                 0.0002 
                 
                   0.5 
                 
                 0.0008 
                 1.47 
                 0.3724 
                 HMDB00056 
               
               
                 3-hydroxybutyrate (BHBA) 
                 
                   5.92 
                 
                 0.0002 
                 0.31 
                 0.1711 
                 
                   0.09 
                 
                 0.0007 
                 HMDB00357 
               
               
                 alanine 
                 
                   0.72 
                 
                 0.0002 
                 
                   0.78 
                 
                 0.015 
                 
                   1.32 
                 
                 0.0133 
                 HMDB00161 
               
               
                 sarcosine (N-Methylglycine) 
                 
                   0.76 
                 
                 0.0002 
                 
                   0.96 
                 
                 0.0758 
                 1.32 
                 0.3949 
                 HMDB00271 
               
               
                 3-methyl-2-oxovalerate 
                 
                   1.71 
                 
                 0.0002 
                 1.04 
                 0.2866 
                 0.67 
                 0.3559 
                 HMDB03736 
               
               
                 1-methylhistidine 
                 
                   0.55 
                 
                 0.0002 
                 1 
                 0.6429 
                 0.88 
                 0.1937 
                 HMDB00001 
               
               
                 1,7-dimethylurate 
                 
                   0.62 
                 
                 0.0002 
                 0.74 
                 0.1286 
                 
                   0.85 
                 
                 0.0177 
                 HMDB11103 
               
               
                 isobutyrylglycine 
                 
                   0.77 
                 
                 0.0002 
                 1.25 
                 0.2172 
                 1.61 
                 0.1927 
                 HMDB00730 
               
               
                 cortisone 
                 
                   1.33 
                 
                 0.0004 
                 0.99 
                 0.9786 
                 1.08 
                 0.9413 
                 HMDB02802 
               
               
                 methionine 
                 
                   0.71 
                 
                 0.0005 
                 
                   0.83 
                 
                 0.0273 
                 0.99 
                 0.9993 
                 HMDB00696 
               
               
                 gamma-aminobutyrate (GABA) 
                 
                   0.52 
                 
                 0.0005 
                 0.95 
                 0.7208 
                 1.11 
                 0.4535 
                 HMDB00112 
               
               
                 anserine 
                 
                   0.34 
                 
                 0.0005 
                 1.44 
                 0.5487 
                 2.75 
                 0.4523 
                 HMDB00194 
               
               
                 hippurate 
                 
                   0.72 
                 
                 0.0006 
                 
                   0.74 
                 
                 0.0318 
                 
                   0.91 
                 
                 0.0576 
                 HMDB00714 
               
               
                 tryptophan 
                 
                   1.53 
                 
                 0.0008 
                 1.16 
                 0.5013 
                 1.1 
                 0.6423 
                 HMDB00929 
               
               
                 hexanoylcarnitine 
                 
                   1.43 
                 
                 0.0008 
                 1.18 
                 0.1281 
                 1 
                 0.8835 
                 HMDB00705 
               
               
                 phenyllactate (PLA) 
                 
                   0.42 
                 
                 0.0009 
                 
                   0.72 
                 
                 0.0623 
                 1.61 
                 0.6146 
                 HMDB00779 
               
               
                 paraxanthine 
                 
                   0.49 
                 
                 0.001 
                 
                   0.38 
                 
                 0.0028 
                 
                   0.59 
                 
                 0.0092 
                 HMDB01860 
               
               
                 pyridoxate 
                 
                   0.36 
                 
                 0.0011 
                 1.1 
                 0.683 
                 1.02 
                 0.773 
                 HMDB00017 
               
               
                 arabinose 
                 
                   0.72 
                 
                 0.0012 
                 
                   0.84 
                 
                 0.0726 
                 
                   0.91 
                 
                 0.0854 
                 HMDB00646 
               
               
                 7-methylxanthine 
                 
                   0.53 
                 
                 0.0012 
                 0.77 
                 0.2641 
                 0.87 
                 0.4015 
                 HMDB01991 
               
