US 2017013 7885A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0137885 A1 Salomon et al. (43) Pub. Date: May 18, 2017

(54) EXPRESSION PROFILES Sep. 9, 2014, which is a continuation-in-part of appli ASSOCATED WITH SUB-CLINICAL cation No. PCT/US2014/054735, filed on May 22, KIDNEY TRANSPLANT RELECTION 2014. (60) Provisional application No. 62/001.902, filed on May (71) Applicants: THE SCRIPPS RESEARCH 22, 2014, provisional application No. 62/001,909, INSTITUTE, LA JOLLA, CA (US); filed on May 22, 2014, provisional application No. NORTHWESTERN UNIVERSITY, 62/001.889, filed on May 22, 2014, provisional ap EVANSTON, IL (US) plication No. 62/029,038, filed on Jul. 25, 2014. (72) Inventors: Daniel R. Salomon, San Diego, CA (US); John Friedewald, Chicago, IL Publication Classification (US); Sunil Kurian, San Diego, CA (51) Int. C. (US); Michael M. Abecassis, Highland CI2O I/68 (2006.01) Park, IL (US); Steven Head, Lakeside, (52) U.S. C. CA (US); Phillip Ordoukhanian, San CPC ..... CI2O 1/6883 (2013.01); C12O 2600/158 Diego, CA (US) (2013.01); C12O 2600/118 (2013.01) (21) Appl. No.: 15/358,390 (57) ABSTRACT (22) Filed: Nov. 22, 2016 By a genome-wide gene analysis of expression profiles of over 50,000 known or putative gene sequences in peripheral Related U.S. Application Data blood, the present inventors have identified a consensus set (63) Continuation of application No. PCT/US2015/ of -based molecular biomarkers associated 032202, filed on May 22, 2015, which is a continu with subclinical acute rejection (subAR). These sets ation-in-part of application No. 14/481,167, filed on are useful for diagnosis, prognosis, monitoring of SubAR. Patent Application Publication May 18, 2017. Sheet 1 of 7 US 2017/O137885 A1

A schematic Overview of certain methods in the disclosure,

10. Obtain sample from a transplant recipient

120. Perform assay to determine gene expression level

130. Apply computer algorithm to the gene expression level

4. Classification Class A Class E Class C based on the results

Patent Application Publication May 18, 2017. Sheet 2 of 7 US 2017/O137885 A1

A system for implementing the methods of the disclosure.

2. Transplant 22. 23, recipient Sample Assay

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Patent Application Publication May 18, 2017. Sheet 3 of 7 US 2017/O137885 A1

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PLNS 3.: 10.7%f2 k s Cl4cras s SATA s TMEM22 Corf.32 R 3. A4 2 RLBP is SP3 f. Patent Application Publication May 18, 2017. Sheet 4 of 7 US 2017/O137885 A1

A system for implementing the methods of the disclosure.

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4. Patent Application Publication May 18, 2017. Sheet 5 of 7 US 2017/O137885 A1

Correlation of fold-change between microarray and NGS analyses (68 common genes).

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- 3. Patent Application Publication May 18, 2017. Sheet 7 of 7 US 2017/O137885 A1

Correlation of fold-change between microarray and NGS analyses (ali expressed NGS 7.378 genes).

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GENE EXPRESSION PROFILES (such as increased perforin, granzyme, c-Bet expression or ASSOCATED WITH SUB-CLINICAL markers), or by an increased ability of the KIDNEY TRANSPLANT REUECTION allograft to withstand immune injury (accommodation). SubAR or SCAR is often diagnosed only on biopsies taken CROSS-REFERENCE TO RELATED as per protocol at a fixed time after transplantation, rather APPLICATIONS than driven by clinical indication. Its diagnosis cannot rely 0001. This application claims the benefit of priority to on traditional kidney function measurements like serum International Application No. PCT/US2015/032202, filed creatinine and glomerular filtration rates. Predicting graft May 22, 2015; to U.S. application Ser. No. 14/481,167, filed outcomes strictly based on the kidney biopsy is difficult and Sep. 9, 2014; to International Application No. PCT/US2014/ this invasive procedure has significant costs and risks for 054735, filed Sep. 9, 2014; to U.S. Provisional Application patients. Organ biopsy results can also be inaccurate, par No. 62/029,038, filed Jul. 25, 2014; to U.S. Provisional ticularly if the area biopsied is not representative of the Application No. 62/001,889, filed May 22, 2014; to U.S. health of the organ as a whole (e.g., as a result of sampling error). There can be significant differences between indi Provisional Application No. 62/001,902, filed May 22, vidual observers when they read the same biopsies indepen 2014; and to U.S. Provisional Application No. 62/001,909, dently and these discrepancies are particularly an issue for filed May 22, 2014, each of which is incorporated by complex histologies that can be challenging for clinicians. In reference herein in their entirety. addition, the early detection of rejection of a transplant STATEMENT CONCERNING GOVERNMENT organ may require serial monitoring by obtaining multiple SUPPORT biopsies, thereby multiplying the risks to the patients, as well as the associated costs. 0002 This invention was made with government support 0008 Transplant rejection is a marker of ineffective under AIO63603 awarded by the National Institutes of immunosuppression and ultimately if it cannot be resolved, Health. government has certain rights in the invention. a failure of the chosen therapy. The fact that 50% of kidney transplant patients will lose their grafts by ten years post COPYRIGHT NOTIFICATION transplant reveals the difficulty of maintaining adequate and 0003 Pursuant to 37 C.F.R. S1.71(e), Applicants note effective long-term immunosuppression. Currently, there are that a portion of this disclosure contains material which is no other effective and reliable blood-based or any other tests Subject to copyright protection. The copyright owner has no for subAR or SCAR diagnosis. Thus, there is a pressing objection to the facsimile reproduction by anyone of the medical need to identify minimally invasive biomarkers that patent document or patent disclosure, as it appears in the are able to identify SubAR or SCAR at a time that changes Patent and Trademark Office patent file or records, but in therapy may alter outcomes. The present invention otherwise reserves all copyright rights whatsoever. addresses this and other unfulfilled needs in the art. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0004 Kidney transplantation offers a significant 0009. In one aspect, the disclosure provides methods of improvement in life expectancy and quality of life for detecting, prognosing, diagnosing or monitoring Subclinical patients with end stage renal disease. Unfortunately, graft acute rejection (subAR or SCAR). These methods typically losses due to allograft dysfunction or other uncertain etiolo entail obtaining nucleic acids of interest, and then (a) gies have greatly hampered the therapeutic potential of determining or detecting expression levels in a Subject of at kidney transplantation. Among various types of graft losses, least 5 genes (e.g., at least 10 genes, at least 20 genes, at least Subclinical acute 50 genes, at least 100 genes, at least 300 genes, at least 500 0005 rejection (subAR or SCAR) is histologically genes, etc.); and (b) detecting, prognosing, diagnosing or defined as acute rejection characterized by tubule-interstitial monitoring subAR or SCAR in the subject from the expres mononuclear infiltration identified from a biopsy specimen, sion levels. In some methods, the nucleic acids of interest but without concurrent functional deterioration (variably comprise mRNA extracted from a sample from the subject defined as a serum creatinine not exceeding 10%, 20% or or nucleic acids derived from the mRNA extracted from the 25% of baseline values). sample from the subject. The methods are particularly useful 0006. A critically important challenge for the future of for analysis of blood samples. molecular diagnostics in transplantation based on peripheral 0010 Some of the methods are directed to subjects who blood profiling is to predict a state of adequate immunosup have or are at risk of developing SubAR or SCAR or acute pression with immune mediated kidney injury before there rejection (AR), or have well-functioning normal transplant is a change in the serum creatinine. This is the challenge of (TX). In some of the methods, the subject has a serum identifying Subclinical acute rejection, which at this time is creatinine level of less than 3 mg/dL, less than 2.5 mg/dL, only occasionally and accidentally picked up by protocol less than 2.0 mg/dL, or less than 1.5 mg/dL. In some biopsies done at arbitrary time points. methods, the Subject has a normal serum creatinine level. In 0007. The terms subAR and SCAR are used interchange Some of the methods, for each of the at least five genes, step ably herein to refer to subclinical acute rejection. SubAR (or (b) involves comparing the expression level of the gene in SCAR) is distinct from clinical acute rejection, which is the subject to one or more reference expression levels of the characterized by acute functional renal impairment. The gene associated with subAR or SCAR, acute rejection (AR) differences between SubAR or SCAR and acute rejection or lack of transplant rejection (TX). In some of these (which may appear histologically indistinguishable on a methods, step (b) further includes, for each of the at least limited sample) can be explained by real quantitative dif five genes, assigning the expression level of the gene in the ferences of renal cortex affected, qualitative differences Subject a value or other designation providing an indication US 2017/O 137885 A1 May 18, 2017

whether the subject has or is at risk of developing SCAR, has methods of the invention, expression levels of the genes are acute rejection (AR), or has well-functioning normal trans determined at the mRNA level or at the level. In (TX). In some methods, the expression level of each of Some methods, step (b) can be performed by a computer. In the at least five genes is assigned a value on a normalized Some preferred embodiments, the at least five genes are scale of values associated with a range of expression levels selected from one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14, in kidney transplant patients with SCAR, with AR, or with 15, 17, or 18. TX. In some methods, the expression level of each of the at 0015. In a related aspect, the invention provides methods least five genes is assigned a value or other designation of detecting, prognosing, diagnosing or monitoring Subclini providing an indication that the Subject has or is at risk of cal acute rejection (subAR or SCAR) in a subject having SCAR, has or is at risk of AR, has well-functioning normal normal serum creatinine level. These methods involve transplant, or that the expression level is uninformative. In obtaining nucleic acids of interest, and then (a) determining Some methods, step (b) further includes combining the or detecting expression levels in the Subject of at least 2 values or designations for each of the genes to provide a genes; and (b) detecting, prognosing, diagnosing or moni combined value or designation providing an indication toring subAR or SCAR in the subject from the expression whether the subject has or is at risk of SCAR, has acute levels. In some of these methods, the methods comprise rejection (AR), or has well-functioning normal transplant determining or detecting the expression levels in the Subject (TX). In some embodiments, the method can be repeated at of at least five genes. In some of these methods, the at least different times on the subject. Some of these methods are two genes or the at least five genes are selected from the directed to Subjects who have been receiving a drug, and a genes in one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, change in the combined value or designation over time 17, or 18. In some of these methods, the nucleic acids of provides an indication of the effectiveness of the drug. interest comprise mRNA extracted from a sample from a 0011. In some embodiments, the expression level is subject or nucleic acids derived from the mRNA extracted determined in a subject of at least five genes selected from from the sample from the subject. In some methods, the the genes in one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14. sample is a blood sample. In some methods, the nucleic 15, 17, or 18. In another aspect, the methods comprise acids of interest are contacted with probes, wherein the detecting or determining the expression level of at least 2, 3, probes are specific for the at least two genes or the at least 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, five genes. In some of these methods, for each of the at least 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 two genes or the at least five genes, step (b) entails com genes selected from at least one of Tables 2, 3, 4, 7, 8, 11, paring the expression level of the gene in the subject to one 12, 14, 15, 17, and 18. or more reference expression levels of the gene associated 0012. In some embodiments, the detection of expression with SCAR, or lack of transplant rejection (TX). In some of levels comprises applying a two-step classifier to the gene these methods, step (b) further includes, for each of the at expression levels. In some embodiments, one step in the least two genes or the at least five genes, assigning the two-step classifier distinguishes between normal transplant expression level of the gene in the subject a value or other (TX) and AR-i-SubAR. In some embodiments, one step in the designation providing an indication whether the Subject has two-step classifier distinguishes between AR and SubAR. or is at risk of developing SCAR. In some methods, the 0013. In various embodiments, the subjects suitable for expression level of each of the at least two genes or the at methods of the invention are patients who have undergone least five genes is assigned a value on a normalized scale of a kidney transplant. Often, the subject has received the values associated with a range of expression levels in kidney kidney transplant within 1 month, 3 months, 1 year, 2 years, transplant patients with and without SCAR. In some meth 3 years or 5 years of performing step (a). In some methods ods, the expression level of each of the at least two genes or of the invention, step (a) is performed on a blood sample of at least five genes is assigned a value or other designation the Subject. In some methods, the sample is a blood sample providing an indication that the Subject has or is at risk of and comprises whole blood, peripheral blood, serum, SCAR, lacks and is not at risk of SCAR, or that the plasma, PBLs, PBMCs, T cells, CD4 T cells CD8 T cells, or expression level is uninformative. In some of these methods, . In some methods, step (a) is performed on a step (b) further includes combining the values or designa urine sample of the Subject. In some methods, step (a) is tions for each of the genes to provide a combined value or performed on a biopsy from the subject, preferably a kidney designation providing an indication whether the Subject has biopsy. In some methods, step (a) is performed on at least 10, or is at risk of SubAR or SCAR. 20, 40, 50, 70, 100, 150, 200, 250, 300, 400, or 500 genes 0016. In various embodiments, the method can be from one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, 17, repeated at different times on the subject. In some methods, or 18. Some methods further include changing the treatment the Subject can be one who is receiving a drug, and a change regime of the patient responsive to the detecting, prognos in the combined value or designation over time provides an ing, diagnosing or monitoring step. In these methods, the indication of the effectiveness of the drug. Some methods of subject can be one who has received a drug before perform the invention are directed to subjects who have undergone a ing the methods, and the change comprises administering an kidney transplant within 1 month, 3 months, 1 year, 2 years, additional drug or administering a higher dose of the same 3 years or 5 years of performing step (a). In some methods, drug or administering a lower dose of the same drug, or step (a) is performed on a blood sample of the Subject. In stopping administering the same drug. Some methods, the sample is a blood sample and comprises 0014. Some methods of the invention further include whole blood, peripheral blood, serum, plasma, PBLs, performing an additional procedure to detect SCAR or risk PBMCs, T cells, CD4 T cells CD8 T cells, or macrophages. thereof if the determining step provides an indication the In some methods, step (a) is performed on a urine sample of subject has or is at risk of SCAR. The additional procedure the Subject. In some methods, step (a) is performed on at can be, e.g., examination of a kidney biopsy sample. In some least 3, 4, 5, 10, 15, 20, 30 or more genes. In some methods, US 2017/O 137885 A1 May 18, 2017

step (a) is performed on at least 10, 20, 40, or 100 or more 0020. The invention additionally provides methods of genes selected from at least one of Tables 2, 3, 4, 7, 8, 11, screening a compound for activity in inhibiting or treating 12, 14, 15, 17, and 18. Some of the methods further include SCAR. The methods involve (a) administering the com changing the treatment regime of the patient responsive to pound to a subject having or at risk of SCAR; (b) determin the detecting, prognosing, diagnosing or monitoring step. In ing, before and after administering the compound to the some of these methods, the subject is one who has received Subject, expression levels of at least five genes in the Subject a drug before performing the methods, and the change selected from one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14, comprises administering an additional drug or administering 15, 17, or 18 and species variants thereof and (c) determin a higher dose of the same drug, or administering a lower ing whether the compound has activity in inhibiting or dose of the same drug, or stopping administering the same treating SCAR from a change in expression levels of the drug. Some other methods can further include performing an genes after administering the compound. In some methods, additional procedure to detect SCAR or risk thereof if the step (c) entails, for each of the at least five changes, determining step provides an indication the Subject has or is assigning a value or designation depending on whether the at risk of SCAR, e.g., a kidney biopsy. In various embodi change in the expression level of the gene relative to one or ments, expression levels of the genes can be determined at more reference levels indicating presence or absence of the mRNA level or at the protein level. In some methods, SCAR. Some methods further include determining a com step (b) is performed by a computer. bined value or designation for the at least five genes from the 0017. In various embodiments, the methods provided values or designations determined for each gene. In some herein compare the gene expression profile in the peripheral preferred embodiments, the Subject is or a nonhuman blood of patients with acute cellular rejection (AR) on a animal model of SCAR. surveillance protocol biopsy (SCAR-normal creatinine) with 0021. In another aspect, the methods disclosed herein that of patients with normal protocol surveillance biopsies have an error rate of less than about 40%. In some embodi (TX normal creatinine), or with a previously validated ments, the method has an error rate of less than about 40%, peripheral blood profile for patients with clinical acute 35%, 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, or 1%. For cellular rejection (CAR-elevated creatinine) found on a “for example, the method has an error rate of less than about cause' biopsy. 10%. In some embodiments, the methods disclosed herein 0018. In another aspect, the invention provides arrays have an accuracy of at least about 60%. 65%, 70%, 75%, which contain a support or supports bearing a plurality of 80%, 85%, 90%, 95%, or 99%. For example, the method has nucleic acid probes complementary to a plurality of mRNAs an accuracy of at least about 70%. In some embodiments, the fewer than 5000 in number. Typically, the plurality of methods disclosed herein have a sensitivity of at least about mRNAs includes mRNAs expressed by at least five genes 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. For selected from one or more of Tables 2, 3, 4, 7, 8, 11, 12, 14, example, the method has a sensitivity of at least about 80%. 15, 17, or 18. In some embodiments, the plurality of mRNAs In some embodiments, the methods disclosed herein have a are fewer than 1000 or fewer than 100 in number. In some positive predictive value of at least about 60%. 65%, 70%, embodiments, the plurality of nucleic acid probes are 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, attached to a planar Support or to beads. In some embodi the methods disclosed herein have a negative predictive ments, the at least five genes are selected from one or more value of at least about 60%, 65%, 70%, 75%, 80%, 85%, of Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, 17, or 18. In a related 90%, 95%, or 99%. aspect, the invention provides arrays that contain a Support 0022. In some embodiments, the gene expression prod or Supports bearing a plurality of ligands that specifically ucts described herein are RNA (e.g., mRNA). In some bind to a plurality of fewer than 5000 in number. embodiments, the gene expression products are polypep The plurality of proteins typically includes at least five tides. In some embodiments, the gene expression products proteins encoded by genes selected from one or more of are DNA complements of RNA expression products from Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, 17, or 18. In some the transplant recipient. embodiments, the plurality of proteins are fewer than 1000 0023. In an embodiment, the algorithm described herein or fewer than 100 in number. In some embodiments, the is a trained algorithm. In another embodiment, the trained plurality of ligands are attached to a planar Support or to algorithm is trained with gene expression data from biologi beads. In some embodiments, the at least five proteins are cal samples from at least three different cohorts. In another encoded by genes selected from one or more of Tables 2, 3, embodiment, the trained algorithm comprises a linear clas 4, 7, 8, 11, 12, 14, 15, 17, or 18. In some embodiments, the sifier. In another embodiment, the linear classifier comprises ligands are different that bind to different proteins one or more linear discriminant analysis, Fisher's linear of the plurality of proteins. discriminant, Naive Bayes classifier, Logistic regression, 0019. In still another aspect, the invention provides meth Perceptron, Support vector machine (SVM) or a combina ods of expression analysis. These methods involve deter tion thereof. In another embodiment, the algorithm com mining expression levels of up to 2,000 genes (including at prises a Diagonal Linear Discriminant Analysis (DLDA) least 5 genes selected from one or more of Tables 2, 3, 4, 7, algorithm. In another embodiment, the algorithm comprises 8, 11, 12, 14, 15, 17, or 18) in a sample from a subject having a Nearest Centroid algorithm. In another embodiment, the a kidney transplant. In some methods, the expression levels algorithm comprises a Random Forest algorithm or statisti of up to 100 or 1000 genes are determined. The gene cal bootstrapping. In another embodiment, the algorithm expression levels can be determined at the mRNA level or at comprises a Prediction Analysis of Microarrays (PAM) the protein level. For example, the expression levels can be algorithm. In another embodiment, the algorithm is not determined by quantitative PCR or hybridization to an array validated by a cohort-based analysis of an entire cohort. In or sequencing. another embodiment, the algorithm is validated by a com US 2017/O 137885 A1 May 18, 2017

bined analysis with an unknown phenotype and a Subset of 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, a cohort with known phenotypes. 700, 800, 900, 1000, 1500, or 2000 genes, step (c) of the 0024. In another aspect, the sample is a blood sample or method comprises comparing the expression level of the is derived from a blood sample. In another embodiment, the gene in the Subject to one or more reference expression blood sample is a peripheral blood sample. In another levels of genes associated with subAR, acute rejection (AR) embodiment, the blood sample is a whole blood sample. In or lack of transplant rejection (TX). another embodiment, the sample does not comprise tissue 0031. A further understanding of the nature and advan from a biopsy of a transplanted organ of the transplant tages of the present invention may be realized by reference recipient. In another embodiment, the sample is not derived to the remaining portions of the specification and claims. from tissue from a biopsy of a transplanted organ of the transplant recipient. BRIEF DESCRIPTION OF THE DRAWINGS 0025. In another aspect, the assay is a microarray, SAGE, blotting, RT-PCR, sequencing and/or quantitative PCR 0032 FIG. 1 shows a schematic overview of certain assay. In another embodiment, the assay is a microarray methods in the disclosure. assay. In another embodiment, the microarray assay com 0033 FIG. 2 shows a schematic overview of certain prises the use of an Affymetrix U133 Plus methods of acquiring samples, analyzing results, and trans 2.0 GeneChip. In another embodiment, the mircroarray uses mitting reports over a computer network. the Hu133 Plus 2.0 cartridge arrays plates. In another 0034 FIG. 3 is an illustration of hierarchical clustering of embodiment, the microarray uses the HT HG-U133+PM gene expression signals of 33 probesets used to differentiate array plates. In another embodiment, determining the assay SCAR versus TX. is a sequencing assay. In another embodiment, the assay is 0035 FIG. 4 shows a computer system for implementing a RNA sequencing assay. the methods of the disclosure. 0026. In some embodiments, the subject or transplant 0036 FIG. 5 shows a correlation of fold-change between recipient has a serum creatinine level of less than 3.0 mg/dL, microarray and NGS analyses (1066 common genes). less than 2.5 mg/dL, less than 2.0 mg/dL, or less than 1.5 0037 FIG. 6 shows a heat map and clustering of fold mg/dL. The Subject may have a serum creatinine level that changes (Microarrays vs NGS) of 1066 genes. is stable over time. In some cases, the Subject or transplant 0038 FIG. 7 shows correlation of fold-change between recipient has a serum creatinine level of at least 0.4 mg/dL, microarray and NGS analyses (all expressed NGS 7076 0.6 mg/dL, 0.8 mg/dL 1.0 mg/dL, 1.2 mg/dL, 1.4 mg/dL. genes). 1.6 mg/dL, 1.8 mg/dL 2.0 mg/dL, 2.2 mg/dL 2.4 mg/dL, 2.6 mg/dL, 2.8 mg/dL, 3.0 mg/dL, 3.2 mg/dL, 3.4 mg/dL, DETAILED DESCRIPTION 3.6 mg/dL, 3.8 mg/dL, or 4.0 mg/dL. For example, the 0039. Sub-clinical acute rejection (referred to herein as transplant recipient has a serum creatinine level of at least “subAR' or “SCAR,” interchangeably) is normally defined 1.5 mg/dl. In another example, the transplant recipient has a as histologic kidney rejection (e.g., histologic acute cellular serum creatinine level of at least 3 mg/dL. rejection) with normal serum creatinine, and is associated 0027. In one aspect, the invention provides methods of with worse long term graft Survival. In some cases, creati detecting Subclinical acute rejection (SubAR) in a subject nine can be a lagging indicator of renal injury. Most times comprising: (a) obtaining nucleic acids of interest, wherein acute rejection (AR) of kidney graft is detected only after the the nucleic acids of interest comprise mRNA extracted from initial injury has started. Early detection of subAR or SCAR a sample from the subject or nucleic acids derived from the can avoid unnecessary complications later in the course of mRNA extracted from the sample from the subject; (b) graft life. However, normally SubAR or SCAR is detected detecting expression levels in the subject of at least five using a protocol kidney biopsy which is invasive, expensive genes using the nucleic acids of interest obtained in Step (a): and involves substantial risk. The present invention is predi and (c) detecting SubAR in the Subject from the expression cated in part on the development by the inventors of a levels detected in step (b). In an example, the sample from peripheral blood gene expression profiling signature that can the Subject is a blood sample. distinguish Sub-Clinical Acute Rejection (subAR or SCAR), 0028. In another aspect, the method detects subAR with well-functioning normal transplant (TX) and Acute Rejec an accuracy of greater than 50%, 55%, 60%. 65%, 70%, tion (AR). As detailed herein, the present inventors have 75%, 80%, 85%, 90% or 95%. In another aspect, the method identified consensus sets of gene expression-based molecu detects subAR with a sensitivity of greater than 50%, 55%, lar biomarkers associated with SCAR. This was accom 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. For plished via a genome-wide gene analysis of expression example, the method detects subAR with an accuracy of profiles of over 50,000 known or putative gene sequences in greater than 75% or a sensitivity of greater than 75%. peripheral blood. More than 2,000 sequences were found to 0029. In another aspect, the method further comprises have differential expressions among the 3 different patient contacting the nucleic acids of interest with probes, wherein groups (Table 4). Among these sequences, the inventors the probes are specific for the at least 2, 3, 4, 5, 6, 7, 8, 9. further identified the top 200 differentially expressed probe 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, sets (Table 2), which can provide more focused and better 600, 700, 800, 900, 1000, 1500, or 2000 genes selected in expression profiles for differentiating the three classes of step (b). patients. In addition, a set of genes with differential expres 0030. In another aspect, detecting subAR comprises sion levels only between SCAR and non-rejected transplants detecting a risk of developing SubAR, detecting acute rejec (TX) were also identified (Table 3). Expression rotocs based tion (AR), detecting a risk of having acute rejection (AR), or on the genes in this set are predictive in differentiating detecting a well-functioning normal transplant (TX). In between transplant patients who will develop SCAR and another aspect, for each of at least 2, 3, 4, 5, 6, 7, 8, 9, 10. patients who will maintain non-rejected transplants. US 2017/O 137885 A1 May 18, 2017