               
                 7-methylguanine 
                 
                   1.29 
                 
                 0.0012 
                 1.06 
                 0.7499 
                 1.16 
                 0.2737 
                 HMDB00897 
               
               
                 decanoylcarnitine 
                 
                   1.65 
                 
                 0.0015 
                 
                   1.58 
                 
                 0.0313 
                 0.91 
                 0.2273 
                 HMDB00651 
               
               
                 ascorbate (Vitamin C) 
                 
                   0.13 
                 
                 0.0017 
                 0.54 
                 0.2485 
                 
                   0.86 
                 
                 0.0675 
                 HMDB00044 
               
               
                 acetylcarnitine 
                 
                   1.95 
                 
                 0.0019 
                 0.82 
                 0.3328 
                 
                   0.68 
                 
                 0.0232 
                 HMDB00201 
               
               
                 lysine 
                 
                   0.66 
                 
                 0.002 
                 1.02 
                 0.2246 
                 1.17 
                 0.2675 
                 HMDB00182 
               
               
                 guanidinoacetate 
                 
                   0.73 
                 
                 0.002 
                 1.17 
                 0.99 
                 1.62 
                 0.5165 
                 HMDB00128 
               
               
                 phenylacetylglutamine 
                 
                   0.81 
                 
                 0.0022 
                 
                   1.14 
                 
                 0.0032 
                 
                   1.46 
                 
                 0.006 
                 HMDB06344 
               
               
                 itaconate (methylenesuccinate) 
                 
                   0.81 
                 
                 0.0028 
                 1.38 
                 0.4912 
                 1.24 
                 0.3215 
                 HMDB02092 
               
               
                 isovalerylglycine 
                 
                   0.66 
                 
                 0.0028 
                 1.18 
                 0.3055 
                 1.17 
                 0.478 
                 HMDB00678 
               
               
                 N-6-trimethyllysine 
                 
                   0.68 
                 
                 0.0029 
                 0.88 
                 0.1121 
                 0.93 
                 0.5685 
                 HMDB01325 
               
               
                 2-hydroxyisobutyrate 
                 
                   1.37 
                 
                 0.0029 
                 
                   1.27 
                 
                 0.0134 
                 
                   0.77 
                 
                 0.0064 
                 HMDB00729 
               
               
                 beta-hydroxypyruvate 
                 
                   1.78 
                 
                 0.0031 
                 0.99 
                 0.74 
                 
                   0.78 
                 
                 0.0062 
                 HMDB01352 
               
               
                 pimelate (heptanedioate) 
                 
                   0.61 
                 
                 0.0035 
                 1.19 
                 0.3425 
                 1.12 
                 0.7102 
                 HMDB00857 
               
               
                 glycine 
                 
                   0.89 
                 
                 0.0036 
                 
                   0.79 
                 
                 0.0037 
                 1.03 
                 0.9682 
                 HMDB00123 
               
               
                 mannose 
                 
                   0.55 
                 
                 0.004 
                 0.82 
                 0.3395 
                 1.12 
                 0.8406 
                 HMDB00169 
               
               
                 cysteine 
                 
                   0.82 
                 
                 0.0052 
                 
                   0.88 
                 
                 0.0567 
                 0.91 
                 0.2935 
                 HMDB00574 
               
               
                 N-acetyltyrosine 
                 
                   0.6 
                 
                 0.0052 
                 0.91 
                 0.8458 
                 
                   1.41 
                 
                 0.0199 
                 HMDB00866 
               
               
                 glutamine 
                 
                   1.53 
                 
                 0.0061 
                 0.92 
                 0.4043 
                 1.49 
                 0.3348 
                 HMDB00641 
               
               
                 leucine 
                 
                   1.28 
                 
                 0.0067 
                 0.96 
                 0.9327 
                 1.04 
                 0.7329 
                 HMDB00687 
               
               
                 indolelactate 
                 
                   0.73 
                 
                 0.007 
                 0.94 
                 0.508 
                 
                   1.67 
                 
                 0.0254 
                 HMDB00671 
               
               
                 xanthine 
                 
                   1.41 
                 
                 0.0073 
                 1.06 
                 0.6782 
                 1.37 
                 0.1721 
                 HMDB00292 
               
               
                 lactose 
                 
                   0.58 
                 
                 0.0074 
                 1.12 
                 0.78 
                 1.27 
                 0.2407 
                 HMDB00186 
               
               
                 threonine 
                 
                   0.86 
                 
                 0.0079 
                 
                   0.87 
                 
                 0.0163 
                 1.21 
                 0.6336 
                 HMDB00167 
               
               
                 kynurenine 
                 
                   1.6 
                 
                 0.008 
                 0.74 
                 0.4686 
                 1.25 
                 0.5888 
                 HMDB00684 
               
               
                 sorbitol 
                 
                   0.75 
                 
                 0.0087 
                 3.42 
                 0.7352 
                 4.56 
                 0.621 
                 HMDB00247 
               
               
                 3-hydroxysebacate 
                 
                   1.75 
                 
                 0.009 
                 0.86 
                 0.7823 
                 0.75 
                 0.1105 
                 HMDB00350 
               
               
                 5-hydroxyindoleacetate 
                 
                   0.7 
                 
                 0.0093 
                 1.07 
                 0.8213 
                 1.13 
                 0.7909 
                 HMDB00763 
               
               
                 pyroglutamine 
                 
                   0.81 
                 
                 0.0103 
                 0.87 
                 0.1065 
                 0.96 
                 0.6105 
               
               
                 azelate (nonanedioate) 
                 
                   0.64 
                 
                 0.0107 
                 0.8 
                 0.1913 
                 
                   1.47 
                 
                 0.0155 
                 HMDB00784 
               
               
                 neopterin 
                 
                   1.41 
                 
                 0.012 
                 1.21 
                 0.3553 
                 
                   1.38 
                 
                 0.0315 
                 HMDB00845 
               
               
                 gamma-glutamyltyrosine 
                 
                   0.74 
                 
                 0.0125 
                 0.99 
                 0.6907 
                 1.1 
                 0.8961 
               
               
                 4-vinylphenol sulfate 
                 
                   0.77 
                 
                 0.0128 
                 1.01 
                 0.877 
                 1.11 
                 0.7154 
                 HMDB04072 
               
               
                 dimethylglycine 
                 
                   0.75 
                 
                 0.0135 
                 
                   0.85 
                 
                 0.0686 
                 0.88 
                 0.3711 
                 HMDB00092 
               
               
                 serine 
                 
                   0.82 
                 
                 0.0138 
                 
                   0.82 
                 
                 0.0222 
                 0.9 
                 0.9516 
                 HMDB03406 
               
               
                 creatine 
                 
                   0.36 
                 
                 0.015 
                 1.16 
                 0.6036 
                 1.62 
                 0.2614 
                 HMDB00064 
               
               
                 octanoylcarnitine 
                 
                   1.29 
                 
                 0.0152 
                 1.22 
                 0.2376 
                 0.86 
                 0.249 
               
               
                 3-methoxytyrosine 
                 
                   1.63 
                 
                 0.0174 
                 1.64 
                 0.1587 
                 3.44 
                 0.1716 
                 HMDB01434 
               
               
                 malate 
                 
                   2.63 
                 
                 0.018 
                 2.28 
                 0.6561 
                 2.02 
                 0.8528 
                 HMDB00156 
               
               
                 mandelate 
                 
                   0.8 
                 
                 0.0187 
                 1.03 
                 0.6199 
                 1.1 
                 0.2628 
                 HMDB00703 
               
               
                 aspartate 
                 
                   0.82 
                 
                 0.0192 
                 
                   0.66 
                 
                 0.005 
                 1.4 
                 0.2923 
                 HMDB00191 
               
               
                 gamma-glutamylthreonine 
                 
                   0.81 
                 
                 0.0196 
                 
                   0.91 
                 
                 0.0883 
                 1.11 
                 0.7569 
               
               
                 4-ureidobutyrate 
                 
                   0.86 
                 
                 0.0234 
                 0.98 
                 0.5831 
                 1.13 
                 0.1905 
               