0040. Results from the present inventors’ studies provide tions Pvt. Ltd. (2002); and A Dictionary of Biology (Oxford the basis of a molecular test that can diagnose SubAR or Paperback Reference), Martin and Hine (Eds.), Oxford SCAR, and also enables minimally invasive methods for University Press (4" ed., 2000). In addition, the following monitoring kidney transplant recipients. The value of a definitions are provided to assist the reader in the practice of blood test for SubAR or SCAR is that it allows detection of the invention. Subclinical immune-mediated transplant rejection prior to 0044) Transplantation is the transfer of tissues, cells oran clinical evidence of kidney injury and dysfunction. This organ from a donor into a recipient. If the donor and blood-based test is minimally invasive and amenable to recipient as the same person, the graft is referred to as an serial monitoring. Moreover, peripheral blood gene expres autograft and as is usually the case between different indi sion profiling may be used to inform when to perform a viduals of the same species an allograft. Transfer of tissue biopsy in patients with normal renal function and/or to between species is referred to as a Xenograft. replace surveillance protocol biopsies. Therefore, the inven tion is useful for post-transplant management of kidney 0045. A biopsy is a specimen obtained from a living recipients. Additional advantages of the test is that serial patient for diagnostic or prognostic evaluation. Kidney monitoring of all patients with a blood test for SCAR and biopsies can be obtained with a needle. treatment of all patients with SCAR by increasing the level 0046. An average value can refer to any of a mean, of effective immunosuppression may significantly improve median or mode. long term graft function and Survival. 0047. A gene expression level is associated with a par 0041 An overview of certain methods in the disclosure is ticular phenotype e.g., presence of SubAR (SCAR) or AR if provided in FIG. 1. In some instances, a method comprises the gene is differentially expressed in a patient having the obtaining a sample from a transplant recipient in a mini phenotype relative to a patient lacking the phenotype to a mally invasive manner (110), such as via a blood draw. The statistically significant extent. Unless otherwise apparent sample may comprise gene expression products (e.g., poly from the context a gene expression level can be measured at peptides, RNA, mRNA isolated from within cells or a the mRNA and/or protein level. cell-free source) associated with the status of the transplant 0048. A target nucleic acid may be a nucleic acid (often (e.g., SubAR.). In some instances, the method may involve derived from a biological sample), to which a polynucle reverse-transcribing RNA within the sample to obtain cDNA otide probe is designed to specifically hybridize. The probe that can be analyzed using the methods described herein. can detect presence, absence and/or amount of the target. The method may also comprise assaying the level of the The term target nucleic acid can refer to the specific Sub gene expression products (or the corresponding DNA) using sequence of a larger nucleic acid to which the probe is methods such as microarray or sequencing technology directed or to the overall sequence (e.g., cDNA or mRNA) (120). The method may also comprise applying an algorithm whose expression level is to be detected. The term target to the assayed gene expression levels (130) in order to detect nucleic acid can also refer to a nucleic acid that is analyzed SubAR. After detection of the presence or absence of subAR, by any method, including by sequencing, PCR, microarray, a treatment decision may be made. In some cases, the or other method known in the art. treatment decision may be that the transplant recipient 0049. The term subject or patient can include human or should be treated more aggressively to mitigate the risk of non-human animals. Thus, the methods and described herein acute rejection. In some cases, the treatment decision may be are applicable to both human and veterinary disease and to reduce an existing treatment regimen, particularly if animal models. Preferred subjects are “patients, i.e., living SubAR is not detected. In the event that no SubAR is that are receiving medical care for a disease or detected, the treatment decision may involve a decision to condition. This includes persons with no defined illness who forego or delay obtaining a kidney biopsy from the patient. are being investigated for signs of pathology. The term 0042. The following sections provide guidance for car Subject or patient can include transplant recipients or donors rying out the methods of the invention. or healthy subjects. The methods can be particularly useful for human Subjects who have undergone a kidney transplant I. DEFINITIONS although they can also be used for Subjects who have gone 0043. Unless defined otherwise, all technical and scien other types of transplant (e.g., heart, liver, lung, stem cell, tific terms used herein have the same meaning as commonly etc.). The Subjects may be mammals or non-mammals. understood by those of ordinary skill in the art to which this Preferably, the subject is a human but in some cases, the invention pertains. The following references provide one of Subject is a non-human mammal. Such as a non-human skill with a general definition of many of the terms used in primate (e.g., ape, monkey, chimpanzee), cat, dog, rabbit, this invention: Academic Press Dictionary of Science and goat, horse, cow, pig, rodent, mouse, SCID mouse, rat, Technology, Morris (Ed.), Academic Press (1 ed., 1992); guinea pig or sheep. The Subject may be male or female; the Illustrated Dictionary of Immunology, Cruse (Ed.), CRC Pr Subject may be and, in some cases, the Subject may be an I LIc (2" ed., 2002); Oxford Dictionary of Biochemistry and infant, child, adolescent, teenager or adult. In some cases, Molecular Biology, Smith et al. (Eds.), Oxford University the methods provided herein are used on a subject who has Press (revised ed., 2000); Encyclopedic Dictionary of Chem not yet received a transplant, such as a subject who is istry, Kumar (Ed.), Anmol Publications Pvt. Ltd. (2002); awaiting a tissue or organ transplant. In other cases, the Dictionary of Microbiology and Molecular Biology, Single Subject is a transplant donor. In some cases, the Subject has ton at al. (Eds.), John Wiley & Sons (3 ed., 2002); not received a transplant and is not expected to receive Such Dictionary of Chemistry, Hunt (Ed.), Routledge (1' ed., transplant. In some cases, the Subject may be a subject who 1999); Dictionary of Pharmaceutical Medicine, Nahler is suffering from diseases requiring monitoring of certain (Ed.), Springer-Verlag Telos (1994); Dictionary of Organic organs for potential failure or dysfunction. In some cases, Chemistry, Kumar and Anandand (Eds.), Anmol Publica the subject may be a healthy subject. US 2017/O 137885 A1 May 18, 2017

0050. Often, the subject is a patient or other individual 0056. A perfectly matched probe has a sequence perfectly undergoing a treatment regimen, or being evaluated for a complementary to a particular target sequence. The probe is treatment regimen (e.g., immunosuppressive therapy). How typically perfectly complementary to a portion (Subse ever, in some instances, the Subject is not undergoing a quence) of a target sequence. The term “mismatch probe' treatment regimen. A feature of the graft tolerant phenotype refer to probes whose sequence is deliberately selected not detected or identified by the subject methods is that it is a to be perfectly complementary to a particular target phenotype which occurs without immunosuppressive Sequence. therapy, e.g., it is present in a Subject that is not receiving 0057 The term “isolated,” “purified” or “substantially immunosuppressive therapy. pure” means an object species (e.g., a nucleic acid sequence 0051 A transplant recipient may be a recipient of a solid described herein or a polypeptide encoded thereby) has been organ or a fragment of a solid organ Such as a kidney. at least partially separated from the components with which Preferably, the transplant recipient is a kidney transplant or it is naturally associated. allograft recipient. In some instances, the transplant recipi 0.058 Differential expression refers to a statistically sig ent may be a recipient of a tissue or cell. In some particular nificant difference in expression levels of a gene between examples, the transplanted kidney may be a kidney differ two populations of samples (e.g., samples with and without entiated in vitro from pluripotent stem cell(s) (e.g., induced SCAR). The expression levels can differ for example by at pluripotent stem cells or embryonic stem cells). least a factor of 1.5 or 2 between such populations of 0052. The donor organ, tissue, or cells may be derived samples. Differential expression includes genes that are from a subject who has certain similarities or compatibilities expressed in one population and are not expressed (at least with the recipient Subject. For example, the donor organ, at detectable levels) in the other populations. Unique expres tissue, or cells may be derived from a donor subject who is sion refers to detectable expression in one population and age-matched, ethnicity-matched, gender-matched, blood undetectable expression (i.e., insignificantly different from type compatible, or HLA-type compatible with the recipient background) in the other population using the same tech Subject. nique (e.g., as in the present example for detection). 0053. In various embodiments, the subjects suitable for 0059 Control populations for comparison with popula methods of the invention are patients who have undergone tions undergoing SCAR are usually referred to as being an organ transplant within 6 hours, 12 hours, 1 day, 2 days, without SCAR. In some embodiments, such a control popu 3 days, 4 days, 5 days, 10 days, 15 days, 20 days, 25 days, lation also means subjects without acute kidney rejection. 1 month, 2 months, 3 months, 4 months, 5 months, 7 months, 0060 Hybridization reactions are preferably performed 9 months, 11 months, 1 year, 2 years, 4 years, 5 years, 10 under stringent conditions in which probes or primers years, 15 years, 20 years or longer of prior to receiving a hybridize to their intended target with which they have classification obtained by the methods disclosed herein, such perfect complementarity and not to or at least to a reduced as detection of SubAR. extent to other targets. An example of stringent hybridization 0054 Diagnosis refers to methods of estimating or deter conditions are hybridization in 6xsodium chloride/sodium mining whether or not a patient is Suffering from a given citrate (SSC) at about 45° C., followed by one or more disease or condition or severity of the condition. Diagnosis washes in 0.2xSSC, 0.1% SDS at 50° C., 55° C., 60° C., and does not require ability to determine the presence or absence even more or 65° C. of a particular disease with 100% accuracy, or even that a 0061 Statistical significance means p-0.05 or <0.01 or given course or outcome is more likely to occur than not. even <0.001 level. Instead, the “diagnosis” refers to an increased probability that a certain disease or condition is present in the Subject II. GENES IN PROFILES compared to the probability before the diagnostic test was 0062 Table 4 lists more than 2000 probesets with corre performed. Similarly, a prognosis signals an increased prob sponding genes whose expression changes significantly ability that a given course or outcome will occur in a patient between kidney transplant patients undergoing SCAR com relative to the probability before the prognostic test. pared with patients not undergoing rejection (TX) and also 0055. A probe or polynucleotide probe is a nucleic acid patients undergoing acute rejection (AR) (3-way prediction). capable of binding to a target nucleic acid of complementary The columns in the table have the following meanings: sequence through one or more types of chemical bonds, column 1 is a number assigned to a gene, column 2 is an usually through complementary base pairing, usually Affymetrix number indicating a set of probes suitable for through hydrogen bond formation, thus forming a duplex measuring expression of the gene, column 3 is a gene name structure. The probe binds or hybridizes to a “probe binding (recognized names of HUGO or similar bodies are used site. A probe can include natural (e.g., A, G, C, U, or T) or when available), column 4 is a further description of the modified bases (e.g., 7-deazaguanosine, inosine.). A probe gene, column 5 is a raw uncorrected measure of the statis can be an oligonucleotide and may be a single-stranded tical significance of change in gene expression between the DNA or RNA. Polynucleotide probes can be synthesized or above patient populations, column 6 corresponds to a value produced from naturally occurring polynucleotides. In addi of the statistical significance after correction for the false tion, the bases in a probe can be joined by a linkage other discovery rate (FDR), and columns 7-9 respectively show than a phosphodiester bond, so long as it does not interfere mean expression levels of AR, SCAR, and TX patients. with hybridization. Thus, probes can include, for example, Table 2 similarly provides a subset of 200 preferred genes peptide nucleic acids in which the constituent bases are from Table 4. Table 3 provides similar information for a joined by peptide bonds rather than phosphodiester linkages subset of genes from Table 4 which show differential expres (see, e.g., Nielsen et al., Science 254, 1497-1500 (1991)). sion between kidney transplant patients undergoing SCAR Some probes can have leading and/or trailing sequences of with kidney transplant patients not undergoing rejection noncomplementarity flanking a region of complementarity. (TX) (2-way prediction). US 2017/013 7885 A1 May 18, 2017

0063. The genes referred to in the above tables are human cellular rejection—characterized by tubule-interstitial genes. In some methods, species variants or homologs of mononuclear infiltration identified from a biopsy specimen, these genes are used in a non-human animal model. Species but without concurrent functional deterioration (variably variants are the genes in different species having greatest defined as a serum creatinine not exceeding 10%. 20% or sequence identity and similarity in functional properties to 25% of baseline values). Some instances of SCR or subAR one another. Many species variants of the above human may represent the beginning or conclusion of an alloimmune genes are listed in the Swiss-Prot database. infiltrate diagnosed fortuitously by protocol sampling, and 0064. To identify differentially expressed genes, raw some episodes of clinical rejection may actually represent gene expression levels are comparable between different subAR or SCAR with an alternative cause of functional genes in the same sample but not necessarily between decline, such as concurrent calcineurin inhibitor (CNI) different samples. As noted above, values given for gene nephrotoxicity A subAR subject may have normal and stable expression levels can be normalized so that values for organ function. For example, a SubAR subject typically particular genes are comparable within and between the shows normal and/or stable serum creatinine levels or populations being analyzed. The normalization eliminates or eGFR. SubAR is usually diagnosed through biopsies that are at least reduces to acceptable levels any sample to sample taken at a fixed time after transplantation (e.g., protocol differences arising from factors other than SCAR (e.g. biopsies or serial monitoring biopsies) which are not driven differences in overall levels of patients due to by clinical indications but rather by standards of care. The general state of health and differences in sample preparation biopsies may be analyzed histologically in order to detect or nucleic acid amplification between samples). The nor the subAR. SubAR may be subclassified by some into acute malization effectively applies a correction factor to the subAR (subAR) or a milder form called borderline SubAR measured expression levels from a given array such that a (suspicious for acute rejection) based on the biopsy histol profile of many expression levels in the array are the same ogy.). A failure to recognize, diagnose and treat subclinical between different patient samples. Software for normalizing AR before significant tissue injury has occurred and the overall expression patterns between different samples is both transplant shows clinical signs of dysfunction could be a commercially and publically available (e.g., XRAY from major cause of irreversible organ damage. Moreover, a Biotique Systems or BRB ArrayTools from the National failure to recognize a chronic, subclinical immune-mediated Cancer Institute). After applying appropriate normalizing organ damage and a failure to make appropriate changes in factors to the measured expression value of a particular gene immunosuppressive therapy to restore a state of effective in different samples, an average or mean value of the immunosuppression in that patient could contribute to late expression level is determined for the samples in a popula organ transplant failure. The methods disclosed herein can tion. The average or mean values between different popu reduce or eliminate these and other problems associated with lations are then compared to determine whether expression transplant rejection or failure. level has changed significantly between the populations. The 0067. In some instances, a normal serum creatinine level changes in expression level indicated for a given gene and/or a normal estimated glomerular filtration rate (eGFR) represent the relative expression level of that gene in may indicate or correlate with healthy transplant (TX) or samples from a population of individuals with a defined subclinical rejection (SCAR). For example, typical refer condition (e.g., transplant patients with SCAR) relative to ence ranges for serum creatinine are 0.5 to 1.0 mg/dL for samples from a control population (kidney transplant women and 0.7 to 1.2 mg/dL for men, though typical kidney patients not undergoing rejection). In some cases, the popu transplant patients have creatinines in the 0.8 to 1.5 mg/dL lation of individuals with a defined condition may be trans range for women and 1.0 to 1.9 mg/dL range for men. This plant recipients with SCAR identified by acute cellular may be due to the fact that most kidney transplant patients rejection (AR) on a surveillance protocol biopsy (SCAR have a single kidney. In some instances, the trend of serum normal creatinine) and the control population is patients creatinine levels over time can be used to evaluate the (e.g., transplant recipients) with normal protocol surveil recipient's organ function. This is why it may be important lance biopsies (TX-normal creatine). In some cases, this to consider both “normal serum creatinine levels and SCAR gene expression profile is compared with a previ “stable” serum creatinine levels in making clinical judg ously validated peripheral blood profile/signature for ments, interpreting testing results, deciding to do a biopsy or patients with clinical acute cellular rejection (CAR-elevated making therapy change decisions including changing immu creatinine), such as a CAR identified with a "for cause” nosuppressive drugs. For example, the transplant recipient biopsy. may show signs of a transplant dysfunction or rejection as 0065. Similar principles apply in normalizing gene indicated by an elevated serum creatinine level and/or a expression levels at the mRNA and protein levels. Compari decreased eGFR. In some instances, a transplant subject sons between populations are made at the same level (e.g., with a particular transplant condition (e.g., AR, ADNR) may mRNA levels in one population are compared with mRNA have an increase of a serum creatinine level of at least 0.1 levels in another population or protein levels in one popu mg/dL, 0.2 mg/dL, 0.3 mg/dL, 0.4 mg/dL, 0.5 mg/dL, 0.6 lation with protein levels in another population). mg/dL, 0.7 mg/dL 0.8 mg/dL, 0.9 mg/dL, 1.0 mg/dL. 1.1 mg/dL, 1.2 mg/dL, 1.3 mg/dL. 1.4 mg/dL. 1.5 mg/dL, 1.6 III. SUBJECT POPULATIONS mg/dL, 1.7 mg/dL, 1.8 mg/dL. 1.9 mg/dL 2.0 mg/dL, 2.1 0066. The methods are suitable for detecting subAR or mg/dL, 2.2 mg/dL, 23 mg/dL 2.4 mg/dL 2.5 mg/dL, 2.6 SCAR in transplant patients, and are particularly useful for mg/dL, 2.7 mg/dL, 2.8 mg/dL 2.9 mg/dL, 3.0 mg/dL, 3.1 detecting subAR or SCAR without relying on a histologic mg/dL, 3.2 mg/dL, 3.3 mg/dL, 3.4 mg/dL, 3.5 mg/dL, 3.6 analysis or obtaining a biopsy. Subclinical rejection (SCR) mg/dL, 3.7 mg/dL, 3.8 mg/dL, 3.9 mg/dL, or 4.0 mg/dL. In including subAR generally refers to histologically defined some instances, a transplant subject with a certain transplant acute rejection particularly, histologically defined acute condition (e.g., AR, ADNR) may have an increase of a US 2017/O 137885 A1 May 18, 2017

serum creatinine level of at least 10%, 20%, 30%, 40%, the recipient’s immune system, which damages or destroys 50%, 60%, 70%, 80%, 90%4 or 100% from baseline. In the transplanted tissue unless immunosuppression is Some instances, a transplant Subject with a certain transplant achieved. T-cells, B-cells and other immune cells as well as condition (e.g., AR. ADNR, etc.) may have an increase of a possibly antibodies of the recipient may cause the graft cells serum creatinine level of at least 1-fold, 2-fold, 3-fold, to lyse or produce cytokines that recruit other inflammatory 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold from cells, eventually causing necrosis of allograft tissue. In some baseline. In some cases, the increase in serum creatinine instances, AR may be diagnosed by a biopsy of the trans (e.g., any increase in the concentration of serum creatinine planted organ. In the case of kidney transplant recipients, AR described herein) may occur over about 0.25 days, 0.5 days, may be associated with an increase in serum creatinine 0.75 days, 1 day, 1.25 days, 1.5 days, 1.75 days, 2.0 days, 3.0 levels. The treatment of AR may include using immunosup days, 4.0 days, 5.0 days, 6.0 days, 7.0 days, 8.0 days, 9.0 pressive agents, corticosteroids, polyclonal and monoclonal days, 10.0 days, 15 days, 30 days, 1 month, 2 months, 3 antibodies, engineered and naturally occurring biological months, 4 months, 5 months, or 6 months, or more. In some molecules, and antiproliferatives. AR more frequently instances, a transplant Subject with a particular transplant occurs in the first three to 12 months after transplantation but condition (e.g., AR, ADNR, CAN, etc.) may have a decrease there is a continued risk and incidence of AR for the first five of a eGFR of at least 10%, 20%, 30%, 40%, 50%, 60%, years post transplant and whenever a patient’s immunosup 70%, 80%, 90%, or 100% from baseline. In some cases, the pression becomes inadequate for any reason for the life of decrease in eGFR may occur over 0.25 days, 0.5 days, 0.75 the transplant. days, 1 day, 1.25 days, 1.5 days, 1.75 days, 2.0 days, 3.0 0070 The methods herein may also be used to distinguish days, 4.0 days, 5.0 days, 6.0 days, 7.0 days, 8.0 days, 9.0 between a kidney transplant patient with subAR and a days, 10.0 days, 15 days, 30 days, 1 month, 2 months, 3 normally functioning kidney transplant. Typically, when the months, 4 months, 5 months, or 6 months, or more. In some patient does not exhibit symptoms or test results of organ instances, diagnosing, predicting, or monitoring the status or dysfunction or rejection, the transplant is considered a outcome of a transplant or condition comprises determining normal functioning transplant (TX: Transplant eXcellent). transplant recipient-specific baselines and/or thresholds. The An unhealthy transplant recipient may exhibit signs of organ methods are particularly useful on human Subjects who have dysfunction and/or rejection (e.g., an increasing serum crea undergone a kidney transplant although can also be used on tinine Subjects who have undergone other types of transplant (e.g., 0071 Regardless of the specific subject population, gene heart, liver, lungs, stem cell) or on non-humans who have expression levels in the patients can be measured, for undergone kidney or other transplant. As detailed herein, the example, within, one month, three months, six months, one methods can be employed to distinguish transplant patients year, two years, five years or ten years after a kidney who (1) have or are at risk of having acute rejection (AR), transplant. In some methods, gene expression levels are (2) have or are at risk of having SCAR, and (3) have normal determined at regular intervals, e.g., every 3 months, 6 functional transplant (TX). In some other applications, the months or every year posttransplant, either indefinitely, or methods are more practically employed to distinguish until evidence of SCAR is observed, in which case the patients who either are either transplant excellent (TX) or frequency of monitoring is sometimes increased. In some have existing SCAR (or risk of developing SCAR). This is methods, baseline values of expression levels are deter because patients with acute rejections can usually be easily mined in a Subject before a kidney transplant in combination diagnosed via conventional assays, e.g., those based on with determining expression levels at one or more time serum creatinine level. points thereafter. Similar methods can be practiced in non 0068. As such, the methods of the invention can be used human species, in which cases, the expression levels mea in patients who have normal and stable creatinine levels to Sured are the species equivalent of the human genes refer diagnose or prognose hidden SCAR without depending on enced above. invasive biopsies. In some cases, the serum creatinine levels of the transplant recipient are stable over at least 10 days, 20 IV. METHODS OF MEASURING PROFILES days, 30 days, 40 days, 50 days, 60 days, 90 days, 100 days, 200 days, 300 days, 400 days or longer. In some cases, the 0072 Samples transplant recipient has a serum creatinine level of less than 0073. The preferred sample type for analysis is a blood 0.2 mg/dL, less than 0.3 mg/dL, less than 0.4 mg/dL, less sample, which refers to whole blood or fractions thereof than 0.5 mg/dL, less than 0.6 mg/dL, less than 0.7 mg/dL Such as plasma, or lymphocytes. Other samples that can be less than 0.8 mg/dL, less than 0.9 mg/dL, less than 1.0 analyzed include urine, feces, saliva, and a kidney biopsy. mg/dL, less than 1.1 mg/dL, less than 1.2 mg/dL, less than The samples are typically isolated from a subject, particu 1.3 mg/dL, 1.4 mg/dL, less than 1.5 mg/dL, less than 1.6 larly as a peripheral blood sample, and not returned to the mg/dL, less than 1.7 mg/dL, less than 1.8 mg/dL, less than Subject. The analytes of interests in the samples can be 1.9 mg/dL, less than 2.0 mg/dL, less than 2.1 mg/dL, less analyzed with or without further processing of the sample, than 2.2 mg/dL, less than 2.3 mg/dL, less than 2.4 mg/dL, Such as purification and amplification. Samples not requiring less than 2.5 mg/dL, less than 2.6 mg/dL, less than 2.7 biopsy to obtain, particularly peripheral blood, are preferred. mg/dL, less than 2.8 mg/dL, less than 2.9 mg/dL, or less than However, a sample may be any material containing tissues, 3.0 mg/dL. cells, nucleic acids, genes, gene fragments, expression prod 0069. As mentioned, often the methods provided herein ucts, polypeptides, exosomes, gene expression products, or can be used to detect SubAR as opposed to a condition Such gene expression product fragments of a Subject to be tested. as acute rejection (AR), or to predict whether the subject is In some cases, the sample is from a single patient. In some at risk of having AR. Acute rejection (AR) or clinical acute cases, the method comprises analyzing multiple samples at rejection may occur when transplanted tissue is rejected by once, e.g., via massively parallel sequencing. US 2017/O 137885 A1 May 18, 2017