               
                 valine 
                 
                   1.25 
                 
                 0.0235 
                 0.93 
                 0.6915 
                 1.08 
                 0.6722 
                 HMDB00883 
               
               
                 alpha-ketoglutarate 
                 
                   1.99 
                 
                 0.0241 
                 1.47 
                 0.3582 
                 1.42 
                 0.2569 
                 HMDB00208 
               
               
                 5-acetylamino-6-amino-3- 
                 
                   0.43 
                 
                 0.0263 
                 0.89 
                 0.6847 
                 1.04 
                 0.8541 
                 HMDB04400 
               
               
                 methyluracil 
               
               
                 4-hydroxyphenylacetate 
                 
                   0.69 
                 
                 0.0269 
                 
                   1.46 
                 
                 0.0015 
                 1.28 
                 0.3338 
                 HMDB00020 
               
               
                 gamma-glutamylphenylalanine 
                 
                   1.34 
                 
                 0.0322 
                 
                   0.9 
                 
                 0.0659 
                 1.14 
                 0.8583 
                 HMDB00594 
               
               
                 isocitrate 
                 
                   0.8 
                 
                 0.0331 
                 0.8 
                 0.1792 
                 1.11 
                 0.9539 
                 HMDB00193, 
               
               
                   
                   
                   
                   
                   
                   
                   
                 HMDB01874 
               
               
                 threitol 
                 
                   0.83 
                 
                 0.0371 
                 0.87 
                 0.842 
                 0.78 
                 0.3598 
                 HMDB04136 
               
               
                 pantothenate 
                 
                   0.64 
                 
                 0.0396 
                 1.12 
                 0.4425 
                 1.01 
                 0.5022 
                 HMDB00210 
               
               
                 N6-carbamoylthreonyladenosine 
                 
                   1.29 
                 
                 0.044 
                 1.13 
                 0.3033 
                 1.19 
                 0.2383 
               
               
                 isoleucine 
                 
                   1.24 
                 
                 0.048 
                 0.88 
                 0.3879 
                 1.09 
                 0.6039 
                 HMDB00172 
               
               
                 N-acetylglutamine 
                 
                   1.41 
                 
                 0.0488 
                 
                   1.58 
                 
                 0.0168 
                 1.27 
                 0.3028 
                 HMDB06029 
               
               
                 androsterone sulfate 
                 
                   1.25 
                 
                 0.0568 
                 
                   1.51 
                 
                 0.0454 
                 0.97 
                 0.4081 
                 HMDB02759 
               
               
                 N4-acetylcytidine 
                 
                   1.23 
                 
                 0.0585 
                 1.19 
                 0.1462 
                 
                   1.19 
                 
                 0.0562 
                 HMDB05923 
               
               
                 galactitol (dulcitol) 
                 
                   0.8 
                 
                 0.0603 
                 1.06 
                 0.4119 
                 1.25 
                 0.3608 
                 HMDB00107 
               
               
                 pro-hydroxy-pro 
                 
                   1.24 
                 
                 0.0663 
                 1.1 
                 0.2669 
                 1.13 
                 0.2931 
                 HMDB06695 
               
               
                 lactate 
                 
                   1.24 
                 
                 0.0667 
                 
                   0.39 
                 
                 3.29E−05 
                 1.34 
                 0.1663 
                 HMDB00190 
               
               
                 1-methylurate 
                 
                   0.84 
                 
                 0.0674 
                 
                   0.7 
                 
                 0.0816 
                 1.01 
                 0.7689 
                 HMDB03099 
               
               
                 indoleacetate 
                 
                   1.42 
                 
                 0.0689 
                 1.34 
                 0.1364 
                 1.32 
                 0.592 
                 HMDB00197 
               