0074 The sample is preferably blood. In some cases, the levels of the amplified nucleic acids can be used to establish sample comprises whole blood, plasma, peripheral blood phenotypic associations representative of the mRNAS. lymphocytes (PBLs), peripheral blood mononuclear cells I0081. A variety of approaches are available for determin (PBMCs), serum, T cells, B Cells, CD3 cells, CD8 cells, ing mRNA levels including probe arrays and quantitative CD4 cells, or other immune cells. PCR. A number of distinct array formats are available. Some 0075. The methods, kits, and systems disclosed herein arrays, such as an Affymetrix HG-U133 PM microarray or may comprise specifically detecting, profiling, or quantitat other Affymetrix GeneChip(R) array, have different probes ing molecules (e.g., nucleic acids, DNA, RNA, polypep occupying discrete known areas of a contiguous Support. tides, etc.) that are within the biological samples. In some Exemplary microarrays include but are not limited to the instances, genomic expression products, including RNA, or Affymetrix Human Genome U133 Plus 2.0 GeneChip or the polypeptides, may be isolated from the biological samples. HT HG-U133+PM Array Plate. In some cases, nucleic acids, DNA, RNA, polypeptides may I0082. Other arrays, such as arrays from Illumina, have be isolated from a cell-free source. In some cases, nucleic different probes attached to different particles or beads. In acids, DNA, RNA, polypeptides may be isolated from cells such arrays, the identity of which probe is attached to which derived from the transplant recipient. particle or beads is usually determinable from an encoding 0076. The sample may be obtained using any method system. The probes can be oligonucleotides. In such case, known to the art that can provide a sample suitable for the typically several match probes are included with perfect analytical methods described herein. The sample may be complementarity to a given target mRNA together, option obtained by a non-invasive method such as a throat Swab, ally together with mismatch probes differing from the match buccal Swab, bronchial lavage, urine collection, Scraping of probes are a known number of oligonucleotides (Lockhart, the skin or cervix, Swabbing of the cheek, Saliva collection, at al., Nature Biotechnology 14:1675-1680 (1996); and feces collection, menses collection, or semen collection. Lipschutz, et al., Nature Genetics Supplement 21: 20-24, 0077. The sample may be obtained by a minimally 1999). Other arrays including full length cDNA sequences invasive method such as a blood draw. The sample may be with perfect or near perfect complementarity to a particular obtained by Venipuncture. In other instances, the sample is cDNA (Schena et al. (Science 270:467-470 (1995); and obtained by an invasive procedure including but not limited DeRisi et al. (Nature Genetics 14:457-460 (1996)). Such to: biopsy, alveolar or pulmonary lavage, or needle aspira arrays can also include various control probes, such as a tion. The method of biopsy may include Surgical biopsy, probe complementarity with a house keeping gene likely to incisional biopsy, excisional biopsy, punch biopsy, shave be expressed in most samples. Regardless of the specifics of biopsy, or skin biopsy. The sample may be formalin fixed array design, an array contains one or more probes either sections. The method of needle aspiration may further perfectly complementary to a particular target mRNA or include fine needle aspiration, core needle biopsy, vacuum sufficiently complementarity to the target mRNA to distin assisted biopsy, or large core biopsy. In some embodiments, guish it from other mRNAs in the sample, and the presence multiple samples may be obtained by the methods herein to of such a target mRNA can be determined from the hybrid ensure a sufficient amount of biological material. In some ization signal of Such probes, optionally by comparison with instances, the sample is not obtained by biopsy. In some mismatch or other control probes included in the array. instances, the sample is not a kidney biopsy. Typically, the target bears a fluorescent label, in which case 0078 Expression Profiles hybridization intensity can be determined by, for example, a 007.9 For prognosis or diagnosis of SCAR in patients as scanning confocal microscope in photon counting mode. opposed to both patients with acute rejection (AR) and Appropriate scanning devices are described by e.g., U.S. patients without rejection (TX), the profiles can contain Pat. No. 5,578,832, and U.S. Pat. No. 5,631,734. The genes selected from at least one of Tables 2, 3, 4, 7, 8, 11, intensity of labeling of probes hybridizing to a particular 12, 14, 15, 17, and 18, for example, from Table 2. In some mRNA or its amplification product provides a raw measure other methods, when the prognosis or diagnosis is intended of expression level. to distinguish between patients having or at risk of devel I0083. In other methods, expression levels are determined oping SCAR and patients without rejection (TX), the genes by so-called “real time amplification methods also known in the profiles can be selected from at least one of Tables 2, as quantitative PCR or Taqman (see, e.g., U.S. Pat. No. 3, 4, 7, 8, 11, 12, 14, 15, 17, and 18, for example, from Table 5,210,015 to Gelfand, U.S. Pat. No. 5,538,848 to Livak, et 3. al., and U.S. Pat. No. 5,863,736 to Haaland, as well as Held, 0080 Expression profiles are preferably measured at the C. A., et al., Genome Research, 6:986-994 (1996); Gibson, nucleic acid level, meaning that levels of mRNA or nucleic U. E. M., et al., Genome Research 6:995-1001 (1996): acid derived therefrom (e.g., cDNA or cRNA). An expres Holland, P. M., et al., Proc. Natl. Acad. Sci. USA 88: 7276 sion profile refers to the expression levels of a plurality of 7280, (1991); and Livak, K. J., et al., PCR Methods and genes in a sample. A nucleic acid derived from mRNA Applications 357-362 (1995)). The basis for this method of means a nucleic acid synthesized using mRNA as a template. monitoring the formation of amplification product is to Methods of isolation and amplification of mRNA are well measure continuously PCR product accumulation using a known in the art, e.g., as described in WO 97/10365, WO dual-labeled fluorogenic oligonucleotide probe. The probe 97/27317, Chapter 3 of Laboratory Techniques in Biochem used in Such assays is typically a short (ca. 20-25 bases) istry and Molecular Biology: Hybridization With Nucleic polynucleotide that is labeled with two different fluorescent Acid Probes, Part 1. Theory and Nucleic Acid Preparation, dyes. The 5' terminus of the probe is typically attached to a (P. Tijssen, ad.) Elsevier, N.Y. (1993). If mRNA or a nucleic reporter dye and the 3' terminus is attached to a quenching acid therefrom is amplified, the amplification is performed dye The probe is designed to have at least substantial under conditions that approximately preserve the relative sequence complementarity with a site on the target mRNA proportions of mRNA in the original samples, such that the or nucleic acid derived from. Upstream and downstream US 2017/O 137885 A1 May 18, 2017

PCR primers that bind to flanking regions of the are utilizes multiple discrete Zones of immobilized antibodies on also added to the reaction mixture. When the probe is intact, membranes to detect multiple target antigens in an array. energy transfer between the two fluorophors occurs and the U.S. Pat. Nos. 5,458,852, 6,019,944, U.S. Pat. No. 6,143, quencher quenches emission from the reporter. During the 576. Microtiter plates or automation can be used to facilitate extension phase of PCR, the probe is cleaved by the 5' detection of large numbers of different proteins. Protein nuclease activity of a nucleic acid polymerase Such as Taq levels can also be determined by mass spectrometry as polymerase, thereby releasing the reporter from the poly described in the examples. nucleotide-quencher and resulting in an increase of reporter I0087. The selection of genes for determination of expres emission intensity which can be measured by an appropriate sion levels depends on the particular application. In general, detector. The recorded values can then be used to calculate the genes are selected from one of the tables indicated above the increase in normalized reporter emission intensity on a as appropriate for the application. In some methods, expres continuous basis and ultimately quantify the amount of the sion levels of at least 2, 3, 4, 5, 10, 20, 25, 50, 100, 150, 250 mRNA being amplified. mRNA levels can also be measured (e.g. 100-250) genes shown in any of Tables 2, 3, 4, 7, 8, 11, without amplification by hybridization to a probe, for 12, 14, 15, 17, or 18 are determined. In some methods, example, using a branched nucleic acid probe, such as a expression levels of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, QuantiGene(R) Reagent System from Panomics. 14, 15, 16, 17, 18, 19, 20, 50, 100, 200, 300, 400, 500, 1000 0084. In certain preferred embodiments, the expression or more genes found in Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, level of the gene products (e.g., RNA) is determined by 17, or 18 are determined. In some methods, genes are sequencing, such as by RNA sequencing or by DNA selected Such that genes from several different pathways are sequencing (e.g., of cDNA generated from reverse-transcrib represented. The genes within a pathway tend to be ing RNA (e.g., mRNA) from a sample). Sequencing may be expressed in a coordinated expression whereas genes from performed by any available method or technique. Sequenc different pathways tend to be expressed more independently. ing methods may include: Next Generation sequencing, Thus, changes in expression based on the aggregate changes high-throughput sequencing, pyrosequencing, classic San of genes from different pathways can have greater statistical gar sequencing methods, sequencing-by-ligation, sequenc significance than aggregate changes of genes within a path ing by synthesis, sequencing-by-hybridization, RNA-Seq way. In some cases, expression levels of the top 5, top 10, (Illumina), Digital Gene Expression (Helicos), next genera top 15, top 20, top 25, top 30, top 35, top 40, top 45, top 50. tion sequencing, single molecule sequencing by synthesis top 55, top 60, top 65, top 70, top 75, top 80, top 85, top 90, (SMSS) (Helicos), Ion Torrent Sequencing Machine (Life top 95, top 100, top 150, top 200, top 250 or top 300 genes Technologies/Thermo-Fisher), massively-parallel sequenc listed in Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, 17, or 18 are ing, clonal single molecule Array (Solexa), shotgun determined. sequencing, Maxim-Gilbert sequencing, primer walking, I0088 Expression levels of the present genes and/or pro and any other sequencing methods known in the art. teins can be combined with or without determination of 0085 Measuring gene expression levels may comprise expression levels of any other genes or proteins of interest reverse transcribing RNA (e.g., mRNA) within a sample in (e.g., genes or proteins associated with rejection of kidneys order to produce cDNA. The cDNA may then be measured or other organs in WO 2007/104537, WO 2009/060035), using any of the methods described herein (e.g., PCR, digital Anglicheau et al., PNAS 106, 5330-5335 (2009)) and ref PCR, qPCR, microarray, SAGE, blotting, sequencing etc.). erences, 16, 20, 21, 22, 23, 25, 26, 37 and 39. In some I0086 Alternatively or additionally, expression levels of methods, the genes in the expression profiles to be measured genes can be determined at the protein level, meaning that do not include at least one or all of the genes encoding levels of proteins encoded by the genes discussed above are urinary granzyme A, granzyme B. glyceraldehyde measured. Several methods and devices are well known for 3-phospate dehydrogenase (GAPDH), perforin, Fas ligand, determining levels of proteins including immunoassays Such CXCL9, CXCL10, and other proteins involved in patients as described in e.g., U.S. Pat. Nos. 6,143,576; 6,113,855: cytolytic attack against the transplant. 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; I0089 Regardless of the format adopted, the present 5,885,527; 5,851,776; 5,824,799; 5,679,526; 5,525,524; and methods can (but need not) be practiced by detection expres 5,480,792. These assays include various sandwich, competi sion levels of a relatively small number of genes or proteins tive, or non-competitive assay formats, to generate a signal compared with the whole genome level expression analysis that is related to the presence or amount of an protein analyte described in the Examples. In some methods, the total of interest. Any Suitable immunoassay may be utilized, for number of genes whose expression levels are determined is example, lateral flow, -linked immunoassays less than 5000, 1000, 500, 200, 100, 50, 25, 10, 5 or 3. In (ELISA), radioimmunoassays (RIAS), competitive binding Some methods, the total number of genes whose expression assays, and the like. Numerous formats for arrays level is determined is 100-1500, 100-250, 500-1500 or have been described proposed employing antibodies. Such 750-1250. In some methods, the total number of proteins arrays typically include different antibodies having speci whose expression levels are determined is less than 5000, ficity for different proteins intended to be detected. For 1000, 500, 200, 100, 50, 25, 10, 5 or 3. In some methods, the example, usually at least one hundred different antibodies total number of proteins whose expression level is deter are used to detect one hundred different protein targets, each mined is 100-1500, 100-250, 500-1500 or 750-1250. Cor antibody being specific for one target. Other ligands having respondingly, when an array form is used for detection of specificity for a particular protein target can also be used, expression levels, the array includes probes or probes sets such as the synthetic antibodies disclosed in WO/2008/ for less than 5000, 1000, 500, 200, 100, 50, 25, 10, 5 or 3 048970. Other compounds with a desired binding specificity genes. Thus, for example, an Affymetrix GeneChip(R) can be selected from random libraries of peptides or small expression monitoring array contains a set of about 20-50 molecules. U.S. Pat. No. 5,922,615 describes a device that oligonucleotide probes (half match and half-mismatch) for US 2017/O 137885 A1 May 18, 2017 monitoring each gene of interest. Such an array design plant with SCAR, and/or an average/mean value of expres would include less than 5000, 1000, 500, 200, 100, 50, 25, sion levels in Subjects having had a kidney transplant with 10, 5 or 3 such probes sets for detecting less than 5000, acute rejection. The reference points can also include a scale 1000, 500, 200, 100, 50, 25, 10, 5 or 3 genes. By further of values found in kidney transplant patients including example, an alternative array including one cDNA for each patients having and not having SCAR. The reference points gene whose expression level is to be detected would contain can also or alternatively include a reference value in the less than 5000, 1000, 500, 200, 100, 50, 25, 10, 5 or 3 such Subject before kidney transplant, or a reference value in a cDNAs for analyzing less than 5000, 1000, 500, 200, 100, population of patients who have not undergone kidney 50, 25, 10, 5 or 3 genes. By further example, an array containing a different antibody for each protein to be transplant Such reference points can be expressed in terms detected would containing less than 5000, 1000, 500, 200, of absolute or relative concentrations of gene products as for 100, 50, 25, 10, 5 or 3 different antibodies for analyzing less measured values in a sample. than 5000, 1000, 500, 200, 100, 50, 25, 10, 5 or 3 gene 0093. For comparison between a measured expression products. level and reference level(s), the measured level sometimes 0090. As described herein, in some cases the methods needs to be normalized for comparison with the reference involve obtaining or analyzing a biopsy sample (e.g., kidney level(s) or vice versa. The normalization serves to eliminate biopsy). The biopsy sample may be used for different or at least minimize changes in expression level unrelated to purposes including to develop an expression profile signa SCAR (e.g., from differences in overall health of the patient ture. In some cases, an analysis described herein may be or sample preparation). Normalization can be performed by performed on a biopsy obtained from a transplant recipient determining what factor is needed to equalize a profile of in order to predict, monitor, or detect SCAR in the transplant expression levels measured from different genes in a sample recipient. In cases where biopsies are obtained, the biopsies with expression levels of these genes in a set of reference may be processed included by placing the samples in a samples from which the reference levels were determined. vessel (e.g., tube, PAX tube, Vial, microfuge tube, etc.) and Commercial Software is available for performing such nor storing them at a specific location Such as a biorepository. malizations between different sets of expression levels. The samples may also be processed by treatment with a specific agent, such as an agent that prevents nucleic acid 0094 Comparison of the measured expression level of a degradation or deterioration, particularly an agent that pro gene with one or more of the above reference points pro tects RNA (e.g., RNALater) or DNA. In some cases, biop vides a value (i.e., numerical) or other designation (e.g., sies Subjected to histologic analysis including staining (e.g., symbol or word(s)) of presence or susceptibility to SCAR. hematoxylin and eosin (H&E) stain) probing (e.g., a probe In some methods, a binary system is used; that is a measured attached to a dye, a probe attached to a fluorescent label). In expression level of a gene is assigned a value or other Some cases, the staining (e.g., H&E) may be analyzed by a designation indicating presence or Susceptibility to SCAR or blinded physician Such as a blinded pathologist, or at least lack thereof without regard to degree. For example, the two blinded pathologists, using criteria such as BANFF expression level can be assigned a value of 1 to indicate criteria. In some cases, a histologic diagnosis is reconciled presence or susceptibility to SCAR and -1 to indicate with laboratory data and clinical courses by one or more absence or lack of susceptibility to SCAR. Such assignment clinicians (e.g., at least two clinicians) prior to biomarker can be based on whether the measured expression level is analyses. closer to an average or mean level in kidney transplant patients having or not having SCAR. In other methods, a ternary system is used in which an expression level is V. ANALYSIS OF EXPRESSION LEVELS assigned a value or other designation indicating presence or 0091 Analysis of expression levels initially provides a susceptibility to SCAR or lack thereof or that the expression measurement of the expression level of each of several level is uninformative. Such assignment can be based on individual genes. The expression level can be absolute in whether the expression level is closer to the average or mean terms of a concentration of an expression product, or relative level in kidney transplant patient undergoing SCAR, closer in terms of a relative concentration of an expression product to an average or mean level in kidney transplant patients of interest to another expression product in the sample. For lacking SCAR or intermediate between such levels. For example, relative expression levels of genes can be example, the expression level can be assigned a value of +1. expressed with respect to the expression level of a house -1 or 0 depending on whether it is closer to the average or keeping gene in the sample. Relative expression levels can mean level in patients undergoing SCAR, is closer to the also be determined by simultaneously analyzing differen average or mean level in patients not undergoing SCAR or tially labeled samples hybridized to the same array. Expres is intermediate. In other methods, a particular expression sion levels can also be expressed in arbitrary units, for level is assigned a value on a scale, where the upper level is example, related to signal intensity. a measure of the highest expression level found in kidney 0092. The individual expression levels, whether absolute transplant patients and the lowest level of the scale is a or relative, can be converted into values or other designa measure of the lowest expression level found in kidney tions providing an indication of presence or risk of SCAR by transplant patients at a defined time point at which patients comparison with one or more reference points. Preferably, may be susceptible to SCAR (e.g., one year post transplant). genes in Table 2 and/or one or more of Tables 2, 3, 4, 7, 8, Preferably, such a scale is normalized scale (e.g., from 0-1) 11, 12, 14, 15, 17, or 18 are used for such analysis. The Such that the same scale can be used for different genes. reference points can include a measure of an average or Optionally, the value of a measured expression level on Such mean expression level of a gene in Subjects having had a a scale is indicated as being positive or negative depending kidney transplant without SCAR, an average or mean value on whether the upper level of the scale associates with of expression levels in Subjects having had a kidney trans presence or susceptibility to SCAR or lack thereof. It does US 2017/O 137885 A1 May 18, 2017 not matter whether a positive or negative sign is used for Subjects, Subjects Suffering from transplant dysfunction with SCAR or lack thereofas long as the usage is consistent for no rejection, Subjects Suffering from transplant rejection, or different genes. a combination thereof. The healthy subjects may be subjects 0095 Values or other designation can also be assigned with normal transplant function. The data pertaining to the based on a change in expression level of a gene relative to sample may be sequentially compared to two or more a previous measurement of the expression level of gene in classes of samples. The data pertaining to the sample may be the same patient. Here as elsewhere expression level of a sequentially compared to three or more classes of samples. gene can be measured at the protein or nucleic acid level. The classes of samples may comprise control samples Such a change can be characterized as being toward, away classified as being from Subjects with normal transplant from or neutral with respect to average or mean expression function, control samples classified as being from Subjects levels of the gene in kidney transplant patients undergoing Suffering from transplant dysfunction with no rejection, or not undergoing SCAR. For example, a gene whose control samples classified as being from Subjects Suffering expression level changes toward an average or mean expres from transplant rejection, or a combination thereof. sion level in kidney transplant patients undergoing SCAR 0099 Classifiers can be assigned a value of 1 and a gene whose express level 0100. The methods include using a trained classifier or changes way from an average or mean expression level in algorithm to analyze sample data, particularly to detect kidney transplant patients undergoing SCAR and toward an SubAR. In some instances, the expression levels from average or mean expression level in kidney transplant sample are used to develop or train an algorithm or classifier patients not undergoing SCAR can be assigned a value -1. provided herein. In some instances, gene expression levels Of course, more Sophisticated systems of assigning values are measured in a sample from a transplant recipient (or a are possible based on the magnitude of changes in expres healthy or transplant excellent control) and a classifier or sion of a gene in a patient. algorithm (e.g., trained algorithm) is applied to the resulting 0096 Having determined values or other designations of data in order to detect, predict, monitor, or estimate the risk expression levels of individual genes providing an indication of a transplant condition (e.g., SubAR). of presence or susceptibility to subAR (or SCAR) or lack 0101 Training of multi-dimensional classifiers (e.g., thereof, the values or designations may be combined to algorithms) may be performed using numerous samples. For provide an aggregate value for all of the genes in the example, training of the multi-dimensional classifier may be signature being analyzed. If each gene is assigned a score of performed using at least about 10, 20, 30, 40, 50, 60, 70, 80, +1 if its expression level indicates presence or susceptibility 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or to SubAR (or SCAR) and -1 if its expression level indicates more samples. In some cases, training of the multi-dimen absence or lack of susceptibility to subAR and optionally sional classifier may be performed using at least about 200, Zero if uninformative, the different values can be combined 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, by addition. The same approach can be used if each gene is 450, 500 or more samples. In some cases, training of the assigned a value on the same normalized scale and assigned multi-dimensional classifier may be performed using at least as being positive or negative depending whether the upper about 525, 550, 600, 650, 700, 750, 800, 850, 900, 950, point of the scale is associate with presence or Susceptibility 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, to SubAR or lack thereof. In some cases, the signal intensity 2000 or more samples. for each gene is obtained and used to compute a score. The 0102. Further disclosed herein are classifier sets and score may be obtained by adding up the values for the methods of producing one or more classifier sets. The upregulated genes to obtain an upregulated gene value and classifier set may comprise one or more genes, particularly adding up the values of the downregulated genes to obtain genes from Tables 2, 3, 4, 7, 8, 11, 12, 14, 15, 17, or 18. In a downregulated gene value; the downregulated gene value Some cases, the classifier set may comprise 1, 2, 3, 4, 5, 6, may be compared with the upregulated value (e.g., by 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 50, 100, 150, calculating a ratio) to determine the score. Other methods of 200, 300 or more genes from Tables 2, 3, 4, 7, 8, 11, 12, 14, combining values for individual markers of disease into a 15, 17, or 18. Disclosed herein is the use of a classification composite value that can be used as a single marker are system comprises one or more classifiers. In some instances, described in US2004.01.26767 and WO/2004/059293. In the classifier is a 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-way Some cases, the score may be used to evaluate severity of a classifier. In some instances, the classifier is a 15-, 20-, 25-, transplant condition, such as by comparing the score with a 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70- 75-, 80-, 85-, 90-, score normally associated with SubAR. In some cases, the 95-, or 100-way classifier. In some preferred embodiments, score may be used to monitor a subject transplant recipient the classifier is a three-way classifier. In some embodiments, over time. In such case, scores at a plurality of timepoints the classifier is a four-way classifier. maybe compared in order to assess the relative condition of 0103) A two-way classifier may classify a sample from a the subject. For example, if the subject’s score rises over Subject into one of two classes. In some instances, a two-way time, that may indicate that the subject has subAR and that classifier may classify a sample from an organ transplant his or her condition is worsening over time. recipient into one of two classes comprising SubAR and 0097 Sample Data normal transplant function (TX). In some instances, a three 0098. The data pertaining to the sample may be compared way classifier may classify a sample from a subject into one to data pertaining to one or more control samples, which of three classes. A three-way classifier may classify a sample may be samples from the same patient at different times. In from an organ transplant recipient into one of three classes Some cases, the one or more control samples may comprise comprising AR, SubAR, and TX In some cases, the classifier one or more samples from healthy Subjects, unhealthy may work by applying two or more classifiers sequentially. subjects, or a combination thereof. The one or more control For example, the first classifier may classify AR+subAR and samples may comprise one or more samples from healthy TX, which results in a set of samples that are classified either US 2017/O 137885 A1 May 18, 2017