               
                 urate 
                 
                   1.11 
                 
                 0.0734 
                 0.94 
                 0.3996 
                 
                   1.18 
                 
                 0.0807 
                 HMDB00289 
               
               
                 phenylalanine 
                 
                   1.26 
                 
                 0.0758 
                 1.21 
                 0.1977 
                 1.16 
                 0.2046 
                 HMDB00159 
               
               
                 gamma-glutamylleucine 
                 
                   0.77 
                 
                 0.0815 
                 1.06 
                 0.8816 
                 0.96 
                 0.6133 
                 HMDB11171 
               
               
                 4-ethylphenylsulfate 
                 
                   0.54 
                 
                 0.0829 
                 0.67 
                 0.8041 
                 0.89 
                 0.2725 
               
               
                 carnosine 
                 
                   0.36 
                 
                 0.0878 
                 0.68 
                 0.8209 
                 0.72 
                 0.6219 
                 HMDB00033 
               
               
                 homocitrulline 
                 
                   0.84 
                 
                 0.0979 
                 0.86 
                 0.1723 
                 1.01 
                 0.4838 
                 HMDB00679 
               
               
                 2-aminobutyrate 
                 
                   1.14 
                 
                 0.0986 
                 
                   0.81 
                 
                 0.0271 
                 0.76 
                 0.3751 
                 HMDB00650 
               
               
                 5-hydroxyhexanoate 
                 
                   0.68 
                 
                 0.099 
                 1.04 
                 0.4115 
                 1.11 
                 0.6993 
                 HMDB00525 
               
               
                 isovalerylcarnitine 
                 0.64 
                 0.1644 
                 0.66 
                 0.1875 
                 
                   0.64 
                 
                 0.0037 
                 HMDB00688 
               
               
                 glycocholate 
                 0.9 
                 0.1771 
                 1.1 
                 0.9661 
                 
                   2.14 
                 
                 0.0079 
                 HMDB00138 
               
               
                 cholate 
                 0.6 
                 0.2725 
                 0.77 
                 0.8537 
                 
                   2 
                 
                 0.0147 
                 HMDB00619 
               
               
                 3-indoxyl sulfate 
                 0.92 
                 0.3457 
                 
                   1.78 
                 
                 1.08E−06 
                 
                   1.52 
                 
                 0.0602 
                 HMDB00682 
               
               
                 proline 
                 1.1 
                 0.3963 
                 0.91 
                 0.5784 
                 
                   1.39 
                 
                 0.0029 
                 HMDB00162 
               
               
                 mannitol 
                 0.94 
                 0.5089 
                 1.06 
                 0.261 
                 
                   3 
                 
                 0.0017 
                 HMDB00765 
               
               
                 succinate 
                 1.11 
                 0.6315 
                 
                   1.72 
                 
                 0.0024 
                 1.14 
                 0.9413 
                 HMDB00254 
               
               
                 pipecolate 
                 0.65 
                 0.7311 
                 1.06 
                 0.5698 
                 
                   1.58 
                 
                 0.0706 
                 HMDB00070 
               
               
                 3-hydroxyisobutyrate 
                 1.05 
                 0.7472 
                 
                   1.16 
                 
                 0.0693 
                 
                   1.23 
                 
                 0.0014 
                 HMDB00336 
               
               
                 choline 
                 1.02 
                 0.8127 
                 
                   0.72 
                 
                 0.0029 
                 
                   1.32 
                 
                 0.0174 
               
               
                 adenosine 
                 1.07 
                 0.8234 
                 
                   1.47 
                 
                 0.0004 
                 1.15 
                 0.8031 
                 HMDB00050 
               
               
                 N-acetylthreonine 
                 0.96 
                 0.9472 
                 1 
                 0.822 
                 
                   1.23 
                 
                 0.0577 
               
               
                 7-ketodeoxycholate 
                 1.79 
                 0.9864 
                 2.15 
                 0.2117 
                 
                   9.64 
                 
                 0.0009 
                 HMDB00391 
               
               
                   
               
             
          
         
       
     