as (1) TX or (2) AR or subAR. In some cases, a second 0110. The algorithm may be a trained algorithm. The classifier capable of distinguishing between AR and subAR algorithm may comprise a linear classifier. The linear clas is applied to the samples classified as having AR or SubAR sifier may comprise one or more linear discriminant analy in order to detect the SubAR samples. sis, Fisher's linear discriminant, Naive Bayes classifier, 0104 Classifiers and/or classifier probe sets may be used Logistic regression, Perceptron, Support vector machine, or to either rule-in or rule-out a sample as healthy. For example, a combination thereof. The linear classifier may be a Support a classifier may be used to classify a sample as being from vector machine (SVM) algorithm. a healthy subject. Alternatively, a classifier may be used to 0111. The algorithm may comprise one or more linear classify a sample as being from an unhealthy Subject. discriminant analysis (LDA), Basic perceptron, Elastic Net, Alternatively, or additionally, classifiers may be used to logistic regression, (Kernel) Support Vector Machines either rule-in or rule-out a sample as transplant rejection. For (SVM), Diagonal Linear Discriminant Analysis (DLDA), example, a classifier may be used to classify a sample as Golub Classifier, Parzen-based, (kernel) Fisher Discriminant being from a Subject Suffering from a transplant rejection. In Classifier, k-nearest neighbor, Iterative RELIEF, Classifica another example, a classifier may be used to classify a tion Tree, Maximum Likelihood Classifier, Random Forest, sample as being from a Subject that is not suffering from a Nearest Centroid, Prediction Analysis of Microarrays transplant rejection. Classifiers may be used to either rule-in (PAM), k-medians clustering, Fuzzy C-Means Clustering, or rule-out a sample as transplant dysfunction with no Gaussian mixture models, or a combination thereof. The rejection. For example, a classifier may be used to classify algorithm may comprise a Diagonal Linear Discriminant a sample as being from a subject with SubAR. In another Analysis (DLDA) algorithm. The algorithm may comprise a example, a classifier may be used to classify a sample as not Nearest Centroid algorithm. The algorithm may comprise a being from a subject Suffering from transplant dysfunction Random Forest algorithm. The algorithm may comprise a with no rejection. Prediction Analysis of Microarrays (PAM) algorithm. 0105. The samples may be classified simultaneously. In 0112 The methods disclosed herein may comprise use of Some cases, the samples may be classified sequentially. The one or more classifier equations. Classifying the sample may two or more samples may be classified at two or more time comprise a classifier equation. The classifier equation may points. The samples may be obtained at 1, 2, 3, 4, 5, 6, 7, 8, be Equation 1: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 100 or more time points. The two or more time points may be 1 day, 10 days, 30 days, 60 days, 100 days, 200 days, 1 year, 2 years or more apart. d(x) = yp (x;x - x;x s- - 2logik, 0106 Methods of simultaneous classifier-based analysis i=1 of one or more samples may comprise applying one or more algorithm to data from one or more samples to simultane ously produce one or more lists, wherein the lists comprise wherein: one or more samples classified as being from healthy 0113 k is a number of possible classes; Subjects (e.g. Subjects with a normal functioning transplant (TX)), unhealthy Subjects. Subjects Suffering from transplant 0114. Ö may be the discriminant score for class k: rejection, Subjects suffering from transplant dysfunction, 0115 x * represents the expression level of gene i: subjects with AR, or subjects with subAR. 0116 x* represents a vector of expression levels for all p 0107 The methods, kits, and systems disclosed herein genes to be used for classification drawn from the sample to may comprise one or more algorithms or uses thereof. The be classified; one or more algorithms may be used to classify one or more 0117 x' may be a shrunken centroid calculated from a samples from one or more Subjects. The one or more training data and a shrinkage factor, algorithms may be applied to data from one or more 0118 x' may be a component of x' corresponding to samples. The data may comprise gene expression data. The gene i: data may comprise sequencing data. The data may comprise array hybridization data. 0119 s, is a pooled within-class standard deviation for 0108. The methods disclosed herein may comprise gene i in the training data; assigning a classification to one or more samples from one 0120 so is a specified positive constant; and or more subjects. Assigning the classification to the sample I0121 t represents a prior probability of a sample may comprise applying an algorithm to the expression level. belonging to class k. In some cases, the gene expression levels are inputted to a 0.122 Assigning the classification may comprise calcu trained algorithm for classifying the sample as one of the lating a class probability. Calculating the class probability conditions comprising subAR, AR, TX, subAR+AR, or p(x*) may be calculated by Equation 2: other condition. 0109 The algorithm may provide a record of its output including a classification of a sample and/or a confidence level. In some instances, the output of the algorithm can be the possibility of the Subject of having a condition, such as SubAR. In some instances, the output of the algorithm can be the risk of the Subject of having a condition, such as AR. In Some instances, the output of the algorithm can be the 0123 Assigning the classification may comprise a clas possibility of the Subject of developing into a condition in sification rule. The classification rule C(x) may be the future, such as AR. expressed by Equation 3: US 2017/O 137885 A1 May 18, 2017 14

method may predict or determine whether a transplant C(x) = argmaxp(x"). recipient does not have or is at reduced risk of SCAR (or kelik AR). The negative predictive value (e.g., for predicting or determining that transplant recipient does not have SCAR or is at reduced risk for SCAR or for distinguishing SCAR versus TX, SCAR versus AR, AR versus TX, and/or any VI. DIAGNOSIS, PROGNOSIS AND combination thereof) may be greater than 85%, 90%, 91%, MONITORING 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99.0%, 0.124. The above described methods can provide a com 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, posite or aggregate value or other designation for a patient, 99.8%, 99.9%, 99.95%, or 99.99%. In some cases, the which indicates whether the patient either has or is at negative predictive value is 100%. enhanced risk of SCAR (or AR), or conversely does not have 0.126 In some instances, the methods, compositions, sys or is at reduced risk of SCAR (or AR). Risk is a relative term tems and kits described herein provide information to a in which risk of one patient is compared with risk of other medical practitioner that can be useful in making a thera patients either qualitatively or quantitatively. For example, peutic decision. Therapeutic decisions may include deci the value of one patient can be compared with a scale of sions to: continue with a particular therapy, modify a par values for a population of patients having undergone kidney ticular therapy, alter the dosage of a particular therapy, stop transplant to determine whether the patient’s risk relative to or terminate a particular therapy, altering the frequency of a that of other patients. In general, diagnosis is the determi therapy, introduce a new therapy, introduce a new therapy to nation of the present condition of a patient (e.g., presence or be used in combination with a current therapy, or any absence of SCAR) and prognosis is developing future course combination of the above. In some instances, the results of of the patient (e.g., risk of developing SCAR in the future or diagnosing, predicting, or monitoring a condition of a trans likelihood of improvement in response to treatment); how plant recipient may be useful for informing a therapeutic ever, the analyses contemplated by these terms may overlap decision Such as removal of the transplant. In some or even be the same. For example, the present methods alone instances, the removal of the transplant can be an immediate do not necessarily distinguish between presence and removal. In other instances, the therapeutic decision can be enhanced risk of SCAR. However, these possibilities can be a retransplant. Other examples of therapeutic regimen can distinguished by additional testing. include a blood transfusion in instances where the transplant recipient is refractory to immunosuppressive or antibody 0125. The methods provided herein can help determine therapy. whether the patient either has or is at enhanced risk of SubAR/SCAR (or AR) with a high degree of accuracy, I0127. If a patient is indicated as having or being at sensitivity, and/or specificity. In some cases, the predictive enhanced risk of SubAR or SCAR, the physician can subject accuracy (e.g., for predicting SubAR/SCAR, for detecting the patient to additional testing including performing a SubAR/SCAR, or for distinguishing SCAR versus TX, kidney biopsy or performing other analyses such as creati SCAR versus AR, AR versus TX, and/or any combination nine, BUN or glomerular filtration rate at increased fre thereof) is greater than 75%, 85%, 90%, 91%, 92%, 93%, quency. Additionally or alternatively, the physician can 94%. 95%, 96%, 97%, 98%, 98.5%, 99.0%, 99.1%, 99.2%, change the treatment regime being administered to the 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, patient. A change in treatment regime can include adminis 99.95%, or 99.99%. In some embodiments, the predictive tering an additional or different drug to a patient, or admin accuracy is 100%. In some cases, the sensitivity (e.g., for istering a higher dosage or frequency of a drug already being detecting or predicting SCAR or for distinguishing SCAR administered to the patient. Many different drugs are avail versus TX, SCAR versus AR, AR versus TX, and/or any able for treating rejection, such as immunosuppressive drugs combination thereof) is greater than 75%, 85%, 90%, 91%, used to treat transplant rejection calcineurin inhibitors (e.g., 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99.0%, cyclosporine, tacrolimus). mTOR inhibitors (e.g., sirolimus 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, and everolimus) anti-proliferatives (e.g., azathioprine, 99.8%, 99.9%, 99.95%, or 99.99%. In some embodiments mycophenolic acid), corticosteroids (e.g., prednisolone and the sensitivity is 100%. In some cases, the specificity (e.g., hydrocortisone) and antibodies (e.g., basiliximab, dacli for detecting or predicting SCAR or for distinguishing Zumab, Orthoclone, anti-thymocyte globulin and anti-lym SCAR versus TX, SCAR versus AR, AR versus TX, and/or phocyte globulin). any combination thereof) is greater than 75%, 85%, 90%, I0128 Conversely, if the value or other designation of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, aggregate expression levels of a patient indicates the patient 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.57%, 99.6%, does not have or is at reduced risk of SCAR, the physician 99.7%, 99.8%, 99.9%, 99.95%, or 99.99%. In some cases, need not order further diagnostic procedures, particularly the specificity is 100%. In some cases, the positive predic not invasive ones Such as biopsy. Further, the physician can tive value (e.g., for detecting or predicting SCAR or for continue an existing treatment regime, or even decrease the distinguishing SCAR versus TX, SCAR versus AR, AR dose or frequency of an administered drug. versus TX, and/or any combination thereof) of the method is I0129. In some methods, expression levels are determined greater than 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, at intervals in a particular patient (i.e., monitoring). Prefer 96%, 97%, 98%, 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, ably, the monitoring is conducted by serial minimally 99.4%, 99.57%, 99.67%, 99.7%, 99.8%, 99.9%, 99.95%, or invasive tests such as blood draws; but, in some cases, the 99.99%. In some cases the positive predictive value is 100%. monitoring may also involve analyzing a kidney biopsy, The AUC after thresholding in any of the methods provided either histologically or by analyzing a molecular profile. The herein may be greater than 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, monitoring may occur at different intervals, for example the 0.96, 0.97, 0.98, 0.99, 0.995, or 0.999. Conversely, the monitoring may be hourly, daily, weekly, monthly, yearly, or US 2017/O 137885 A1 May 18, 2017

Some other time period. Such as twice a month, three times later in time. Such as allograft loss or procedures such as a month, every two months, every three months, etc. kidney dialysis. In some cases, such early treatments may be 0130. Such methods can provide a series of values chang administered after the patient receives both a molecular ing over time indicating whether the aggregate expression profiling blood test and a biopsy analyzed either by molecu levels in a particular patient are more like the expression lar profiling or histologically. levels in patients undergoing subAR or SCAR or not under I0134. The diagnosis or detection of condition of a trans going SubAR or SCAR. Movement in value toward or away plant recipient may be particularly useful in limiting the from SubAR or SCAR can provide an indication whether an number of invasive diagnostic interventions that are admin existing immunosuppressive regime is working, whether the istered to the patient. For example, the methods provided immunosuppressive regime should be changed or whether a herein may limit or eliminate the need for a transplant biopsy or increased monitoring by markers such as creati recipient (e.g., kidney transplant recipient) to receive a nine or glomerular filtration rate should be performed. biopsy (e.g., kidney biopsies) or to receive multiple biopsies. 0131 The methods provided herein include administer In a further embodiment, the methods provided herein can ing a blood test (e.g., a test to detect Subclinical acute be used alone or in combination with other standard diag rejection) to a transplant recipient who has already under nosis methods currently used to detect or diagnose a con gone a Surveillance or protocol biopsy of the kidney and dition of a transplant recipient, such as but not limited to received a biopsy result in the form of a histological analysis results of biopsy analysis for kidney allograft rejection, or a molecular profiling analysis. In some particular results of histopathology of the biopsy sample, serum crea instances, the analysis of the kidney biopsy (e.g., by histol tinine level, creatinine clearance, ultrasound, radiological ogy or molecular profiling) may result in ambiguous, incon imaging results for the kidney, urinalysis results, elevated clusive or borderline results. In such cases, a blood test levels of inflammatory molecules such as neopterin, and provided herein may assist a caregiver with determining lymphokines, elevated plasma interleukin (IL)-1 in azathio whether the transplant recipient has subclinical acute rejec prine-treated patients, elevated IL-2 in cyclosporine-treated tion or with interpreting the biopsy. In other cases the biopsy patients, elevated IL-6 in serum and urine, intrarenal expres itself may be inconclusive or ambiguous, and in Such cases sion of cytotoxic molecules (granzyme B and perforin) and the molecular analysis of the biopsy may be used in adjunct immunoregulatory cytokines (IL-2, -4, -10, interferon with the histology to confirm a diagnosis. In some instances, gamma and transforming growth factor-b1). the analysis of the kidney biopsy may yield a negative result. 0.135 The methods herein may be used in conjunction In such cases, the subject may receive a blood test provided with kidney function tests, such as complete blood count herein in order to confirm the negative result, or to detect (CBC), serum electrolytes tests (including Sodium, potas Subclinical acute rejection. In some cases, after receiving sium, chloride, bicarbonate, calcium, and phosphorus), any type of biopsy result (e.g., negative result, ambiguous, blood urea test, blood nitrogen test, serum creatinine test, inconclusive, borderline, positive), the patient may receive urine electrolytes tests, urine creatinine test, urine protein multiple, serial blood tests to monitor changes in molecular test, urine fractional excretion of sodium (FENA) test, markers correlated with Subclinical acute rejection. glomerular filtration rate (GFR) test. Kidney function may 0132) The methods provided herein also include admin also be assessed by a renal biopsy. Kidney function may also istering a biopsy test (e.g., histology or molecular profiling) be assessed by one or more gene expression tests. to a transplant recipient who has received a molecular blood profiling test. For example, the transplant recipient may VII. DRUG SCREENING receive an ambiguous, inconclusive or borderline result on 0.136 The expression profiles associated with SCAR or a blood molecular profiling test. In Such cases, the patients lack thereof (TX) provided by the invention are useful in healthcare worker may use the results of a kidney biopsy test screening drugs, either in clinical trials or in animal models as a complement to the blood test to determine whether the of SCAR. A clinical trial can be performed on a drug in Subject is experiencing Subclinical acute rejection. In similar fashion to the monitoring of an individual patient another example, the transplant recipient may have received described above, except that drug is administered in parallel a positive result on a blood molecular profiling test, indi to a population of kidney transplant patients, usually in cating that the transplant recipient has, or likely has, Sub comparison with a control population administered a pla clinical acute rejection, or even multiple positive results cebo. over time. In Such cases, the patient's physician or other 0.137 The changes in expression levels of genes can be healthcare worker may decide to biopsy the patient’s kidney analyzed in individual patients and across a treated or in order to detect SubAR. Such kidney biopsy test may be a control population. Analysis at the level of an individual molecular profiling analysis of the patient's kidney, as patient provides an indication of the overall status of the described herein. In some cases, a histological analysis of patient at the end of the trial (i.e., whether gene expression the kidney biopsy may be performed instead of, or in profile indicates presence or enhanced Susceptibility to addition to, the molecular analysis of the biopsy. In some SCAR) and/or an indication whether that profile has cases, the physician may decide to wait a certain period of changed toward or away from Such indication in the course time after receiving the positive blood result to perform the of the trial. Results for individual patients can be aggregated biopsy test. for a population allowing comparison between treated and 0133. The methods provided herein may often provide control population. early detection of subAR and may help a patient to obtain 0.138 Similar trials can be performed in non-human early treatment Such as receiving immunosuppressive animal models of chronic kidney disease, e.g., the mouse therapy or increasing an existing immunosuppressive regi model of Mannon et al., Kidney International 55: 1935 men. Such early treatment may enable the patient to avoid 1944, 1999. In this case, the expression levels of genes more serious consequences associated with acute rejection detected are the species variants or homologs of the human US 2017/O 137885 A1 May 18, 2017

genes referenced above in whatever species of non-human Some instances, the Subject (e.g. patient) may be able to animal on which tests are being conducted. Although the access the result by using a standalone software and/or a average or mean expression levels of human genes deter web-based application on a local computer capable of mined in human kidney transplant patients undergoing or accessing the internet (260). In some instances, the result not undergoing SCAR are not necessarily directly compa can be accessed via a mobile application (270) provided to rable to those of homolog genes in an animal model, the a mobile digital processing device (e.g. mobile phone, tablet, human values can nevertheless be used to provide an indi etc.). In some instances, the result may be accessed by cation whether a change in expression level of a non-human physicians and help them identify and track conditions of homolog is In a direction toward or away from SCAR or their patients (280). In some instances, the result may be susceptibility thereto. The expression profile of individual used for other purposes (290) such as education and animals in a trial can provide an indication of the status of research. the animal at the end of the trial with respect to presence or 0.142 Computer Program Susceptibility to SCAR and/or change in Such status during 0143. The methods, kits, and systems disclosed herein the trial. Results from individual animals can be aggregated may include at least one computer program, or use of the across a population and treated and control populations same. A computer program may include a sequence of compared. Average changes in the expression levels of genes instructions, executable in the digital processing device's can then be compared between the two populations. CPU, written to perform a specified task. Computer readable instructions may be implemented as program modules. Such VIII. COMPUTER IMPLEMENTED METHODS as functions, objects, Application Programming Interfaces 0139 Expression levels can be analyzed and associated (APIs), data structures, and the like, that perform particular with status of a Subject (e.g., presence or Susceptibility to tasks or implement particular abstract data types. In light of SCAR) in a digital computer. Optionally, such a computer is the disclosure provided herein, those of skill in the art will directly linked to a scanner or the like receiving experimen recognize that a computer program may be written in tally determined signals related to expression levels. Alter various versions of various languages. natively, expression levels can be input by other means. The 0144. The functionality of the computer readable instruc computer can be programmed to convert raw signals into tions may be combined or distributed as desired in various expression levels (absolute or relative), compare measured environments. The computer program will normally provide expression levels with one or more reference expression a sequence of instructions from one location or a plurality of levels, or a scale of such values, as described above. The locations. In various embodiments, a computer program computer can also be programmed to assign values or other includes, in part or in whole, one or more web applications, designations to expression levels based on the comparison one or more mobile applications, one or more standalone with one or more reference expression levels, and to aggre applications, one or more web browser plug-ins, extensions, gate such values or designations for multiple genes in an add-ins, or add-ons, or combinations thereof. expression profile. The computer can also be programmed to 0.145) Further disclosed herein are systems for classifying output a value or other designation providing an indication one or more samples and uses thereof. The system may of presence or susceptibility to SCAR as well as any of the comprise (a) a digital processing device comprising an raw or intermediate data used in determining such a value or operating system configured to perform executable instruc designation. tions and a memory device; (b) a computer program includ 0140. A typically computer (see U.S. Pat. No. 6,785,613 ing instructions executable by the digital processing device FIGS. 4 and 5) includes a bus which interconnects major to classify a sample from a subject comprising: (i) a first Subsystems such as a central processor, a system memory, an Software module configured to receive a gene expression input/output controller, an external device Such as a printer profile of one or more genes from the sample from the via a parallel port, a display screen via a display adapter, a Subject; (ii) a second software module configured to analyze serial port, a keyboard, a fixed disk drive and a floppy disk the gene expression profile from the Subject; and (iii) a third drive operative to receive a floppy disk. Many other devices Software module configured to classify the sample from the can be connected Such as a scanner via I/O controller, a Subject based on a classification system comprising three or mouse connected to serial port or a network interface. The more classes. At least one of the classes may be selected computer contains computer readable media holding codes from transplant rejection, transplant dysfunction with no to allow the computer to perform a variety of functions. rejection and normal transplant function. At least two of the These functions include controlling automated apparatus, classes may be selected from transplant rejection, transplant receiving input and delivering output as described above. dysfunction with no rejection and normal transplant func The automated apparatus can include a robotic arm for tion. All three of the classes may be selected from transplant delivering reagents for determining expression levels, as rejection, transplant dysfunction with no rejection and nor well as Small vessels, e.g., microtiter wells for performing mal transplant function. Analyzing the gene expression the expression analysis. profile from the Subject may comprise applying an algo 0141. The methods, systems, kits and compositions pro rithm. Analyzing the gene expression profile may comprise vided herein may also be capable of generating and trans normalizing the gene expression profile from the Subject. In mitting results through a computer network. As shown in Some instances, normalizing the gene expression profile FIG. 2, a sample (220) is first collected from a subject (e.g. does not comprise quantile normalization. transplant recipient, 210). The sample is assayed (230) and 0146 FIG. 4 shows a computer system (also “system” gene expression products are generated. A computer system herein) 401 programmed or otherwise configured for imple (240) is used in analyzing the data and making classification menting the methods of the disclosure. Such as producing a of the sample. The result is capable of being transmitted to selector set and/or for data analysis. The system 401 different types of end users via a computer network (250). In includes a central processing unit (CPU, also “processor US 2017/O 137885 A1 May 18, 2017 and “computer processor herein) 405, which can be a single embodiments, the digital processing device is optionally core or multi core processor, or a plurality of processors for connected to a data storage device. parallel processing. The system 401 also includes memory 0151. In accordance with the description herein, suitable 410 (e.g., random-access memory, read-only memory, flash digital processing devices include, by way of non-limiting memory), electronic storage unit 415 (e.g., hard disk), examples, server computers, desktop computers, laptop communications interface 420 (e.g., network adapter) for computers, notebook computers, Sub-notebook computers, communicating with one or more other systems, and periph netbook computers, netpad computers, set-top computers, eral devices 425. Such as cache, other memory, data storage handheld computers, Internet appliances, mobile Smart and/or electronic display adapters. The memory 410, Storage phones, tablet computers, personal digital assistants, video unit 415, interface 420 and peripheral devices 425 are in game consoles, and vehicles. Those of skill in the art will communication with the CPU 405 through a communica recognize that many Smartphones are Suitable for use in the tions bus (solid lines). Such as a motherboard. The storage system described herein. Those of skill in the art will also unit 415 can be a data storage unit (or data repository) for recognize that select televisions, video players, and digital storing data. The system 401 is operatively coupled to a music players with optional computer network connectivity computer network (“network”) 430 with the aid of the are suitable for use in the system described herein. Suitable communications interface 420. The network 430 can be the tablet computers include those with booklet, slate, and Internet, an internet and/or extranet, or an intranet and/or convertible configurations, known to those of skill in the art. extranet that is in communication with the Internet. The 0152 The digital processing device will normally include network 430 in some instances is a telecommunication an operating system configured to perform executable and/or data network. The network 430 can include one or instructions. The operating system is, for example, software, more computer servers, which can enable distributed com including programs and data, which manages the device's puting. Such as cloud computing. The network 430 in some hardware and provides services for execution of applica instances, with the aid of the system 401, can implement a tions. Those of skill in the art will recognize that suitable peer-to-peer network, which may enable devices coupled to server operating systems include, by way of non-limiting the system 401 to behave as a client or a server. examples, FreeBSD, OpenBSD, NetBSDR), Linux, Apple(R) 0147 The system 401 is in communication with a pro Mac OS X Server R, Oracle(R) Solaris(R), Windows Server R, cessing system 435. The processing system 435 can be and Novell(R) NetWare(R). Those of skill in the art will configured to implement the methods disclosed herein. In recognize that Suitable personal computer operating systems some examples, the processing system 435 is a nucleic acid include, by way of non-limiting examples, Microsoft(R) sequencing system, Such as, for example, a next generation Windows(R), Apple(R) Mac OS X(R), UNIX(R), and UNIX-like sequencing system (e.g., Illumina sequencer, Ion Torrent operating systems such as GNU/Linux(R). In some embodi sequencer, Pacific Biosciences sequencer). The processing ments, the operating system is provided by cloud computing. system 435 can be in communication with the system 401 Those of skill in the art will also recognize that suitable through the network 430, or by direct (e.g., wired, wireless) mobile Smart phone operating systems include, by way of connection. The processing system 435 can be configured non-limiting examples, Nokia R Symbian(R) OS, Apple(R) for analysis, such as nucleic acid sequence analysis. iOS.R., Research In Motion R. BlackBerry OSR), Google(R) 0148 Methods as described herein can be implemented Android R, Microsoft(R) Windows PhoneR OS, Microsoft(R) by way of machine (or computer processor) executable code Windows MobileR OS, Linux(R), and PalmR) WebOS(R). (or software) stored on an electronic storage location of the 0153. The device generally includes a storage and/or system 401, such as, for example, on the memory 410 or memory device. The storage and/or memory device is one or electronic storage unit 415. During use, the code can be more physical apparatuses used to store data or programs on executed by the processor 405. In some examples, the code a temporary or permanent basis. In some embodiments, the can be retrieved from the storage unit 415 and stored on the device is volatile memory and requires power to maintain memory 410 for ready access by the processor 405. In some stored information. In some embodiments, the device is situations, the electronic storage unit 415 can be precluded, non-volatile memory and retains stored information when and machine-executable instructions are stored on memory the digital processing device is not powered. In further 410. embodiments, the non-volatile memory comprises flash memory. In some embodiments, the non-volatile memory 0149 Digital Processing Device comprises dynamic random-access memory (DRAM). In 0150. The methods, kits, and systems disclosed herein Some embodiments, the non-volatile memory comprises may include a digital processing device, or use of the same. ferroelectric random access memory (FRAM). In some In further embodiments, the digital processing device embodiments, the non-volatile memory comprises phase includes one or more hardware central processing units change random access memory (PRAM). In other embodi (CPU) that carry out the device's functions. In still further ments, the device is a storage device including, by way of embodiments, the digital processing device further com non-limiting examples, CD-ROMs, DVDs, flash memory prises an operating system configured to perform executable devices, magnetic disk drives, magnetic tapes drives, optical instructions. In some embodiments, the digital processing disk drives, and cloud computing based storage. In further device is optionally connected a computer network. In embodiments, the storage and/or memory device is a com further embodiments, the digital processing device is option bination of devices such as those disclosed herein. ally connected to the Internet such that it accesses the World 0154) A display to send visual information to a user will WideWeb. In still further embodiments, the digital process normally be initialized. Examples of displays include a ing device is optionally connected to a cloud computing cathode ray tube (CRT, a liquid crystal display (LCD), a thin infrastructure. In other embodiments, the digital processing film transistor liquid crystal display (TFT-LCD, an organic device is optionally connected to an intranet. In other light emitting diode (OLED) display. In various further US 2017/O 137885 A1 May 18, 2017

embodiments, on OLED display is a passive-matrix OLED more software frameworks and one or more database sys (PMOLED) or active-matrix OLED (AMOLED) display. In tems. In some embodiments, a web application is created Some embodiments, the display may be a plasma display, a upon a software framework such as Microsoft(R) .NET or Video projector or a combination of devices such as those Ruby on Rails (RoR). In some embodiments, a web appli disclosed herein. cation utilizes one or more database systems including, by 0155 The digital processing device would normally way of non-limiting examples, relational, non-relational, include an input device to receive information from a user. object oriented, associative, and XML database systems. In The input device may be, for example, a keyboard, a further embodiments, suitable relational database systems pointing device including, by way of non-limiting examples, include, by way of non-limiting examples, Microsoft(R) SQL a mouse, trackball, track pad, joystick, game controller, or Server, mySQLTM, and Oracle(R). Those of skill in the art will stylus; a touch screen, or a multi-touch screen, a microphone also recognize that a web application, in various embodi to capture Voice or other sound input, a video camera to ments, is written in one or more versions of one or more capture motion or visual input or a combination of devices languages. A web application may be written in one or more Such as those disclosed herein. markup languages, presentation definition languages, client 0156 Non-Transitory Computer Readable Storage side scripting languages, server-side coding languages, data Medium base query languages, or combinations thereof. In some 0157. The methods, kits, and systems disclosed herein embodiments, a web application is written to some extent in may include one or more non-transitory computer readable a markup language such as Hypertext Markup Language storage media encoded with a program including instruc (HTML), Extensible Hypertext Markup Language tions executable by the operating system to perform and (XHTML), or eXtensible Markup Language (XML). In analyze the test described herein; preferably connected to a Some embodiments, a web application is written to some networked digital processing device. The computer readable extent in a presentation definition language such as Cascad storage medium is a tangible component of a digital that is ing Style Sheets (CSS). In some embodiments, a web optionally removable from the digital processing device. application is written to some extent in a client-side Scripting The computer readable storage medium includes, by way of language such as Asynchronous JavaScript and XML non-limiting examples, CD-ROMs, DVDs, flash memory (AJAX), FlashR) Actionscript, Javascript, or Silverlight(R). In devices, Solid state memory, magnetic disk drives, magnetic Some embodiments, a web application is written to some tape drives, optical disk drives, cloud computing systems extent in a server-side coding language Such as Active and services, and the like. In some instances, the program Server Pages (ASP), ColdFusion(R), Perl, JavaTM, JavaServer and instructions are permanently, Substantially permanently, Pages (JSP), Hypertext Preprocessor (PHP), PythonTM, semi-permanently, or non-transitorily encoded on the media. Ruby, Tcl, Smalltalk, WebDNAR, or Groovy. In some 0158. A non-transitory computer-readable storage media embodiments, a web application is written to some extent in may be encoded with a computer program including instruc a database query language such as Structured Query Lan tions executable by a processor to create or use a classifi guage (SQL). In some embodiments, a web application cation system. The storage media may comprise (a) a integrates enterprise server products such as IBM(R) Lotus database, in a computer memory, of one or more clinical Domino (R). In some embodiments, a web application features of two or more control samples, wherein (i) the two includes a media player element. In various further embodi or more control samples may be from two or more subjects; ments, a media player element utilizes one or more of many and (ii) the two or more control samples may be differen Suitable multimedia technologies including, by way of non tially classified based on a classification system comprising limiting examples, Adobe R Flash R, HTML 5, Apple(R) three or more classes; (b) a first Software module configured QuickTime(R), Microsoft(R) Silverlight(R), JavaTM, and to compare the one or more clinical features of the two or Unity(R). more control samples; and (c) a second software module 0162 Mobile Application configured to produce a classifier set based on the compari 0163. In some embodiments, a computer program Son of the one or more clinical features. includes a mobile application provided to a mobile digital 0159. At least two of the classes may be selected from processing device. In some embodiments, the mobile appli transplant rejection, transplant dysfunction with no rejection cation is provided to a mobile digital processing device at and normal transplant function. All three classes may be the time it is manufactured. In other embodiments, the selected from transplant rejection, transplant dysfunction mobile application is provided to a mobile digital processing with no rejection and normal transplant function. The Stor device via the computer network described herein. age media may further comprise one or more additional 0164. In view of the disclosure provided herein, a mobile Software modules configured to classify a sample from a application is created by techniques known to those of skill Subject. Classifying the sample from the Subject may com in the art using hardware, languages, and development prise a classification system comprising three or more environments known to the art. Those of skill in the art will classes. At least two of the classes may be selected from recognize that mobile applications are written in several transplant rejection, transplant dysfunction with no rejection languages. Suitable programming languages include, by and normal transplant function. All three classes may be way of non-limiting examples, C, C++, C#, Objective-C, selected from transplant rejection, transplant dysfunction JavaTM, Javascript, Pascal, Object Pascal, PythonTM, Ruby, with no rejection and normal transplant function. VB.NET, WML, and XHTML/HTML with or without CSS, (0160 Web Application or combinations thereof. 0161 In some embodiments, a computer program 0.165 Suitable mobile application development environ includes a web application. In light of the disclosure pro ments are available from several Sources. Commercially vided herein, those of skill in the art will recognize that a available development environments include, by way of web application, in various embodiments, utilizes one or non-limiting examples, AirplaySDK, alcheMo, Appcelera US 2017/O 137885 A1 May 18, 2017

tor(R), Celsius, Bedrock, Flash Lite, .NET Compact Frame fox R, Google(R) Chrome, Apple(R) Safari (R, Opera Soft work, Rhomobile, and WorkLight Mobile Platform. Other ware(R) OperaR), and KDE Konqueror. In some embodi development environments are available without cost ments, the web browser is a mobile web browser. Mobile including, by way of non-limiting examples, Lazarus, Mobi web browsers (also called mircrobrowsers, mini-browsers, Flex, MoSync, and Phonegap. Also, mobile device manu and wireless browsers) are designed for use on mobile facturers distribute software developer kits including, by digital processing devices including, by way of non-limiting way of non-limiting examples, iPhone and iPad (iOS) SDK, examples, handheld computers, tablet computers, netbook Android TM SDK, BlackBerry(R) SDK, BREW SDK, PalmR) computers, Subnotebook computers, Smartphones, music OS SDK, Symbian SDK, webOS SDK, and Windows(R) players, personal digital assistants (PDAs), and handheld Mobile SDK. video game systems. Suitable mobile web browsers include, 0166 Those of skill in the art will recognize that several by way of non-limiting examples, Google R. Android R. commercial forums are available for distribution of mobile browser, RIM BlackBerry(R) Browser, Apple(R) Safari(R), applications including, by way of non-limiting examples, Palm R. Blazer, Palm(R) WebOSR) Browser, Mozilla(R) Fire Apple(R). App Store, AndroidTM Market, BlackBerry R. App fox(R) for mobile, Microsoft(R) Internet Explorer(R) Mobile, World, App Store for Palm devices, App Catalog for webOS, Amazon R. KindleR Basic Web, Nokia R. Browser, Opera Windows(R Marketplace for Mobile, Ovi Store for Nokia(R) Software(R) Opera R. Mobile, and Sony(R) PSPTM browser. devices, Samsung R. Apps, and Nintendo(R DSi Shop. (0173 Software Modules 0167 Standalone Application 0.174. The methods, kits, and systems disclosed herein 0168 In some embodiments, a computer program may include Software, server, and/or database modules, or includes a standalone application, which is a program that is use of the same. In view of the disclosure provided herein, run as an independent computer process, not an add-on to an Software modules are created by techniques known to those existing process, e.g., not a plug-in. Those of skill in the art of skill in the art using machines, Software, and languages will recognize that standalone applications are often com known to the art. The software modules disclosed herein are piled. A compiler is a computer program(s) that transforms implemented in a multitude of ways. In various embodi Source code written in a programming language into binary ments, a Software module comprises a file, a section of code, object code such as assembly language or machine code. a programming object, a programming structure, or combi Suitable compiled programming languages include, by way nations thereof. In further various embodiments, a software of non-limiting examples, C, C++, Objective-C, COBOL, module comprises a plurality of files, a plurality of sections Delphi, Eiffel, JavaTM, Lisp, PythonTM, Visual Basic, and VB of code, a plurality of programming objects, a plurality of .NET, or combinations thereof. Compilation is often per programming structures, or combinations thereof. In various formed, at least in part, to create an executable program. In embodiments, the one or more Software modules comprise, Some embodiments, a computer program includes one or by way of non-limiting examples, a web application, a more executable complied applications. mobile application, and a standalone application. In some (0169 Web Browser Plug-in embodiments, software modules are in one computer pro 0170 In some embodiments, the computer program gram or application. In other embodiments, Software mod includes a web browser plug-in. In computing, a plug-in is ules are in more than one computer program or application. one or more software components that add specific func In some embodiments, Software modules are hosted on one tionality to a larger software application. Makers of Software machine. In other embodiments, Software modules are applications Support plug-ins to enable third-party develop hosted on more than one machine. In further embodiments, ers to create abilities which extend an application, to Support Software modules are hosted on cloud computing platforms. easily adding new features, and to reduce the size of an In some embodiments, Software modules are hosted on one application. When Supported, plug-ins enable customizing or more machines in one location. In other embodiments, the functionality of a software application. For example, Software modules are hosted on one or more machines in plug-ins are commonly used in web browsers to play video, more than one location. generate interactivity, Scan for , and display particular (0175 Databases file types. Those of skill in the art will be familiar with 0176 The methods, kits, and systems disclosed herein several web browser plug-ins including, Adobe R. FlashR) may comprise one or more databases, or use of the same. In Player, Microsoft(R) Silverlight(R), and Apple(R). QuickTime(R). view of the disclosure provided herein, those of skill in the In some embodiments, the toolbar comprises one or more art will recognize that many databases are Suitable for web browser extensions, add-ins, or add-ons. In some storage and retrieval of information pertaining to gene embodiments, the toolbar comprises one or more explorer expression profiles, sequencing data, classifiers, classifica bars, tool bands, or desk bands. tion systems, therapeutic regimens, or a combination 0171 In view of the disclosure provided herein, those of thereof. In various embodiments, suitable databases include, skill in the art will recognize that several plug-in frame by way of non-limiting examples, relational databases, non works are available that enable development of plug-ins in relational databases, object oriented databases, object data Various programming languages, including, by Way of non bases, entity-relationship model databases, associative data limiting examples, C++, Delphi, JavaTM, PHP, PythonTM, bases, and XML databases. In some embodiments, a and VB.NET, or combinations thereof. database is internet-based. In further embodiments, a data 0172 Web browsers (also called Internet browsers) are base is web-based. In still further embodiments, a database Software applications, designed for use with network-con is cloud computing-based. In other embodiments, a database nected digital processing devices, for retrieving, presenting, is based on one or more local computer storage devices. and traversing information resources on the World Wide 0177. Data Transmission Web. Suitable web browsers include, by way of non-limiting 0.178 The methods, kits, and systems disclosed herein examples, Microsoft(R) Internet Explorer R, Mozilla R. Fire may be used to transmit one or more reports. The one or US 2017/O 137885 A1 May 18, 2017 20 more reports may comprise information pertaining to the over 2700 probesets. The corresponding genes for 2156 classification and/or identification of one or more samples probes are listed in Table 4. Therefore for the purpose of a from one or more subjects. The one or more reports may diagnostic signature we used the top 200 differentially comprise information pertaining to a status or outcome of a expressed probe sets (Table 2) to build predictive models transplant in a Subject. The one or more reports may that could differentiate the three classes. The top 200 probe comprise information pertaining to therapeutic regimens for sets have FDR values of <0.05%. We used three different use in treating transplant rejection in a Subject in need predictive algorithms, namely Diagonal Linear Discriminant thereof. The one or more reports may comprise information Analysis (DLDA), Nearest Centroid (NC) and Support pertaining to therapeutic regimens for use in treating trans Vector Machines (SVM) to build the predictive models. We plant dysfunction in a subject in need thereof. The one or the predictive models using two different methodologies more reports may comprise information pertaining to thera and calculated the Area Under the Curve (AUC). SVM, peutic regimens for use in Suppressing an immune response DLDA and NC picked classifier sets of 200, 192 and 188 in a subject in need thereof. probesets as the best classifiers. Since there was very little 0179 The one or more reports may be transmitted to a difference in the AUC's we decided to use all 200 probesets subject or a medical representative of the subject. The as classifiers for all methods. We also demonstrated that medical representative of the Subject may be a physician, these results were not the consequence of statistical over physicians assistant, nurse, or other medical personnel. The fitting by using the replacement method of Harrell to per medical representative of the subject may be a family form a version of 1000-test cross-validation. Table 1 shows member of the subject. A family member of the subject may the performance of these classifier sets using both one-level be a parent, guardian, child, sibling, aunt, uncle, cousin, or cross validation as well as the Optimism Corrected Boot spouse. The medical representative of the Subject may be a strapping (1000 data sets). legal representative of the Subject. 0.184 An important point here is that in real clinical practice the challenge is actually not to distinguish SCAR EXAMPLES from AR because generally only AR presents with a signifi 0180. The following examples are offered to illustrate, cant increase in baseline serum creatinine. The real chal lenge is to take a patient with normal and stable creatinine but not to limit the present invention. and diagnose the hidden SCAR without having to depend on Example 1 Materials and Methods invasive and expensive protocol biopsies that cannot be done frequently in any case. Though we have already 0181. This Example describes some of the materials and Successfully done this using our 3-way analysis, we also methods employed in identification of differentially tested a 2-way prediction of SCAR vs. TX. The point was to expressed genes in SCAR. further validate that a phenotype as potentially subtle clini 0182. The discovery set of samples consisted of the cally as SCAR can be truly distinguished from TX. At a following biopsy-documented peripheral blood samples. 69 p-value <0.001, there were 33 probesets whose expression PAXgene whole blood samples were collected from kidney signals highly differentiated SCAR and TX, a result in transplant patients. The samples were histology confirmed, marked contrast with the >2500 probesets differentially and comprised 3 different phenotypes: (1) Acute Rejection expressed between AR vs. TX at that same p-value. (FIG. 3 (AR; n=21); (2) Sub-Clinical Acute Rejection (SCAR; shows the hierarchical clustering of gene expression profil n=23); and (3) Transplant Excellent (TX; n=25). Specifi ing of these 33 probesets.) However, when these 33 probe cally, SCAR was defined by a protocol biopsy done on a sets (Table 3) were used in NC to predict SCAR and TX patient with totally stable kidney function and the light creating a 2-way classifier, the predictive accuracies with a histology revealed unexpected evidence of acute rejection one-level cross-validation was 96% and with the Harrell (16 “Borderline', 7 Banff 1A). The SCAR samples consisted 1000 test optimism correction it was 94%. Thus, we are of 3 month and 1 year protocol biopsies, whereas the TXs confident that we can distinguish SCAR, TX and AR by were predominantly 3 month protocol biopsies. The mean peripheral blood gene expression profiling using this proof age of the patients is 49.3 years (ranging from 22-71); 35% of principle data set. female: 52% deceased donors. Table 5 presents time to biopsies where time is defined as days post transplantation. Example 3 Microarray and NGS Analyses All the AR biopsies were “for cause' where clinical indi cations like a rise in serum creatinine prompted the need for 0185. This Example describes the identification of dif a biopsy. All patients were induced with Thymoglobulin. ferentially expressed genes in SCAR using microarray and next-generation sequencing (NGS) analyses. Example 2 Gone Expression Profiling and Data Biopsy Samples Analysis 0186. 0187 To compare the methods using blood and biopsy 0183 All samples were processed on the Affymetrix samples, we performed microarray and NGS analyses on the HG-U133 PM only peg microarrays. To eliminate low blood and biopsy samples from the same kidney transplant expressed signals we used a signal filter cut-off that was data patients. The discovery set of blood samples consisted of the dependent, and therefore expression signals

0188 Microarray Analyses—Biopsy Samples 0194 NGS Analyses—Biopsy Samples (0189 All samples were processed on the HG-U133 Plus (0195 All samples were processed on the ION PRO PM microarrays. All samples were normalized using RMA TONTM System. Only runs with >10 million reads were used in Partek Genomics Suite 6.6. To facilitate biomarker dis for analysis. There was an average of 16 million reads across covery by removing probe sets with low signal intensities all samples. Samples were aligned using the STAR aligner we used a signal filter cut-off that was data dependent, and (Dobin et al. Bioinformatics 2012). Differential expression therefore expression signals

TABLE 1.

Blood Expression Profiling of Kidney Transplants: 3-Way Classifier AR vs. SCAR vs. TX

Positive Negative AUC after Predictive Sensitivity Specificity Predictive Predictive Algorithm Predictors Comparison Thresholding Accuracy (%) (%) (%) Value (%) Value (%)

Nearest Centroid 2OO SCAR ws. TX 1.OOO 1OO 100 1OO 100 1OO Nearest Centroid 2OO SCAR ws. AR O.953 95 92 1OO 100 90 Nearest Centroid 2OO AR ws. TX O.932 93 96 90 92 95

TABLE 2 200 Probeset classifer for distinguishing AR, SCAR and TX based on a 3-way ANOVA stepup AR SCAR TX Gene p-value p-value Mean Mean Mean # Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 238108 PM a 17OE-10 8.27E-06 73.3 45.4 44.4 243524 PM a 3.98E-10 9.7OE-06 72.3 41.3 37.7 1558,831 PM X at 5.11E-09 8.3OE-OS 48.1 30.8 31.4 229858 PM a 7.49E-09 8.31E-OS 576.2 359.3 348.4 236685 PM a 8.53E-09 8.31E-OS 4O9.1 213.3 211.O 213546 PM a DKFZP5861420 hypothetical protein 3.S2E-08 2.6OE-04 619.2 453.7 446.0 DKFZP5861420 7 231958 PM a C3orf51 3 open 4.35E-08 2.6OE-04 22.8 20.1 16.4 reading frame 31 8 210275 PM sat ZFANDS , AN1-type 4.96E-08 2.6OE-04 1045.9 1513.6 1553.8 domain 5 9 244341 PM a S.75E-08 2.6OE-04 398.3 270.7 262.8 10 1558822 PM at 5.84E-08 2.6OE-04 108.6 62.9 56.8 11 242175 PM a 5.87E-08 2.6OE-04 69.1 37.2 40.O 12 222357 PM a ZBTB20 Zinc finger and BTB 6.97E-08 2.83E-04 237.4 127.4 109.8 domain containing 20 13 206288 PM a PGGT1B protein 9.42E-08 3.53E-04 20.8 34.7 34.2 geranylgeranyltransferase type I, beta subunit 14 222306 PM a 1.03E-07 3.59E-04 23.3 15.8 16.0 15 1569601 PM at 1.67E-07 4.8OE-04 49.5 34.1 29.7 16 235138 PM a 1.69E-07 4.8OE-04 1169.9 780.0 829.7 17 240452 PM a GSPT1 G1 to S phase transition 1.74E-07 4.8OE-04 97.7 544 48.6 1 18 243003 PM a 1.77E-07 4.8OE-04 92.5 52.5 51.3 19 218109 PM S at MFSD1 major facilitator 1.90E-07 4.87E-04 1464.O 1881.O 1886.4 Superfamily domain containing 1 2O 241681 PM a 2.OOE-07 4.87E-04 1565.7 845.7 794.6 21 243878 PM a 2.19E-07 S.O8E-04 76.1 39.7 39.5 22 233296 PM x at 2.33E-07 S.17E-04 347.7 251.5 244.7 23 243318 PM a DDB1 and CUL4 2.S2E-07 5.34E-04 326.2 229.5 230.2 associated factor 8 24 236354 PM a 3.23E-07 6.39E-04 47.1 31.2 27.8 25 243768 3.35E-07 6.39E-04 1142.O 730.6 768.5 26 238558 3.65E-07 6.39E-04 728.5 4.09.4 358.4 27 237825 at 3.66E-07 6.39E-04 34.2 20.9 19.9 28 244414 3.67E-07 6.39E-04 S48.7 275.2 284.0 29 21.5221 C 4.06E-07 6.83E-04 327.2 176.7 1719 30 23.5912 C 4.46E-07 7.25E-04 114.1 71.4 59.5 31 239348 C 4.87E-07 7.54E-04 20.1 14.5 13.4 32 240499 C S.06E-07 7.54E-04 271.4 18O1 150.2 33 208054 C S.11E-07 7.54E-04 114.9 57.6 6O.O 34 240263 C S.46E-07 7.81E-04 120.9 78.7 66.6 35 241303 C at 5.78E-07 7.81E-04 334.5 2SO.3 261.5 36 233692 S.92E-07 7.81E-04 22.4 15.5 1S.O 37 243561 5.93E-07 7.81E-04 341.1 215.1 2O7.3 38 232778 6.91E-07 8.86E-04 46.5 31.0 28.5 39 237632 7.09E-07 8.86E-04 108.8 61.0 57.6 40 233690 7.3OE-07 8.89E-04 351.1 222.7 178.1 41 220221 C VPS13D vacuolar protein sorting 7.5OE-07 8.89E-04 93.5 6O.O 59.9 13 homolog D (S. cerevisiae) US 2017/O 137885 A1 May 18, 2017 24

TABLE 2-continued 200 Probeset classifer for distinguishing AR, SCAR and TX based on a 3-way ANOVA

Ste. pup AR SCAR TX Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 42 242877 PM at 7.72 -07 8.89 -04 173.8 108.1 104.O 43 218155 PM X at TSR1 TSR1, 205 rRNA 7.86 -07 8.89 -04 217.2 165.6 1647 accumulation, homolog (S. cerevisiae) 44 2396.03 PM X at 8.24 8.89 120.9 75.5 81.1 45 242859 PM at 8.48 8.89 221.1 1354 138.3 46 240866 PM at 8.54 8.89 65.7 33.8 35.2 47 239661 PM at 8.72 8.89 1OO.S 48.3 45.2 48 224493 PM X at C18Orfals chromosome 18 open 8.77 E-E-E-E-E- 8.89 E-E-E-E-E- 101.8 78.O 89.7 reading frame 45 49 1569202 PM x at 8.98 8.89 23.3 18.5 16.6 50 1560474 PM at 9.12 8.89 25.2 17.8 18.5 51 232511 PM a 9.48 9.06 77.2 46.1 49.9 52 228119 PM a LRCH3 -rich repeats O1 9.51 E-E-E-E- 117.2 84.2 76.1 and calponin homology (CH) domain containing 3 53 228545 PM a ZNF148 Zinc finger protein 148 17 9.99 789.9 571.1 579.7 S4 232779 PM a 17 9.99 36.7 26.O 20.7 55 239005 PM a Hypothetical FLJ39739 18 9.99 339.1 2O3.7 177.7 56 244478 PM a leucine rich repeat 2O E-E-E-E- 9.99 E-E-E-E- 15.7 12.6 12.7 containing 37, member A3 57 244535 PM a 28 9.99 261.5 139.5 137.8 58 1562673 PM at 28 9.99 774 46.5 51.8 59 240601 PM a 29 9.99 212.6 107.7 97.7 60 239533 PM a GPR155 G protein-coupled 30 E-E-E-E- 9.99 E-E-E-E- 656.3 396.7 SOO.1 155 61 222358 PM X at 32 9.99 355.2 263.1 273.7 62 214707 PM X at ALMS1 Alstrom Syndrome 1 32 9.99 340.2 255.9 266.0 63 236435 PM a 32 9.99 144.0 92.6 91.1 64 232333 PM a .33 9.99 487.7 243.7 244.3 65 222366 PM a .33 9.99 289.1 1861 1928 66 215611 PM a TCF12 12 38 O2 45.5 32.4 30.8 67 15580O2 STRAP Serine/threonine kinase .40 O2 - g 199.6 146.7 139.7 receptor associated protein 68 239716 PM a 43 77.6 49.5 45.5 69 239091 PM a 45 76.9 44.0 4S.O 70 238883 PM a 68 857.1 475.5 495.1 71 235615 PM a protein 72 E-E-E-E- E-E-E-E- 127.0 23S.O 245.6 geranylgeranyltransferase type I, beta subunit 72 204055 PM S at CTAGES CTAGE family, member 77 E O 6 O 3 178.8 115.2 105.9 5 73 239757 PM a ZFAND6 Zinc finger, AN1-type O 3 769.6 483.3 481.9 domain 6 74 15584.09 PM at 82 14.8 10.9 11.8 75 242688 PM a .85 61O.S 338.4 363.4 76 242377 PM X at THUMPD3 THUMP domain .87 E-E-E- o E-E-E- o 95.5 79.0 813 containing 3 77 242650 PM a 88 86.O 55.5 47.4 78 243589 PM a KIAA1267 KIAA1267 89 EE g 5 377.8 220.3 210.4 LOC10O294,337 hypothetical LOC10O294,337 79 227384 PM S at 90 3257.0 2255.5 2139.7 8O 237864 PM a .91 121.0 69.2 734 81 243490 PM a 92 24.6 17.5 16.5 82 244383 PM a .96 1417 93.0 77.5 83 215908 PM a 2.06 98.5 67.9 67.5 84 230651 PM a 2.09 125.9 74.3 71.5 85 1561195 PM at 2.14 86.6 45.1 43.9 86 239268 PM a NDUFS1 NADH dehydrogenase 2.14 14.0 12.O 11.3 (ubiquinone) Fe—S protein 1, 75 kDa (NADH-coenzyme Q reductase) 87 236431 PM at SR140 U2-associated SR140 1.19E-03 69.4 47.9 43.9 protein 88 236978 PM at 2.19E-06 1.19E-03 142.4 88.6 88.1 89 1562957 PM at 2.21E-O6 1.19E-03 268.3 1818 1654 US 2017/O 137885 A1 May 18, 2017 25