         [0169]    The biomarkers were then used to create a statistical model to identify subjects having kidney cancer. Using Random Forest analysis, the biomarkers were used in a mathematical model to classify subjects as having kidney cancer or normal. The results of the Random Forest analysis show that the samples were classified with 93% prediction accuracy. The Confusion Matrix presented in Table 12 shows the number of samples predicted for each classification and the actual in each group (RCC or Normal). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from a RCC subject or a normal subject). The OOB error was approximately 7%, and the model estimated that, when used on a new set of subjects, the identity of RCC subjects could be predicted 93% of the time and normal subjects could be predicted correctly 94% of the time. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Results of Random Forest, RCC vs. Normal 
               
             
          
           
               
                   
                   
                 Predicted Group 
                 class. 
               
             
          
           
               
                   
                   
                 RCC 
                 Normal 
                 Error 
               
               
                   
               
             
          
           
               
                 Actual 
                 RCC 
                 45 
                  3 
                 0.067416 
               
               
                 Group 
                 Normal 
                  6 
                 83 
                 0.0625 
               
               
                   
               
             
          
         
       
     
         [0170]    Based on the OOB Error rate of 7%, the Random Forest model that was created predicted whether a sample was from an individual with RCC with about 93% accuracy based on the levels of the biomarkers measured in samples from the subject. Exemplary biomarkers for distinguishing the groups are methyl-4-hydroxybenzoate, catechol-sulfate, glycerol, 2-hydroxyhippurate (salicylurate), N(2)-furoyl-glycine, 3-hydroxyphenylacetate, gulono 1,4-lactone, 2-isopropylmalate, 2-3-dihydroxyisovalerate, 1-2-propanediol, gluconate, cinnamoylglycine, phenylacetylglycine, sorbose, sucrose, adenosine 5′-monophosphate (AMP), hexanoylglycine, methyl-indole-3-acetate, 3-hydroxyhippurate, N6-methyladenosine, 4-hydroxy-2-oxoglutaric acid, alpha-CEHC-glucuronide, phenylpropinylglycine, vanillate, ethanolamine, galactose, adipate, 2-oxindole-3-acetate, 1, 3-7-trimethylurate, and 3-4-dihydroxyphenylacetate. 
         [0171]    The Random Forest results demonstrated that by using the biomarkers, RCC subjects were distinguished from normal subjects with 94% sensitivity, 93% specificity, 88% PPV, and 97% NPV. 
         [0172]    The biomarkers were used to create a statistical model to distinguish subjects having kidney cancer from those having prostate cancer. The biomarkers were evaluated using Random Forest analysis to classify subjects as having RCC or PCA. The Random Forest results show that the samples were classified with 80% prediction accuracy. The Confusion Matrix presented in Table 15 shows the number of samples predicted for each classification and the actual in each group (RCC or PCA). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from a RCC subject or a PCA subject). The OOB error was approximately 20%, and the model estimated that, when used on a new set of subjects, the identity of RCC subjects could be predicted 77% of the time and PCA subjects could be predicted correctly 83% of the time and as presented in Table 13. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Results of Random Forest, RCC vs. PCA 
               
             
          
           
               
                   
                   
                 Predicted Group 
                 class. 
               
             
          
           
               
                   
                   
                 RCC 
                 PCA 
                 Error 
               
               
                   
               
               
                 Actual 
                 RCC 
                 37 
                 11 
                 0.229167 
               
               
                 Group 
                 PCA 
                 10 
                 48 
                 0.172414 
               
               
                   
               
             
          
         
       
     