TABLE 2-continued 200 Probeset classifer for distinguishing AR, SCAR and TX based on a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean # Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 90 238913 PM at 2.21E-O6 19E-03 30.9 2O2 20.1 91 239646 PM at 2.23E-O6 19E-03 100.3 63.1 60.8 92 235701 PM at 2.34E-O6 24E-03 133.2 66.1 6O.O 93 2356O1 PM at 2.37E-06 24E-03 121.9 75.5 79.0 94 230918 PM at 2.42E-O6 25E-03 170.4 114.5 94.4 95 219112 PM at FNIP1 folliculin interacting 2.49E-06 28E-03 568.2 400.2 393.4 RAPGEF6 protein 1 ff Rap guanine nucteotide exchange factor (GEF) 6 96 202228 PM S at NPTN neuroplastin 2.52E-O6 28E-O3 1017.7 1331.S 1366.4 97 242839 PM a 2.78E-06 39E-03 17.9 14.O 13.6 98 244778 PM X at 2.85E-06 42E-03 105.1 66.O 65.9 99 23.7388 PM a 2.91E-O6 42E-03 59.3 38.0 33.0 OO 202770 PM S at CCNG2 cyclin G2 2.92E-O6 42E-03 1422, 269.O 2700 O1 240008 PM a 2.96E-O6 42E-03 96.2 65.6 56.2 O2 1557718 PM at PPP2RSC protein pnosphatase 2, 2.97E-06 42E-03 615.2 399.8 399.7 regulatory Subunit B", gamma O3 215528 PM a 3.01E-O6 42E-03 126.8 62.6 69.0 04 204689 PM a HHEX hematopoietically 3O8E-O6 44E-03 381.O 499.9 S67.9 expressed 05 213718 PM a RBM4 RNA binding motif 3.21E-O6 46E-03 199.3 1406 132.2 protein 4 O6 243233 PM a 3.22E-O6 46E-03 S82.3 343.0 337.1 07 239597 PM a 3.23E-O6 46E-03 1142.9 7O6.6 720.8 08 232890 PM a 3.24E-O6 46E-03 218.0 148.7 139.9 09 232883 PM a 3.42E-O6 S3E-03 127.5 79.0 73.1 O 241391 PM a 3.67E-06 .62E-03 103.8 51.9 48.3 1 244197 PM X at 3.71E-06 62E-03 SS8.O 397.3 418.8 2 205434 PM S at AAK1 AP2 associated kinase 1 3.75E-06 62E-03 495.2 339.9 301.2 3 235725 PM a SMAD4 SMAD family member 4 3.75E-06 62E-03 147.1 102.1 112.O 4 203137 PM a WTAP Wilms tumor 1 3.89E-06 66E-03 424.1 6094 SSS.8 associated protein 5 231075 PM X at RAPH1 Ras association 3.91E-O6 66E-03 30.4 19.3 18.2 (RalGDS/AF-6) and pleckstrin homology domains 1 6 236043 PM a LOC10O1301.75 hypothetical protein 3.98E-O6 67E-03 220.6 146.2 146.5 LOC10O1301.75 7 238299 PM a 4.09E-06 .7OE-03 217.1 13O4 1303 8 243667 PM a 4.12E-06 .7OE-03 314.5 225.3 232.8 9 223937 PM a FOXP1 forkhead box P1 4.2OE-06 .72E-03 147.7 85.5 90.9 20 238666 PM a 4.25E-06 .72E-03 219.1 1483 14.S.S 21 1554771 PM at 4.28E-06 .72E-03 67.2 41.5 40.8 22 202379 PM S at NKTR natural killer-tumor 4.34E-06 73E-O3 1498.2 1170.6 1042.6 recognition sequence 23 244695 PM a GHRLOS ghrelin opposite strand 4.56E-06 .79E-03 78.0 53.0 52.5 (non-protein coding) 24 239393 PM a 4.58E-06 .79E-03 852.O SS4.2 591.7 25 242920 PM a 4.6OE-06 .79E-03 392.8 220.9 251.8 26 242405 PM a 4.66E-06 8OE-03 415.8 193.8. 2074 27 1556432 PM at 4.69E-06 8OE-03 61.5 43.1 38.1 28 1570299 PM at 4.77E-06 81E-03 27.0 18.0 19.8 29 2251.98 PM a WAPA VAMP (vesicle- 4.85E-06 83E-03 192.O 258.3 273.9 associated membrane protein)-associated protein A, 33 kDa 30 230702 PM a 4.94E-06 85E-03 28.2 18.4 17.5 31 240262 PM a S.O7E-06 88E-03 46.9 22.8 28.0 32 2.32216 PM a YME1L1 YME1-like 1 5.14E-O6 89E-03 2O8.6 146.6 1301 (S. cerevisiae) 33 2251.71 PM a ARHGAP18 Rho GTPase activating 5.16E-O6 89E-03 65.9 109.1 121.5 protein 18 34 243992 PM a 5.28E-O6 92E-03 187.1 116.O 125.6 35 227082 PM a 5.45E-06 96E-03 2O3.8 1404 123.O 36 239948 PM a NUP153 153 kDa S.SOE-06 96E-03 39.6 26.5 27.8 37 221905 PM a CYLD cylindromatosis (turban S.S1E-06 96E-03 433.O 316.8 315.1 tumor syndrome) US 2017/O 137885 A1 May 18, 2017 26

TABLE 2-continued 200 Probeset classifer for distinguishing AR, SCAR and TX based on a 3-way ANOVA stepup AR SCAR TX Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 38 242578 PM X at Solute carrier family 22 148.4 109.2 120.1 (extraneuronal monoamine transporter), member 3 39 1569238 PM a at 5.73 1.99 71.O 36.1 40 201453 PM X at RHEB Ras homolog enriched 5.76 1.99 453.3 599.0 in brain 41 236802 PM at 1.99E 47.9 29.1 29.6 42 232615 PM at 199E-03 4O68.5 3073.4 2907.4 43 237179 PM at PCMTD2 protein-L-isoaspartate 1.99E 48.7 30.2 26.8 (D-aspartate) O methyltransferase domain containing 2 44 203255 PM at FBXO11 F-box protein 11 S.98 2.02 748.3 529.4 539.6 45 212989 PM at SGMS1 sphingomyelin synthase 6.04 2.03 57.2 93.1 107.9 1 46 236754 PM at PPP1R2 protein phosphatase 1, 6.17E-06 2.OSE-O3 505.3 380.7 370.1 regulatory (inhibitor) subunit 2 47 1559496 PM at PPA2 pyrophosphatase 6.24E O 6 2.0SE O 3 68.8 39.7 39.3 (inorganic) 2 48 236494 PM X at 6.26 2.05 135.0 91.1 82.9 49 237554 PM at 6.30 2.05 53.4 31.5 30.1 50 243469 PM at 6.37 2.05 635.2 3O8.1 341.5 51 24O155 PM X at ZNF493 Zinc finger protein 493 6.45 E-E-E-E- 2.05 E-E-E-E- 483.9 299.9 316.6 ZNF738 if Zinc finger protein 738 52 222442 PM S at ADP-ribosylation factor 6.47E O 6 2.0SE O 3 201S 292.6 268.3 ike 8B 53 240307 PM at 6.48 2.05 SS.4 36.8 33.1 S4 200864 PM S at RAB11A RAB11A, member RAS 6.50 g 2.05 g 142.1 210.9 233.0 oncogene family 55 235757 PM at 6.53 2.05 261.4 1852 158.9 56 222351 PM at protein phosphatase 2, 6.58 2.06 g s 75.8 S1.1 45.4 regulatory Subunit A, beta 57 222788 PM S at RSBN1 round spermatid basic 6.63E O 6 2.06E O 3 389.9 302.7 288.2 protein 1 58 239815 PM at 6.70 2.06 216.9 171.4 159.5 59 219392 PM X at PRR11 proline rich 11 6.77 2.07 1065.3 827.5 913.2 60 240458 PM at 6.8O 2.07 414.3 244.6 242.0 61 235879 PM at MBNL1 Muscleblind-like 6.88 E-E-E-E- 2.08 E-E-E-E- 1709.2 116S.S 1098.0 (Drosophila) 62 230529 PM at HECA headcase homolog O 6 2.13E O 3 585.1 364.3 418.4 (Drosophila) 63 1562O63 PM x at KIAA1245 KIAA1245 7.35E O 6 2.2OE O 3 350.4 238.8 260.8 NBPF1 neuroblastoma NBPF10 breakpoint family, NBPF11 member 1 NBPF12 neuroblastoma NBPF24 if breakpoint fam NBPF8 NBPF9 164 202769 PM at CCNG2 cyclin G2 2.2OE-03 697.1 1164.O 1264.6 16S 1556493 PM a at KDM4C ysine (K)-specific 2.24E-O3 81.4 49.0 445 demethylase 4C 166 21 6509 PM X at MLLT10 myeloid/lymphoid or 22.4 17.9 19.3 mixed-lineage leukemia (trithorax homolog, Drosophila); translocate 167 223697 PM X at chromosome 9 open 7.7OE-06 2.25E-03 1013.6 771.2 836.8 reading frame 64 168 235999 PM at 7.77E-06 2.25E-03 227.6 1741 1821 169 244766 PM at LOC100271836 if SMG 1 homolog, 8.03E-06 2.31E-O3 1334 99.4 87.5 LOC44O3S4 phosphatidylinositol 3 LOCS951O1 if kinase-related kinase LOC641298 iff PI-3- SMG1 kinase-r 170 230332 PM at ZCCHC7 Zinc finger, CCHC 8.07E-06 467.4 265.1 263.2 domain containing 7 US 2017/O 137885 A1 May 18, 2017 27

TABLE 2-continued 200 Probeset classifer for distinguishing AR, SCAR and TX based on a 3-way ANOVA stepup AR - SCAR TX Gene p-value p-value Mean Mean Mean # Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 71 2353O8 PM at ZBTB20 Zinc finger and BTB 8.17 2.32E-O3 256.7 1842 167.3 domain containing 20 72 242492 PM at CLNS1A Chloride channel, 8.19E 2.32E-O3 128.5 82.8 79.2 nucleotide-sensitive, 1A 73 215898 PM at TTLL5 tubulin tyrosine 8.24E 2.32E-O3 20.9 14.O 13.8 like family, member 5 74 244840 PM X at DOCK4 dedicator of cytokinesis 4 8.6S 2.42E-O3 43.1 16.5 21.5 7S 220235 PM S at C1orf103 open 8.72 2.43E-O3 88.4 13 O.S 143.3 reading frame 103 76 229467 PM at PCBP2 Poly(rC) binding protein 2.44E-O3 186.5 125.4 135.8 2 77 232527 PM at 8.99 2.48E-O3 667.4 453.9 461.3 78 243286 PM at 9.24 2.53E-03 142.6 98.2 87.2 79 215628 PM X at 9.28 2.53E-03 49.6 36.3 39.4 80 1556412 PM at 9.45 2.56E-03 34.9 24.7 23.8 81 204786 PM S at IFNAR2 Interferon (alpha, beta 9.64 E-E-E-E-E- 2.59E-03 795.6 573.O 639.2 and omega) receptor 2 82 234258 PM at 9.73 2.6OE-03 27.4 17.8 20.3 83 233274 PM at 9.76 2.6OE-03 109.9 77.5 79.4 84 239784 PM at 9.82 2.6OE-03 137.0 80.1 70.1 85 242498 PM X at O1 26SE-03 59.2 40.4 38.9 86 231351 PM at O2 2.67E-03 124.8 70.8 60.6 87 222368 PM at O3 2.67E-03 89.9 54.5 44.3 88 236524 PM at O3 2.67E-03 313.2 234.7 214.2 89 243834 PM at TNRC6A trinucleotide repeat .04 2.67E-03 2118 145.1 146.9 containing 6A 90 2391.67 PM at .04 2.67E-03 287.4 150.2 1603 91 239238 PM at OS 2.67E-03 136.0 81.6 92.0 92 23.7194 PM at OS 2.67E-03 57.2 34.4 27.9 93 242772 PM X at O6 2.67E-03 299.2 185.2 1894 94 243827 PM at O6 2.67E-03 115.9 SO.1 56.4 95 1552.536 PM at VTI1A vesicle transport 1O 2.75E-03 61.7 35.1 34.6 through interaction with t-SNAREs homolog 1A (yeast) 96 243696 PM at KIAAO562 KIAAO562 .12 2.77E-03 19.0 14.8 1S.O 97 233648 PM at .12 2.77E-03 33.9 21.O 24.1 98 225858 PM S at XIAP X-linked Inhibitor of 16 O 5 2.85E-03 1020.7 760.3 772.6 apoptosis 99 238736 PM at REV3L REV3-like, catalytic 19E 2.91E-O3 214.2 135.8 151.6 subunit of DNA polymerase Zeta (yeast) 221192 PM X at MFSD11 major facilitator 2.92E-O3 100.4 74.5 81.2 Superfamily domain containing 11

TABLE 3 33 probesets that differentiate SCAR and TX at p-value is 0.001 in PAXGene blood tubes Fold Change Gene p-value (SCAR SCAR - TX Probeset ID Symbol Gene Title (Phenotype) vs. TX) ID Mean Mean 1553094 PM at TAC4 tachykinin 4 0.000375O27 -1.1 1553094 PM at 8.7 9.6 (hemokinin) 1553352 PM x at ERVWE1 endogenous 0.000494742 -1.26 1553352 PM X at 15.5 19.6 retroviral family W. env(C7), member 1 1553644 PM at C14orfA9 chromosome 14 O.OOO868817 -1.16 1553644 PM at 10.1 11.7 open reading frame 49 15561.78 PM X at TAF8 TAF8 RNA O.OOO431074 1.24 1556.178 PM X at 39.2 31.7 polymerase II, TATA box binding protein (TBP)-associated factor, 43 kDa US 2017/O 137885 A1 May 18, 2017 28

TABLE 3-continued 33 probesets that differentiate SCAR and TX at p-value is 0.001 in PAXGene blood tubes Fold Change Gene p-value (SCAR SCAR - TX Probeset ID Symbol Gene Title (Phenotype) vs. TX) ID Mean Mean

1559687 PM at TMEM221 transmembrane 8.09E-OS -1.16 1559687 PM at 3.0 S.1 protein 221 1562492 PM at LOC340090 hypothetical O.OOO81096 -1. 1562492 PM at 8.8 9.7 LOC340090 1563204 PM at ZNF627 Zinc finger protein 0.000784254 -1.15 1563204 PM at O6 2.2 627 1570.124 PM at 0.000824814 -1.14 15701.24 PM at O6 2.2 204681 PM S at RAPGEFS Rap guanine 0.000717727 -1.18 204681 PM S at 9.6 1.3 nucleotide exchange actor (GEF) 5 206154 PM at RLBP1 retinaldehyde 0.000211941 -1.13 206154 PM at 1.O 2.4 binding protein 1 209053 PM S at WHSC1 Wolf Hirschhorn O.OOO77241.2 23 209053 PM S at S.1 2.3 syndrome candidate 1 209228 PM X at TUSC3 Lumor suppressor 0.000954529 -1.13 209228 PM X at 8.9 O.1 candidate 3 211701 PM S at TRO trophinin 0.000684486 -1.13 211701 PM S at O.O 1.3 213369 PM at CDHR1 cadherin-related 0.000556648 -1.14 213369 PM at O.8 2.3 amily member 1 215110 PM at MBL1P mannose-binding 0.000989176 -1.13 215110 PM at 9.2 0.4 ectin (protein A) 1, pseudogene 215232 PM at ARHGAP44 Rho GTPase 0.000332776 -1.18 215232 PM at 11.1 3.1 activating protein 44 217158 PM at LOC442421 hypothetical 2.98E-OS 18 217158 PM at 14.2 2.0 LOC442421 prostaglandin E2 receptor EP4 Subtype-like 218365 PM S at DARS2 aspartyl-tRNA O.OOO716O3S 1.18 218365 PM S at 17.2 14.5 synthetase 2, mitochondrial 219695 PM at SMPD3 sphingomyelin 0.000377,151 -1.47 219695 PM at 12.0 17.6 phosphodiesterase 3, neutral membrane (neutral sphingomyelinase II) 220603 PM S at MCTP2 multiple C2 domains, 0.000933412 -1.38 220603 PM S at 338..S 465.8 transmembrane 2 224963 PM a SLC26A2 Solute carrier family O.OOO961242 47 224963 PM a 94.3 64.O 26 (sulfate transporter), member 2 226729 PM a USP37 specific O.OOO891O38 24 226729 PM a 32.9 26.6 peptidase 37 228226 PM S at ZNF775 Zinc finger protein O.OOOS89512 .2 228226 PM S at 2O.S 17.1 775 230608 PM a C1orf182 chromosome 1 open 0.00015.3478 -1.18 230608 PM a 15.9 18.8 reading frame 182 230756 PM a ZNF683 Zinc finger protein O.OOO447S1 .52 230756 PM a 26.7 17.6 683 231757 PM a TAS2RS taste receptor, type O.OOO869775 -1.12 231757 PM a 9.3 10.4 2, member 5 231958 PM a C3orf51 open 4.09E-05 .22 231958 PM a 20.1 16.4 reading frame 31 237290 PM a 0.000948318 -1.22 237290 PM a 10.3 12.5 237806 PM S at LOC729296 hypothetical 0.00092234 -1.18 237806 PM S at 10.2 12.0 LOCA29296 238459 PM X at SPATA6 spermatogenesis 0.000116525 -1.15 238459 PM X at 9.2 1O.S associated 6 24.1331 PM at SKAP2 Src kinase associated 0.000821476 -1.39 24.1331 PM at 16.4 22.9 phosphoprotein 2 241368 PM at PLINS perilipin 5 0.000406066 -1.61 241368 PM at 84.S 136.3 24.1543 PM at 0.000478221 -1.17 24.1543 PM at 9.4 11.O US 2017/O 137885 A1 May 18, 2017 29

TABLE 4 List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA

Ste pup AR SCAR TX Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phen otype) Signal Signal Signal 238108 PM a 1.7OE-10 8.27 73.3 45.4 44.4 243524 PM a 3.98E-10 9.70 72.3 41.3 37.7 1558,831 PM X at 5.11E-09 8.30 48.1 30.8 31.4 229858 PM a 7.49E-09 8.31 576.2 359.3 348.4 236685 PM a 8.53E-09 8.31 409.1 213.3 211.O 213546 PM a hypothetical protein 3.S2E-08 2.60 O4 619.2 453.7 446.0 DKFZp586|1420 231958 PM a Chromosome 3 open 4.35E-08 O4 22.8 20.1 16.4 reading frame 31 210275 PM S at ZFANDS Zinc finger, AN1-type 4.96E-08 2.60 E-04 1045.9 1513.6 1553.8 domain 5 244341 PM a S.7SE-08 2.60 -04 398.3 270.7 262.8 10 1558822 PM at 5.84E-08 2.60 -04 1086 62.9 56.8 11 242175 PM a 5.87E-08 2.60 O4 69.1 37.2 40.0 12 222357 PM a ZBTB20 Zinc finger and BTB 6.97E-08 2.83 -04 237.4 127.4 109.8 domain containing 20 13 206288 PM a protein 9.42E-08 3.53 -04 20.8 34.7 34.2 geranylgeranyltransferase type I, beta subunit 14 222306 PM a 1.03E-07 3.59 -04 23.3 15.8 16.O 15 1569601 PM at 1.67E-07 4.8O -04 49.5 34.1 29.7 16 235138 PM a 1.69E-07 4.8O -04 1169.9 780.0 829.7 17 240452 PM a GSPT1 G1 to S phase transition 1 1.74E-07 4.8O -04 97.7 544 48.6 18 243003 PM a 1.77E-07 4.8O -04 92.8 52.5 51.3 19 218109 PM S at MFSD1 major facilitator 1.90E-07 4.87 -04 1464.O 1881.0 1886.4 Superfamily domain containing 1 2O 241681 PM a 2.OOE-07 4.87 -04 1565.7 845.7 794.6 21 243878 PM a 2.19E-07 5.08 -04 76.1 39.7 39.5 22 233296 PM X at 2.33E-07 5.17 -04 347.7 251.5 244.7 23 243318 PM a DDB1 and CUL4 associated 2.S2E-07 S.34 -04 326.2 229.5 230.2 factor 8 24 236354 PM a 3.23E-07 6.39 -04 47.1 31.2 27.8 25 243768 PM a 3.35E-07 6.39 -04 1142.O 730.6 768.5 26 238558 PM a 3.6SE-07 6.39 -04 728.5 4.09.4 358.4 27 237825 PM X at 3.66E-07 6.39 -04 34.2 20.9 19.9 28 244414 PM a 3.67E-07 6.39 -04 S48.7 275.2 284.0 29 21.5221 PM a 4.06E-07 6.83 -04 327.2 176.7 1719 30 235912 PM a 4.46E-07 7.25 -04 114.1 71.4 59.5 31 239348 PM a 4.87E-07 7.54 -04 20.1 14.5 13.4 32 240499 PM a S.O6E-07 7.54 -04 271.4 180.1 150.2 33 208054 PM a S.11E-07 7.54 -04 114.9 57.6 6O.O 34 240263 PM a S.46E-07 7.81 -04 120.9 78.7 66.6 35 241303 PM X at 5.78E-07 7.81 -04 334.5 250.3 261.5 36 233692 PM a S.92E-07 7.81 -04 22.4 15.5 1S.O 37 243561 PM a S.93E-07 7.81 -04 341.1 215.1 2O7.3 38 232778 PM a 6.91E-07 8.86 -04 46.5 31.0 28S 39 237632 PM a 7.09E-07 8.86 -04 108.8 61.O 57.6 40 233690 PM a 7.3OE-07 8.89 -04 351.1 222.7 178.1 41 220221 PM a VPS13D vacuolar protein sorting 7.5OE-07 8.89 -04 93.5 6O.O 59.9 13 homolog D (S. cerevisiae) 42 242877 PM a 7.72E-07 8.89 -04 173.8 108.1 104.O 43 218155 PM X at TSR1 TSR1, 20S rRNA 7.86E-07 8.89 -04 217.2 165.6 1647 accumulation, homolog (S. cerevisiae) 2396.03 PM X at 8.24E-07 8.89 120.9 75.5 81.1 45 242859 PM at 8.48E-07 8.89 221.1 135.4 138.3 46 240866 PM at 8.54E-07 8.89 65.7 33.8 35.2 47 239661 PM at 8.72E-07 8.89 10O.S 48.3 45.2 48 224493 PM X at chromosome 18 open 8.77E-07 8.89 E-E-E-E-E- 101.8 78.0 89.7 reading frame 45 49 1569202 PM X at 8.98E-07 8.89 23.3 18.5 16.6 50 1560474 PM at 9.12E-07 8.89 25.2 17.8 18.5 51 232511 PM at 9.48E-O7 9.06 77.2 46.1 49.9 52 228119 PM at LRCH3 leucine-rich repeats and 1.01E-O6 9.51 E-E-E-E- 117.2 84.2 76.1 calponin homology (CH) domain containing 3 53 228545 PM at ZNF148 Zinc finger protein 148 1.17E-O6 9.99 O4 789.9 571.1 579.7 S4 232779 PM at 1.17E-O6 9.99 36.7 26.0 20.7 55 239005 PM at FLJ39739 Hypothetical FLJ39739 1.18E-O6 9.99 E-E-E 339.1 2O3.7 177.7 US 2017/O 137885 A1 May 18, 2017 30

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 56 244478 PM a LRRC37A3 leucine rich repeat 2OE-06 9.99E-04 15.7 12.6 12.7 containing 37, member A3 57 244535 PM a 28E-06 9.99E-04 261.5 139.5 137.8 58 1562673 PM at 28E-06 9.99E-04 77.4 46.5 51.8 59 240601 PM a 29E-06 9.99E-04 212.6 107.7 97.7 60 239533 PM a GPR155 G protein-coupled 3OE-06 9.99E-04 656.3 396.7 SOO.1 receptor 155 61 222358 PM X at 32E-06 9.99E-04 355.2 263.1 273.7 62 214707 PM X at ALMS1 Alstrom Syndrome 1 32E-06 9.99E-04 340.2 2S5.9 266.0 63 236435 PM a 32E-06 9.99E-04 144.0 92.6 91.1 64 232333 PM a .33E-06 9.99E-04 487.7 243.7 244.3 65 222366 PM a .33E-06 9.99E-04 289.1 186.1 1928 66 215611 PM a TCF12 transcription factor 12 38E-06 O2E-03 45.5 32.4 30.8 67 1558.002 PM at STRAP Serine/threonine kinase 4OE-06 O2E-03 1996 146.7 139.7 receptor associated protein 68 239716 PM a 43E-06 O2E-03 77.6 49.5 45.5 69 239091 PM a 45E-06 O2E-03 76.9 44.0 45.0 70 238883 PM a 68E-06 15E-03 857.1 47S.S 495.1 71 235615 PM a PGGT1B protein 72E-06 15E-03 127.O 23S.O 245.6 geranylgeranyltransferase type 1, beta subunit 72 204055 PM S at CTAGES CTAGE family, member 5 .77E-06 15E-03 178.8 115.2 105.9 73 239757 PM a ZFAND6 Zinc finger, AN1-type 81E-06 15E-03 769.6 483.3 481.9 domain 6 74 15584O9 PM at 82E-06 15E-03 14.8 10.9 11.8 75 242688 PM a 85E-06 15E-03 61O.S. 338.4 363.4 76 242377 PM X at THUMPD3 THUMP domain 87E-06 15E-03 95.5 79.0 813 containing 3 77 242650 PM a 88E-06 15E-03 86.O 55.5 47.4 78 243589 PM a KIAA1267 KIAA1267 i? hypothetical 89E-06 15E-03 377.8 220.3 210.4 LOC10O294,337 LOC10O294337 79 227384 PM S at 90E-06 1SE-O3 3257.O 225S.S 2139.7 80 237854 PM a 91E-06 15E-03 121.0 69.2 734 81 243490 PM a 92E-06 15E-03 24.6 17.5 16.5 82 244383 PM a 96E-06 17E-03 1417 93.0 77.5 83 215908 PM a 2.06E-O6 19E-03 98.5 67.9 67.5 84 230651 PM a 2.09E-06 19E-03 125.9 74.3 71.5 85 1561195 PM at 2.14E-O6 19E-03 86.6 45.1 43.9 86 239268 PM a NDUFS1 NADH dehydrogenase 2.14E-O6 19E-03 14.0 12.0 11.3 (ubiquinone) Fe—S protein 1, 75 kDa (NADH coenzyme Q reductase) 87 236431 PM a SR140 U2-associated SR140 2.16E-O6 9E-03 694 47.9 43.9 protein 88 236978 PM a 2.19E-06 19E-03 142.4 88.6 88.1 89 1562957 PM at 2.21E-O6 19E-03 268.3 1818 1654 90 238913 PM a 2.21E-O6 19E-03 30.9 2O2 20.1 91 239646 PM a 2.23E-O6 19E-03 100.3 63.1 60.8 92 235701 PM a 2.34E-O6 24E-03 133.2 66.1 6O.O 93 2356O1 PM a 2.37E-06 24E-03 121.9 75.5 79.0 94 230918 PM a 2.42E-O6 25E-03 1704 114.5 94.4 95 219112 PM a FNIP1 folliculin interacting 2.49E-06 28E-03 568.2 400.2 393.4 RAPGEF6 protein 1 Rap guanine nucleotide exchange factor (GEF) 6 96 202228 PM s at NPTN neuroplastin 2.52E-O6 28E-03 1017.7 1331.S 1366.4 97 242839 PM at 2.78E-06 39E-03 17.9 14.0 13.6 98 244778 PM X at 2.85E-06 42E-03 2O5.1 68.0 65.9 99 23.7388 PM at 2.91E-O6 42E-03 59.3 38.0 33.O 100 202770 PM S at CCNG2 cyclin G2 2.92E-O6 42E-03 1422, 269.O 2700 101 240008 PM at 2.96E-O6 42E-03 96.2 65.6 56.2 102 1557718 PM at PPP2RSC protein phosphatase 2, 2.97E-06 42E-03 615.2 399.8 399.7 regulatory Subunit B", gamma 103 215528 PM at 3.01E-O6 42E-03 126.8 62.6 69.0 104 204689 PM at HHEX hematopoietically 3.08E-OS 44E-03 381.O 499.9 567.9 expressed homeobox 105 213718 PM at RBM4 RNA binding motif protein 3.21E-O6 46E-03 1993 140.6 132.2 4 106 243233 PM at 3.22E-O6 46E-03 S82.3 343.0 337.1 US 2017/O 137885 A1 May 18, 2017 31

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 07 239597 PM at 3.23E-O6 46E-03 1142.9 7O6.6 720.8 08 232890 PM at 3.24E-O6 46E-03 218.0 148.7 139.9 09 232883 PM at 3.42E-O6 S3E-03 127.5 79.0 73.1 10 241391 PM at 3.67E-06 62E-03 103.8 S1.9 48.3 11 244197 PM X at 3.71E-06 62E-03 SS8.O 397.3 418.8 12 205434 PM S at AAK1 AP2 associated kinase 1 3.75E-06 62E-03 495.2 339.9 301.2 13 235725 PM at SMAD4 SMAD family member 4 3.75E-06 62E-03 147.1 102.1 112.O 14 203137 PM at WTAP Wilms tumor 1 associated 3.89E-06 66E-03 424.1 6094 SSS.8 protein 15 231075 PM X at RAPH1 Ras association 3.91E-O6 66E-03 3O4 193 18.2 (RalGDS/AF-6) and pleckstrin homology domains 1 16 236043 PM a LOC10O1301.75 hypothetical protein 3.98E-O6 67E-03 220.6 146.2 146.5 LOC10O1301.75 17 238299 PM a 4.09E-06 .7OE-03 217.1 130.4 1303 18 243667 PM a 4.12E-06 .7OE-03 3.14.S 225.3 232.8 19 223937 PM a FOXP1 forkhead box P1 4.2OE-06 .72E-03 147.7 85.5 90.9 20 238666 PM a 4.25E-06 .72E-03 219.1 1483 145.5 21 1554771 PM at 4.28E-06 .72E-03 67.2 41.5 40.8 22 202379 PM S at NKTR natural killer-tumor 4.34E-06 .73E-03 1498.2 1170.6 1042.6 recognition sequence 23 244695 PM a GHRLOS ghrelin opposite strand 4.56E-06 .79E-03 78.0 53.0 52.5 (non-protein coding) 24 239393 PM a 4.58E-06 .79E-03 852.O SS4.2 591.7 25 242920 PM a 4.6OE-06 .79E-03 392.8 220.9 251.8 26 242405 PM a 4.66E-06 8OE-03 415.8 193.8. 207.4 27 1556432 PM at 4.69E-06 8OE-03 61.5 43.1 38.1 28 1570299 PM at 4.77E-06 81E-03 27.0 18.0 19.8 29 2251.98 PM a WAPA VAMP (vesicle-associated 4.85E-06 83E-03 192.O 258.3 273.9 membrane protein)- associated protein A, 33 kDa 3O 230702 PM a 4.94E-06 85E-03 28.2 18.4 17.5 31 240262 PM a S.O7E-06 88E-03 46.9 22.8 28.0 32 2.32216 PM a YME1L1 YME1-like 1 (S. cerevisiae) 5.14E-O6 89E-03 2O8.6 146.6 1301 33 2251.71 PM a ARHGAP18. Rho GTPase activating 5.16E-O6 89E-03 65.9 109.1 121.5 protein 18 34 243992 PM a 5.28E-O6 92E-03 1871 115.O 125.6 35 227082 PM a S4SE-06 96E-03 2O3.8 140.4 123.0 36 239948 PM a NUP153 nucleoporin 153 kDa S.SOE-06 96E-03 39.6 26.5 27.8 37 221905 PM a CYLD cylindromatosis (turban S.S1E-06 96E-03 433.O 316.8 315.1 tumor syndrome) 38 242578 PM X at SLC22A3 Solute carrier family 22 S.S6E-06 96E-03 1484 109.2 120.1 (extraneuronal monoamine transporter), member 3 39 1569238 PM a at - S.73E-06 99E-03 71.O 33.0 36.1 40 201453 PM X at RHEB Ras homolog enriched in S.76E-06 99E-03 453.3 6OO.O 599.0 brain 41 236802 PM at S.76E-06 99E-03 47.9 29.1 29.6 42 232615 PM at 5.82E-O6 .99E-03 4O68.S. 3073.4 2907.4 43 237179 PM at PCMTD2 protein-L-isoaspartate (D- 5.84E-O6 99E-03 48.7 30.2 26.8 aspartate) O methyltransferase domain containing 2 44 203255 PM at FBXO11 F-box protein 11 S.98E-06 2.02E-O3 748.3 529.4 S39.6 45 212989 PM at SGMS1 sphingomyelin synthase 1 6.04E-06 2.03E-O3 57.2 93.1 107.9 46 236754 PM at PPP1R2 protein phosphatase 1, 6.17E-06 2.OSE-03 505.3 380.7 370.1 regulatory (inhibitor) subunit 2 47 1559456 PM at PPA2 pyrophosphatase 6.24E-06 2.OSE-03 68.8 39.7 39.3 (inorganic) 2 48 236494 PM X at 6.26E-06 2.OSE-03 135.0 91.1 82.9 49 23.7554 PM at 6.3OE-06 2.OSE-03 53.4 31.5 30.1 50 243469 PM at 6.37E-06 2.OSE-03 635.2 308.1 341.5 51 24O155 PM X at ZNF493 Zinc finger protein 493 fif 6.45E-06 2.OSE-03 483.9 299.9 316.6 ZNF738 Zinc finger protein 738 52 222442 PM S at ARL8B ADP-ribosylation factor- 6.47E-06 2.OSE-03 201S 292.6 268.3 like 8B 53 240307 PM at 6.48E-06 2.OSE-03 SS.4 36.8 33.1 US 2017/O 137885 A1 May 18, 2017 32

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 154 200864 PM S at RAB11A RAB11A, member RAS 6.5OE-06 2.OSE-03 142.1 210.9 233.0 oncogene family 155 235757 PM at 6.53E-06 2.OSE-03 2614 1852 158.9 156 222351 PM at PPP2R1B protein phosphatase 2, 6.58E-06 2.06E-O3 75.8 S1.1 45.4 regulatory Subunit A, beta 157 222788 PM S at RSBN1 round spermatid basic 6.63E-06 2.06E-O3 389.9 302.7 288.2 protein 1 158 239815 PM at 6.7OE-06 2.06E-O3 216.9 171.4 159.5 159 219392 PM X at PRR11 proline rich 11 6.77E-06 2.07E-03 1065.3 827.5 913.2 160 240458 PM at 6.8OE-06 2.07E-03 414.3 244.6 242.O 161 235879 PM at MBNL1 Muscleblind-like 6.88E-06 2O8E-O3 1709.2 116SS 1098.0 (Drosophila) 162 230529 PM at HECA headcase homolog 7.O8E-06 2.13E-O3 585.1 3643 418.4 (Drosophila) 163 1562063 PM x at KIAA1245 KIAA1245 7.35E-06 2.2OE-03 350.4 238.8 260.8 NBPF1 neuroblastoma breakpoint NBPF10 amily, member 1 if NBPF11 neuroblastoma breakpoint NBPF12 8 NBPF24 NBPF8 NBPF9 164 202769 PM at CCNG2 cyclin G2 7.42E-O6 2.2OE-03 697.1 1164.O 1264.6 165 1556493 PM a at KDM4C lysine (K)-specific 7.64E-O6 2.24E-O3 81.4 49.0 44.5 demethylase 4C 166 21 6509 PM X at MLLT10 myeloid/lymphoid or 7.64E-O6 2.24E-O3 22.4 17.9 19.3 mixed-lineage leukemia (trithorax homolog, Drosophila); translocate 167 223697 PM X at C9orf64 chromosome 9 open 7.7OE-06 2.25E-03 1013.6 771.2 836.8 reading frame 64 168 235999 PM at 7.77E-06 2.25E-03 227.6 1741 1821 169 244766 PM at LOC100271836 SMG 1 homolog, 8.03E-06 2.31E-O3 1334 99.4 87.5 LOC44O3S4 phosphatildylinositol 3 LOCS951O1 if kinase-related kinase LOCS41298 pseudogene if PI-3- SMG1 kinase-r 7O 230332 PM at ZCCHC7 Zinc finger, CCHC domain 8.07E-06 2.31E-O3 4674 265.1 263.2 containing 7 71 2353O8 PM at ZBTB20 Zinc finger and BTB 8.17E-06 2.32E-O3 256.7 1842 167.3 domain containing 20 72 242492 PM at CLNS1A Chloride channel, 8.19E-06 2.32E-O3 128.5 82.8 79.2 nucleotide-sensitive, 1A 73 215898 PM at TTLL5 tubulin tyrosine ligase-like 8.24E-05 2.32E-O3 20.9 14.O 13.8 family, member 5 74 244840 PM x at DOCK4 dedicator of cytokinesis 4 8.65E-06 2.42E-O3 43.1 16.5 21.5 7S 220235 PM S at C1orf103 chromosome 1 open 8.72E-06 2.43E-O3 88.4 13 O.S 143.3 reading frame 103 76 229467 PM at PCBP2 Poly(rC) binding protein 2 8.8OE-06 2.44E-O3 186.5 125.4 135.8 77 232527 PM at 8.99E-06 2.48E-O3 667.4 453.9 461.3 78 243286 PM at 9.24E-O6 2.53E-03 142.6 98.2 87.2 79 215628 PM x at 9.28E-O6 2.53E-03 49.6 36.3 39.4 80 1556412 PM at 945E-06 2.56E-03 34.9 24.7 23.8 81 204786 PM S at IFNAR2 Interferon (alpha, beta 9.64E-O6 2.59E-03 795.6 573.0 639.2 and omega) receptor 2 82 234258 PM at 9.73E-06 2.6OE-03 27.4 17.8 20.3 83 233274 PM at 9.76E-06 2.6OE-03 109.9 77.5 79.4 84 239784 PM at 9.82E-OS 2.6OE-03 137.0 80.1 70.1 85 242498 PM X at 1.01E-OS 2.65E-03 59.2 40.4 38.9 86 231351 PM at 1.02E-OS 2.67E-03 124.8 70.8 60.6 87 222368 PM at 1.03E-OS 2.67E-03 89.9 54.5 44.3 88 236524 PM at 1.03E-OS 2.67E-03 313.2 234.7 214.2 89 243834 PM at TNRC6A trinucleotide repeat 1.04E-OS 2.67E-03 211.8 145.1 146.9 containing 6A 90 2391.67 PM at 1.04E-OS 2.67E-03 287.4 150.2 1603 91 239238 PM at 1.OSE-OS 2.67E-03 136.0 81.6 92.0 92 23.7194 PM at 1.OSE-OS 2.67E-03 57.2 34.4 27.9 93 242772 PM X at 1.06E-OS 2.67E-03 299.2 1852 1894 94 243827 PM at 1.06E-OS 2.67E-03 115.9 SO.1 56.4 US 2017/O 137885 A1 May 18, 2017 33

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 195 1552536 PM at VT1A vesicle transport through 1OE-05 2.75E-03 61.7 35.1 34.6 interaction with t-SNAREs homolog 1A (yeast) 196 243696 PM at KIAAO562 KIAAO562 12E-05 2.77E-03 19.0 14.8 1S.O 197 233648 PM at 12E-05 2.77E-03 33.9 21.0 24.1 198 225858 PM S at XLAP X-linked inhibitor of .16E-05 2.85E-03 1020.7 760.3 772.6 apoptosis 199 238736 PM at REV3L REV3-like, catalytic 19E-05 2.91E-O3 214.2 135.8 151.6 subunit of DNA polymerase Zeta (yeast) 200 221192 PM x at MFSD11 major facilitator 2OE-OS 2.92E-O3 100.4 74.5 81.2 Superfamily domain containing 11 201 238,549 PM at CBFA2T2 core-binding factor, runt 22E-05 2.95E-03 277.S 222.O 206.6 domain, alpha Subunit 2: translocated to, 2 202 213015 PM at BBX bobby Sox homolog 23E-OS 2.96E-O3 567.2 446.8 419.6 (Drosophila) 203 60528 PM at JMJD7- JMJD7-PLA2G4B 28E-05 3.07E-03 37.3 29.2 28.7 PLA2G4B .. readthrough if PLA2G4B phospholipase A2, group IVB (cytosolic) 204 242014 PM a 3OE-OS 3.09E-03 121.9 75.6 86.1 205 238277 PM a 3OE-OS 3.09E-03 30.9 20.4 20.9 206 243527 PM a 32E-OS 3.11E-O3 869.5 517.7 530.8 207 23.7383 PM a .33E-OS 3.11E-O3 167.0 86.8 93.6 208 218854 PM a DSE dermatan Sulfate .33E-OS 3.11E-O3 223.O 318.1 360.7 epimerase 209 239331 PM a 3SE-OS 3.14E-O3 SS6.S 296.9 302.5 210 228105 PM a 3SE-OS 3.14E-O3 387.4 274.O 270.3 211 237006 PM a 37E-OS 3.15E-03 316.4 177.8 1853 212 244822 PM a 4OE-05 3.21E-O3 45.3 32.6 27.3 213 241965 PM a 43E-05 3.27E-03 1947 121.1 130.9 214 23O389 PM a FNBP1 formin binding protein 1 4SE-OS 3.3OE-03 760.9 567.6 527.1 215 239171 PM a 4SE-OS 3.3OE-03 112.1 67.6 65.2 216 236450 PM a 46E-05 3.3OE-03 28.3 2O2 18.5 217 204236 PM a FLI1 Friend leukemia 48E-05 3.33E-03 862.O. 1066.1 1074.7 integration 1 218 23.5925 PM a 49E-05 3.33E-03 61.2 41.7 35.3 219 243736 PM a SOE-OS 3.33E-03 131.8 76.7 7O.O 220 236293 PM a PDSS1 Prenyl (decaprenyl) S1E-OS 3.33E-03 79.7 59.5 60.9 diphosphate synthase, subunit 1 221 1558410 PM S at - S1E-OS 3.33E-03 40.1 24.8 22.6 222 1570621 PM at S2E-OS 3.33E-03 24.1 16.1 18.0 223 233228 PM a S4E-OS 3.35E-03 256.6 149.9 137.1 224 244801 PM a PSMB7 Proteasome (prosome, S4E-OS 3.35E-03 71.6 53.7 48.7 macropain) subunit, beta type, 7 225 236779 PM a MRPS5 Mitochondrial ribosomal SSE-OS 3.35E-03 25.4 2O.S 17.1 protein S5 226 241063 PM a SSE-OS 3.35E-03 16.8 13.4 12.4 227 239166 PM a S6E-OS 3.35E-03 1514 846 79.8 228 222371 PM a S9E-OS 3.38E-03 1038.5 638.6 629.2 229 1553349 PM at ARID2 AT rich interactive domain S9E-OS 3.38E-03 98.2 66.1 65.9 2 (ARID, RFX-like) 230 238.894 PM a 6OE-05 3.38E-03 95.0 S8.9 56.8 231 236621 PM a RPS27 ribosomal protein S27 61E-05 3.4OE-03 74.6 38.2 41.4 232 222310 PM a SFRS15 splicing factor, 62E-05 3.41E-O3 154.5 95.5 106.7 arginine?serine-rich 15 233 1569180 PM at 6SE-OS 3.44E-O3 232.8 126.6 126.8 234 240544 PM a 67E-OS 3.48E-O3 45.3 24.9 25.8 235 226062 PM X at FAM63A family with sequence .74E-OS 3.61E-O3 532.9 375.1 412.3 similarity 63, member A 236 210679 PM x at .75E-05 3.62E-O3 167.5 119.6 1236 237 203482 PM a FAM178A family with sequence .76E-OS 3.62E-O3 88.2 69.3 66.3 similarity 178, member A 238 203318 PM S at ZNF148 Zinc finger protein 148 86E-05 3.8OE-03 812.1 633.8 647.6 239 23.3027 PM a .87E-OS 3.8OE-03 167.2 107.4 119.2 240 236966 PM a ARMC8 armadillo repeat .87E-OS 3.8OE-03 373.4 272.2 240.4 containing 8 US 2017/O 137885 A1 May 18, 2017 34

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 241. 217446 PM X at 1.89E-OS 3.82E-O3 204.7 158.6 170.8 242 241508 PM a 1.91E-OS 3.85E-03 O6.6 62.3 69.3 243 213940 PM s at FNBP1 formin binding protein 1 194E-OS 3.87E-03 911.3 766.O 710.7 244 215373 PM X at 194E-OS 3.87E-03 77.9 544 65.9 245 242480 PM a 1.9SE-OS 3.89E-03 605.9 358.6 393.2 246 228271 PM a 1.97E-OS 3.90E-03 O9.8 813 64.9 247 216211 PM a 1.98E-OS 3.90E-03 82.9 132.4 111.1 248. 1557632 PM at 1.99E-OS 3.90E-03 576.5 426.S 400.0 249 244826 PM a 2.OOE-OS 3.90E-03 363.7 257.1 267.9 250 239264 PM a 2.01E-OS 3.90E-03 62.6 98.9 89.0 251 227931 PM a INO8OD INO80 complex subunit D 2.01E-OS 3.90E-03 841.6 63S.S 661.8 252 242563 PM a 2.03E-OS 3.93E-03 246.4 126.9 13S.O 253 238172 PM a 2.OSE-OS 3.95E-03 886 56.1 514 254 241893 PM a 2.06E-OS 3.96E-O3 23.1 59.6 59.3 255 233323 PM a 2.O8E-OS 3.96E-O3 223.8 136.7 1352 256 242865 PM a 2.O8E-OS 3.96E-O3 382.4 247.8. 273.3 257 226252 PM a 2.09E-OS 3.97E-03 24.6 91.1 84.O 258 225490 PM a ARID2 AT rich interactive domain 2.11E-OS 3.97E-03 240.9 185.3 1692 2 (ARID, RFX-like) 259 208654 PM S at CD164 CD164 molecule, 2.12E-OS 3.97E-03 676.3 1044.O 939.9 sialomucin 260 215338 PM S at NKTR natural killer-tumor 2.13E-OS 3.97E-03 457.1 352.4 328.2 recognition sequence 261 242110 PM at 2.13E-OS 3.97E-03 54.2 31.6 29.8 262 218360 PM at RAB22A RAB22A, member RAS 2.1SE-OS 4.OOE-03 78.8 122.7 118.7 oncogene family 263 1570166 PM a at - 2.16E-OS 4.OOE-03 38.7 26.0 27.1 264. 208724 PM S at RAB1A RAB1A, member RAS 2.17E-OS 4.OOE-03 1357.9 1688.2 1672.7 oncogene family 265 239901 PM at 2.19E-OS 4.O3E-03 455.7 255.1 273.1 266 238988 PM at 2.21E-OS 4.OSE-O3 315.4 1947 209.8 267 235O23 PM at VPS13C Vacuolar protein sorting 2.23E-OS 4.O8E-03 649.4 471.9 435.1 13 homolog C (S. cerevisiae) 268 217619 PM X at 2.24E-OS 4.O8E-03 48.0 39.5 43.3 269 215618 PM at RSU1 Ras Suppressor protein 1 2.27E-OS 4.1OE-03 34.5 24.9 25.4 27O 230779 PM at TNRC68 trinucleotide repeat 2.27E-OS 4.1OE-03 767.7 495.5 SO8.6 containing 68 271 243981 PM at STK4 serine/threonine kinase 4 2.31E-OS 4.16E-03 490.0 312.1 335.1 272 1569181 PM X at - 2.33E-OS 4.17E-03 233.9 127.7 121.5 273 203321 PM S at ADNP2 ADNP homeobox2 2.34E-OS 4.17E-03 150.5 117.4 113.4 274 204373 PM s at CEP350 centrosomal protein 2.36E-OS 4.19E-03 439.2 350.3 352.4 350 kDa 275 239071 PM at RBBP4 Retinoblastoma binding 2.37E-OS 4.2OE-03 173.1 131.7 1229 protein 4 276 224437 PM s at WTA1 Vps20-associated 1 2.38E-OS 4.21E-03 229.2 335.9 33O.O homolog (S. cerevisiae) 277 243522 PM at 2.41E-OS 4.24E-03 14.9 12.5 11.7 278 237803 PM X at 2.42E-OS 4.24E-03 89.4 65.8 54.7 279 229036 PM at TNRC6B trinucleotide repeat 2.45E-OS 4.28E-03 S75.8 426.S. 436.5 containing 6B 280 222282 PM at 2.47E-OS 4.29E-03 3404 214.O 2304 281 227074 PM at LOC100131564 hypothetical 2.49E-05 4.32E-03 389.3 291.8 239.7 LOC100131564 282 242343 PM X at 2.SSE-OS 4.38E-03 595.3 403.S. 403.1 283 213086 PM S at CSNK1A1 casein kinase 1, alpha 1 2.SSE-OS 4.38E-03 S6SO 667.9 66O.S 284 205383 PM s at ZBTB20 Zinc finger and BTB 2.56E-OS 4.38E-03 151.5 104.9 92.1 domain containing 20 285 233919 PM S at HASP4 hyaluronan binding 2.57E-05 4.38E-03 33.3 22.3 20.4 protein 4 286 231552 PM at 2.57E-05 4.38E-03 258.2 173.1 1820 287 239017 PM at LOC100507273 collagen alpha-4(VI) chain- 2.58E-OS 4.39E-03 75.4 40.3 39.1 like 288 240072 PM at ASXL2 Additional sex combs like 2.61E-OS 4.42E-03 81.5 SO.O 56.O 2 (Drosophila) 289 242362 PM at 26SE-OS 4.47E-03 414.8 279.8 307.1 290 238317 PM X at 2.67E-OS 4.49E-03 386.3 284.6 287.8 291 242471 PM at 2.71E-OS 4.53E-03 741.8 426.8 386.9 292 2093O8 PM s at BNIP2 BCL2fadenovirus E1B 2.73E-OS 4.SSE-03 306.3 4444 45O1 19 kDa interacting protein 2 293 240254 PM at 2.75E-05 4.57E-03 41.2 27.6 21.5 US 2017/O 137885 A1 May 18, 2017 35