         [0173]    Based on the OOB Error rate of 20%, the Random Forest model that was created predicted whether a sample was from an individual with RCC with about 80% accuracy based on the levels of the biomarkers measured in samples from the subject. The biomarkers that are the most important biomarkers for distinguishing the groups are gluconate, 1-2-propanediol, galactose, gulono 1,4-lactone, orotidine, quinate, 1, 3-7-trimethylurate, guanine, phenylacetylglutamine, mannitol, 2-oxindole-3-acetate, 1,3-aminopropyl-2-pyrrolidone, 1,3-dimethylurate, Isobar-glucuronate-galacturonate-5-keto-gluconate, glycocholate, azelate (nonanedioate), N-acetylthreonine, 7-ketodeoxycholate, 3-sialyllactose, isovalerylcarnitine, cholate, adenosine 5′-monophosphate (AMP), 2-3-butanediol, 2-hydroxyhippurate, pipecolate, N-acetylphenylalanine, 12-dehydrocholate, alpha-ketoglutarate, sulforaphane. 
         [0174]    The Random Forest results demonstrated that by using the biomarkers, RCC subjects were distinguished from PCA subjects with 77% sensitivity, 83% specificity, 79% PPV, 81% NPV. 
         [0175]    The biomarkers were used to create a statistical model to classify subjects as having kidney cancer from those having bladder cancer. The biomarkers were evaluated using Random Forest analysis to classify subjects as having RCC or BCA. The Random Forest results show that the samples were classified with 75% prediction accuracy. The Confusion Matrix presented in Table 14 shows the number of samples predicted for each classification and the actual in each group (RCC or BCA). The “Out-of-Bag” (OOB) Error rate gives an estimate of how accurately new observations can be predicted using the Random Forest model (e.g., whether a sample is from a RCC subject or a BCA subject). The OOB error was approximately 25%, and the model estimated that, when used on a new set of subjects, the identity of RCC subjects could be predicted 76% of the time and BCA subjects could be predicted correctly 73% of the time and as presented in Table 14. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Results of Random Forest, RCC vs. BCA 
               
             
          
           
               
                   
                   
                 Predicted Group 
                 class. 
               
             
          
           
               
                   
                   
                 RCC 
                 BCA 
                 Error 
               
               
                   
               
               
                 Acutal 
                 RCC 
                 35 
                 13 
                 0.242424 
               
               
                 Group 
                 BCA 
                 16 
                 50 
                 0.270833 
               
               
                   
               
             
          
         
       
     
         [0176]    Based on the OOB Error rate of 25%, the Random Forest model that was created predicted whether a sample was from an individual with RCC with about 75% accuracy based on the levels of the biomarkers measured in samples from the subject. The biomarkers that are the most important biomarkers for distinguishing the groups are 3-indoxyl-sulfate, methyl-indole-3-acetate, methyl-4-hydroxybenzoate, lactate, N(2)-furoyl-glycine, N6-methyladenosine, gamma-CEHC, glycerol, 2-3-butanediol, palmitoyl-sphingomyelin, succinate, 4-hydroxyphenylacetate, caffeate, imidazole-prpionate, beta-alanine, 4-androsten-3beta-17beta-diol-disulfate-2,5-methylthioadenosine, (MTA), N2-acetyllysine, sucrose, phenylacetylglycine, 4-androsten-3beta-17beta-diol-disulfate-1, cyclo-gly-pro, N-methyl-proline, catechol-sulfate, serine, vanillate, threonine, 21-hydroxypregnenolone-disulfate, adenosine 5′-monophosphate (AMP), phenylacetylglutamine. 
         [0177]    The Random Forest results demonstrated that by using the biomarkers, RCC subjects were distinguished from BCA subjects with 73% sensitivity, 78% specificity, 69% PPV, and 79% NPV. 
       Example 7 
     Algorithm to Monitor Kidney Cancer Progression/Regression 
       [0178]    Using the biomarkers for kidney cancer, an algorithm could be developed to monitor kidney cancer progression/regression in subjects. The algorithm, based on a panel of metabolite biomarkers from Tables 1, 2, 4, 8, 10 and/or 11, when used on a new set of patients, would assess and monitor a patient&#39;s progression/regression of kidney cancer. Using the results of this biomarker algorithm, a medical oncologist could assess the risk-benefit of surgery (i.e., full or partial nephrectomy), drug treatment or a watchful waiting approach. 
         [0179]    The biomarker algorithm would monitor the levels of a panel of biomarkers for kidney cancer identified in Tables 1, 2, 4, 8, 10 and/or 11.