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 294 233313 PM a 2.8OE-OS 4.61E-03 46.3 33.3 3O.S 295 1559401 PM a at - 2.8OE-OS 4.61E-03 2O.O 14.2 13.3 296 217158 PM a LOC442421 hypothetical LOC442421 fif 2.82E-OS 4.61E-03 12.6 14.2 12.O LOCA28297 prostaglandin E2 receptor EP4 subtype-like 297 239758 PM a 2.82E-OS 4.61E-03 133.3 79.2 78.9 298 232882 PM a 2.82E-OS 4.61E-03 2O3.8 95.0 85.1 299 226250 PM a 2.83E-OS 4.61E-03 151.7 105.8 97.6 300 201619 PM a PRDX3 peroxiredoxin 3 2.84E-OS 4.62E-03 605.8 852.3 804.1 301 213229 PM a DICER1 dicer 1, ribonuclease type 2.87E-OS 4.62E-03 971.6 652.O 668.8 III 302 242068 PM a 2.87E-OS 4.62E-03 281.2 157.5 152.9 303 243470 PM a 2.87E-OS 4.62E-03 6O.O 43.1 44.4 304 218519 PM a SLC3SAS solute carrier family 35, 2.88E-OS 4.62E-03 173.2 228.3 234.9 member A5 305 240399 PM a 2.92E-OS 4.64E-03 15.6 11.2 12.6 306 24.1501 PM a 2.92E-OS 4.64E-03 265.7 1756 164.5 3.07 228623 PM a 2.93E-OS 4.64E-03 369.6 2234 226.O 3O8 225.007 PM a G3BP1 GTPase .99E-OS 4.72E-03 549.8 423.9 371.4 (SH3 domain) binding protein 1 309 244239 PM a 3.04E-OS 4.78E-03 13.6 9.8 9.9 310 243054 PM a 3.04E-OS 4.78E-03 73.9 53.0 SO.8 311 219724 PM S at KIAAO748 KIAAO748 3.07E-OS 4.81E-03 16.6 12.4 12.O 312 240594 PM a 3.09E-OS 4.82E-03 44.0 27.7 28.2 313 208003 PM s at NFAT5 nuclear factor of activated 3.13E-OS 4.88E-03 763.2 S10.3 539.6 T-cells 5, tonicity responsive 314 243147 PM X at 3.16E-OS 4.91E-03 420.2 325.4 351.8 315 236742 PM at 3.18E-OS 4.92E-03 102.3 61.7 60.2 316 209964 PM S at ATXN7 ataxin 7 3.2OE-OS 4.92E-03 361.1 250.7 229.7 317 202106 PM at GOLGA3 golgin A3 3.2OE-OS 4.92E-03 136.8 110.1 96.O 318 237001 PM at 3.22E-OS 4.93E-03 64.6 39.1 38.5 319 202539 PM s at HMGCR 3-hydroxy-3- 3.2SE-OS 4.93E-03 128.3 175.3 192.0 methylglutaryl-CoA reductase 320 244474 PM at 3.26E-OS 4.93E-03 86.2 624 52.5 321 41512 PM at BRAP BRCA1 associated protein 3.26E-OS 4.93E-03 287.1 234.9 234.3 322 215707 PM S at PRNP prion protein 3.27E-OS 4.93E-03 25.5 42.5 34.2 323 243O88 PM at 3.27E-OS 4.93E-03 201S 119.7 132.3 324 244733 PM at 3.29E-OS 4.95E-03 38.9 27.1 26.4 325 223215 PM s at JKAMP JNK1 MAPK8-associated 3.31E-OS 4.96E-03 327.6 455.8 450.7 membrane protein 326 15594.10 PM at 3.34E-OS 4.96E-03 31.4 20.7 16.7 327 222311 PM S at SFRS15 splicing factor, 3.34E-OS 4.96E-03 121.9 92.5 89.7 arginine?serine-rich 15 328 242696 PM at 3.34E-OS 4.96E-03 138.7 10O.S 88.5 329 223021 PM X at WTA1 Vps20-associated 1 3.35E-OS 4.96E-03 1401. 205.9 1945 homolog (S. cerevisiae) 330 241472 PM at 3.36E-OS 4.97E-03 1721 122.6 120.7 331 238000 PM at 3.37E-OS 4.97E-03 131.5 83.1 82.O 332 236492 PM at PPP2R2A protein phosphatase 2, 3.41E-OS S.O1E-03 3.07.2 1959 205.4 regulatory Subunit B, alpha 333 220939 PM S at DPP8 dipeptidyl-peptidase 8 3.44E-OS S.O2E-03 1061.4 845.7 839.7 334 200733 PM s at PTP4A1 protein tyrosine 3.44E-OS S.O2E-03 1989 272.5 268.8 phosphatase type IVA, member 1 335 233440 PM at 3.SOE-OS S.06E-03 58.5 35.2 36.5 336 205435 PM S at AAK1 AP2 associated kinase 1 3.S1E-OS S.06E-03 71.1 51.7 42.O 337 233893 PM S at KIAA1530 KLAA1530 3.S1E-OS S.06E-03 470.7 303.9 368.9 338 232180 PM at UGP2 UDP-glucose 3.S2E-OS S.06E-03 276.2 182.6 185.7 pyrophosphorylase 2 339 244450 PM at 3.S2E-OS S.06E-03 88.9 59.8 59.7 340 238619 PM at 3.53E-OS S.06E-03 906.1 477.0 493.4 341 1555372 PM at BCL2L11 BCL2-like 11 (apoptosis 3.56E-OS S.O8E-03 254.9 1610 1946 acilitator) 342 210742 PM at CDC14A CDC14 cell division cycle 3.59E-OS S.09E-03 2141 160.8 113.2 4 homolog A (S. cerevisiae) US 2017/O 137885 A1 May 18, 2017 36

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 343 225351 PM at FAM45A family with sequence 3.59E-OS S.09E-03 421.1 568.4 623.5 similarity 45, member A 344 231716 PM at RC3H2 ring finger and CCCH-type 3.61E-OS S.11E-03 334.S. 272.9 279.1 domains 2 345 239673 PM at 3.63E-OS S.13E-03 71.8 29.9 21.2 346 232509 PM at PDE4DIP phosphodiesterase 4D 3.66E-OS S.15E-03 19.8 15.3 15.2 interacting protein 347 202749 PM at WRB tryptophan rich basic 3.77E-05 5.3OE-03 240.9 333.2 316.9 protein 348 231199 PM at 3.79E-05 5.3OE-03 415.2 293.5 3O3.8 349 215513 PM at HYMAI hydatidiform mole 3.8OE-OS 5.3OE-03 66.4 35.9 42.9 associated and imprinted (non-protein coding) 350 232323 PM S at TTC17 tetratricopeptide repeat 3.81E-OS 5.3OE-03 3S4.O 286.9 265.6 domain 17 351 240824 PM a 3.85E-OS S.34E-03 300.3 202.7 216.3 352 243640 PM X at 3.86E-OS S.34E-03 36.3 26.9 25.6 353 239902 PM a 3.96E-OS S47E-03 40.7 32.O 25.5 354 244495 PM x at C18orf25 chromosome 18 open 4.OOE-05 5.48E-O3 111.4 89.7 1OOO reading frame 45 355 221176 PM X at 4.02E-05 5.48E-O3 1352 107.7 114.4 356 236243 PM a ZCCHC6 Zinc finger, CCHC domain 4.O3E-05 5.48E-O3 868.0 S34.2 S30.6 containing 6 357 243964 PM a 4.O3E-05 5.48E-O3 114.O 75.3 69.3 358 226970 PM a FBXO33 F-box protein 33 4.O3E-05 5.48E-O3 460.9 359.9 344.O 359 206169 PM x at ZC3H7B Zinc finger CCCH-type 4.04E-05 5.48E-O3 439.3 319.9 341.9 containing 7B 360 227969 PM a LOC4OO960 hypothetical LOC400960 4.OSE-OS 5.48E-O3 65.4 50.7 46.7 361. 207186 PM S at BPTF bromodomain PHD finger 4.09E-05 S.S2E-03 1217.2 958.4 894.3 transcription factor 362 242918 PM a NASP Nuclear autoantigenic 4.13E-05 S.S6E-03 212.8 127.0 158.1 sperm protein (histone binding) 363 241226 PM a 4.14E-05 S.S6E-03 32.6 22.4 21.0 364 1556382 PM a at NAA15 N(alpha)-acetyltransferase 4.1SE-OS S.S6E-03 15.9 12.4 12.3 15, NatA auxiliary subunit 365 237018 PM a 4.19E-05 S.S8E-03 460.1 322.7 305.5 366 225367 PM a PGM2 phosphoglucomutase 2 4.2OE-05 S.S8E-03 550.7 709.4 778.0 367 236134 PM a DCAF7 DDB1 and CUL4 associated 4.2OE-05 S.S8E-03 12O.O 78.1 74.3 factor 7 368 242143 PM a 4.24E-05 S.62E-03 295.6 1774 179.6 369 237881 PM a 4.31E-05 S.69E-03 128.5 56.6 S2.1 370 203100 PM S at CDYL chromodomain protein, Y- 4.32E-05 S.69E-03 85.5 116.1 121.1 like 371 244236 PM a 4.34E-05 S.7OE-03 22.7 18.1 16.O 372 23.6561 PM a 4.36E-05 S.71E-03 577.8 412.5 389.2 373 236149 PM a 4.38E-05 S.71E-03 52.7 31.8 29.7 374 214715 PM X at ZNF160 Zinc finger protein 160 4.38E-05 S.71E-03 860.O 646.3 690.2 375 219326 PM S at B3GNT2 UDP-GlcNAc: beta Gal beta- 4.4OE-05 S.72E-03 18.1 26.8 28.6 1,3-N- acetylglucosaminyltransferase 2 376 201959 PM S at MYCBP2 binding protein 2 4.44E-05 5.75E-03 1010.4 762.O 722.2 377 236404 PM a 4.47E-05 5.77E-03 3.10.1 182.7 1853 378 233O37 PM a 4S2E-OS 5.83E-03 19.4 14.3 14.8 379 23.7768 PM x at 4.SSE-OS 5.85E-03 531.4 367.3 361.5 380 202549 PM a WAPB VAMP (vesicle-associated 4.57E-OS 5.86E-03 21.9 15.6 18.9 membrane protein)- associated protein B and C 381 237264 PM a 4.61E-05 5.89E-03 1925 114.O 115.6 382 226465 PM S at SON SON DNA binding protein 4.64E-05 5.89E-03 1664.7 1345.0 1359.5 383 226412 PM a SFRS18 splicing factor, 4.6SE-OS 5.89E-03 619.8 4431 467.6 arginine?serine-rich 18 384 244860 PM a 4.66E-05 5.89E-03 37.8 22.5 21.1 385 24O139 PM a 4.67E-OS 5.89E-03 1628 110.0 101.9 386 238807 PM a GAPDHP62 glyceraldehyde 3 4.67E-OS 5.89E-03 126.7 88.3 78.4 phosphate dehydrogenase pseudogene 62 387 23O866 PM a CYSLTR1 cysteinyl leukotriene 4.72E-OS S.93E-03 1712 267.5 284.1 receptor 1 388 23.6000 PM S at 4.72E-OS S.93E-03 326.9 240.3 242.0 389 23.7895 PM a 4.74E-05 5.94E-O3 469.8 258.1 223.3 US 2017/O 137885 A1 May 18, 2017 37

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 390 243966 PM a 4.79E-05 S.97E-03 227.7 174.9 1654 391 1556060 PM a at ZNF451 Zinc finger protein 451 4.8OE-05 S.97E-03 SSO.1 418.S. 416.6 392 242598 PM a 4.81E-05 S.97E-03 465.2 2SO.1 3O8.0 393 1569237 PM at 4.83E-05 S.97E-03 52.8 35.4 37.1 394 232791 PM a 4.83E-05 S.97E-03 25.2 17.7 16.8 395 1565567 PM at 4.8SE-OS S.97E-03 1032.1 665.2 779.1 396 222252 PM x at UBQLN4 ubiquilin 4 4.8SE-OS S.97E-03 73.1 59.3 61.8 397 229765 PM a ZNF2O7 Zinc finger protein 207 4.90E-05 6.O1E-03 722.8 S81.6 S40.4 398 201302 PM a ANXA4 annexin A4 4.92E-05 6.O1E-03 3O3.7 429.1 454.7 399 1556783 PM a at - 4.92E-05 6.O1E-03 15.2 11.7 11.7 400 215200 PM x at 4.94E-05 6.02E-03 97.7 79.4 804 401 231005 PM a 4.98E-05 6.04E-03 243.5 155.8 167.8 402 243249 PM a 4.99E-05 6.04E-03 832.1 598.5 633.O 403 233702 PM X at S.OOE-OS 6.04E-03 381.S. 289.O 318.0 404 1564077 PM at S.O1E-OS 6.04E-03 99.8 65.3 47.8 405 232613 PM a PBRM1 polybromo 1 S.O4E-OS 6.06E-03 1523 108.9 117.0 406 225859 PM a XLAP X-linked inhibitor of S.11E-OS 6.13E-03 716.1 535.6 524.7 apoptosis 407 240302 PM a S.2OE-OS 6.23E-03 70.6 46.5 423 408 244791 PM a S.22E-OS 6.24E-03 724 41.7 43.0 409 244.508 PM a 7-Sep Septin 7 S.26E-OS 6.26E-03 8O.O SO.2 46.2 410 1554251 PM at HP18P3 heterochromatin protein S.28E-OS 6.26E-03 1921 150.9 123.2 1, binding protein 3 411 242862 PM x at S.28E-OS 6.26E-03 114.4 82.9 88.5 412 243381 PM a S.29E-OS 6.26E-03 35.7 24.3 23.6 413 1561763 PM at 5.38E-OS 6.35E-03 92.4 56.7 59.8 414 239102 PM S at S.41E-OS 6.35E-03 1585.7 933.9 1087.2 415 215179 PM X at PGF Placental growth factor S.41E-OS 6.35E-03 820.1 625.4 683.9 416 200730 PM S at PTP4A1 protein tyrosine S.42E-OS 6.35E-03 76.9 1208 125.1 phosphatase type IVA, member 1 417 233309 PM at 5.44E-OS 6.35E-03 142.7 89.0 102.0 418 210282 PM at ZMYM2 Zinc finger, MYM-type 2 S.48E-OS 6.39E-03 246.4 166.5 1632 419 243025 PM at S.62E-OS 6.53E-03 74.O S2O 54.7 420 237475 PM X at CCDC152 coiled-coil domain 5.72E-05 6.63E-03 830.9 624.3 684.3 containing 152 421 212526 PM at SPG20 spastic paraplegia 20 5.73E-05 6.63E-03 150.6 1973 204.9 (Troyer syndrome) 422 210146 PM x at ULRB2 leukocyte 5.75E-05 6.64E-03 992.O 1158.S 1393.3 immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 423 236274 PM at EIF3B eukaryotic translation S.76E-OS 6.64E-03 3O4 24.7 22.7 initiation factor 3, Subunit B 424 232383 PM at TFEC transcription factor EC 5.79E-05 6.66E-03 49.6 132.2 94.3 425 235803 PM at 5.84E-OS 6.7OE-03 116.O 734 66.2 426 208.238 PM X at 5.86E-OS 6.7OE-03 589.1 460.7 496.6 427 1555057 PM at NDUFS4 NADH dehydrogenase 5.87E-OS 6.7OE-03 27.7 2O.O 19.1 (ubiquinone) Fe—S protein 4, 18 kDa (NADH coenzyme Q reductase) 428 209188 PM X at DR1 down-regulator of 5.88E-OS 6.7OE-03 157.9 207.6 214.8 transcription 1, TBP binding (negative 2) 429 1559020 PM a at - S.92E-OS 6.73E-03 60.4 39.6 38.3 430 212872 PM S at MED2O mediator complex subunit S.9SE-OS 6.75E-03 65.5 89.8 88.9 2O 431 234032 PM at S.98E-OS 6.76E-03 245.4 134.1 120.3 432 232516 PM X at YY1AP1 YY1 associated protein 1 6.02E-05 6.76E-03 277.O 206.7 227.8 433 218611 PM at IERS Immediate early response 5 6.02E-05 6.76E-03 384.O 516.5 548.6 434 242712 PM X at RANBP2 if RAN binding protein 2 fif 6.02E-05 6.76E-03 92.4 52.4 61.2 RGPD1 RANBP2-like and GRIP RGPD2 domain containing 1 RGPD3 RANBP2-like and RGPD4 RGPD5 RGPD6 RGPD8 US 2017/O 137885 A1 May 18, 2017 38

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 435 229434 PM a 6.1OE-05 6.81E-03 1281.8 99O.S 982.O 436 236379 PM a 6.11E-OS 6.81E-03 489.O 318.7 299.6 437 231495 PM a 6.12E-05 6.81E-03 261.0 1630 13S.O 438 232012 PM a CAPN1 calpain 1, (mul) large 6.13E-OS 6.81E-03 179.6 143.7 133.3 Subunit 439 1558740 PM S at - 6.1 SE-OS 6.81E-03 246.8 179.6 171.8 440 235837 PM a 6.17E-OS 6.81E-03 97.7 76.6 73.6 441 201737 PM S at 6-Mar membrane-associated ring 6.18E-05 6.81E-03 SS8.7 409.2 370.6 finger (C3HC4) 6 442 239561 PM a 6.2OE-05 6.81E-03 1431 75.4 80.9 443 243473 PM a 6.23E-OS 6.81E-03 2O.O 15.1 15.1 444 215887 PM a ZNF277 Zinc finger protein 277 6.24E-05 6.81E-03 144.3 101.2 106.6 445 241155 PM a 6.25E-05 6.81E-03 3O8.3 207.2 204.8 446 1563455 PM at SIK3 SIK family kinase 3 6.27E-OS 6.81E-03 133.1 86.6 90.7 447 243O89 PM a 6.27E-OS 6.81E-03 49.4 28.7 24.7 448 232726 PM a 6.27E-OS 6.81E-03 185.5 77.8 84.3 449 238880 PM a GTF3A general transcription 6.28E-05 6.81E-03 471.O 322.6 305.2 factor IIIA 450 216652 PM S at DR1 down-regulator of 6.3OE-OS 6.82E-03 110.6 152.5 153.6 transcription 1, TBP binding (negative cofactor 2) 451. 215605 PM at NCOA2 6.41E-05 6.92E-03 302.5 1843 22O.S coactivator 2 452 239383 PM at 6.47E-OS 6.98E-03 95.2 62.9 54.6 453 230713 PM at 6. SOE-OS 6.99E-03 179.2 116.7 108.1 454 201300 PM S at PRNP prion protein 6.53E-OS 7.01E-03 327.7 516.1 S38.4 455 232264 PM at 6.59E-OS 7.06E-03 124.7 63.8 62.6 456 243759 PM at SFRS15 Splicing factor, 6.6SE-OS 7.11E-03 103.6 67.4 71.4 arginine?serine-rich 15 457 235493 PM at 6.72E-OS 7.16E-03 97.5 67.3 66.6 458 1561346 PM at 6.73E-OS 7.16E-03 126.0 89.3 97.7 459 234989 PM at 6.78E-OS 7.19E-03 S60.8 300.7 287.5 460 221616 PM S at TAF9B TAF9B RNA polymerase II, 6.87E-OS 7.27E-03 241.5 1624 1688 TATA box binding protein (TBP)-associated factor, 31 kDa 461 1562062 PM at KIAA1245 KIAA1245 6.93E-OS 7.31E-03 345.4 232.4 266.6 N8PF1 neuroblastoma breakpoint NBPF10 family, member 1 if NBPF11 neuroblastoma breakpoint NBPF12 fam NBPF24 NBPF8 NBPF9 462 202829 PM S at VAMP7 vesicle-associated 6.93E-OS 7.31E-03 563.9 752.2 674.2 membrane protein 7 463 1557830 PM at 7.06E-OS 7.42E-O3 48.1 33.4 29.9 464 200667 PM at UBE2D3 ubiquitin-conjugating 7.06E-OS 7.42E-O3 1057.4 1367.1. 1384.4 enzyme E2D 3 (UBC4/5 homolog, yeast) 465 221899 PM at N4BP2L2 NEDD4 binding protein 2- 7.1OE-OS 7.44E-O3 40544 31.96.6 31715 like 2 466 236934 PM at 7.13E-OS 7.45E-03 143.5 63.2 56.1 467 1565762 PM at 7.21E-OS 7...SOE-03 59.0 40.2 33.8 468 222316 PM at 7.21E-OS 7...SOE-03 247.1 154.8 164.9 469 239811 PM at 7.26E-OS 7.53E-03 1050.3 645.8 708.3 470 212326 PM at VPS13D vacuolar protein sorting 7.26E-OS 7.53E-03 3O4 23.0 23.6 13 homolog D (S. cerevisiae) 471 228070 PM at PPP2RSE protein phosphatase 2, 7.29E-OS 7.54E-03 365.2 286.1 2750 regulatory Subunit B", epsilon isoform 472 1563080 PM at 7.33E-OS 7.56E-03 21.3 16.7 15.5 473 1560O82 PM at 7.41E-OS 7.63E-03 39.8 29.5 27.4 474 224778 PM S at 7.44E-OS 7.65E-03 1054.6 845.9 906.9 475 240174 PM at 7.48E-OS 7.66E-03 249.8 144.1 143.7 476 1566887 PM X at - 7.48E-OS 7.66E-03 320.8 247.9 284.8 477 222104 PM x at GTF2H3 general transcription 7.54E-OS 7.7OE-03 468.3 361.7 374.9 factor IIH, polypeptide 3, 34 kDa US 2017/O 137885 A1 May 18, 2017 39

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 478 233427 PM X at 7.58E-OS 7.73E-03 278.5 218.3 236.5 479 241917 PM at 7.6OE-OS 7.74E-03 115.7 62.5 64.7 480 23O392 PM at 7.63E-OS 7.74E-03 119.3 8O.S 83.5 481 242876 PM at AKT3 V-akt murine thymoma 7.74E-OS 7.83E-03 29.6 19.3 18.5 viral oncogene homolog 3 (protein kinase B, gamma) 482 217482 PM at 7.74E-OS 7.83E-03 53.7 33.0 30.6 483 205647 PM at RADS2 RAD52 homolog 7.76E-OS 7.83E-03 17.6 15.1 13.8 (S. cerevisiae) 484 1570007 PM at LRRC8C leucine rich repeat 7.8OE-OS 7.85E-03 21.6 15.4 16.5 containing 8 family, member C 485 2305.05 PM at LOC145474 hypothetical LOC145474 7.81E-OS 7.85E-03 302.3 137.3 148.1 486 232929 PM at 7.87E-05 7.89E-03 51.2 28.8 28.1 487 239868 PM at 7.91E-OS 7.92E-03 21.5 14.5 14.5 488 236974 PM at 8.OSE-OS 8.04E-03 245.7 165.1 16S.S 489 204342 PM at SLC25A24 solute carrier family 25 8.09E-OS 8.06E-03 281.9 4641 438.3 (mitochondrial carrier; phosphate carrier), member 24 490 2295 74 PM at TRA2A transformer 2 alpha 8.1 OE-05 8.06E-03 850.9 620.8 645.7 homolog (Drosophila) 491 228694 PM at 8.13E-OS 8.07E-03 167.1 125.4 121.9 492 208082 PM X at 8.1 SE-OS 8.07E-03 716.5 S87.4 601.3 493 235983 PM at 8.28E-OS 8.18E-03 121.1 88.8 72.2 494 232169 PM x at NDUFS8 NADH dehydrcgenase 8.39E-OS 8.28E-03 466.1 349.6 373.1 (ubiquinone) Fe—S protein 8, 23 kDa (NADH coenzyme Q reductase) 495 237290 PM at 8.S2E-OS 8.38E-03 10.1 10.3 12.5 496 244599 PM at 8.54E-OS 8.39E-03 257.4 185.5 1694 497 1557433 PM at 8.56E-OS 8.39E-03 23.1 17.8 16.7 498 244433 PM at 8.59E-OS 8.39E-03 752.7 478.2 540.7 499 242748 PM at SREBF2 sterol regulatory element 8.59E-OS 8.39E-03 87.O 61.1 61.9 binding transcription factor 2 500 1563505 PM at DUSP16 Dual specificity 8.73E-OS 8.S1E-03 14.0 11.O 11.7 phosphatase 16 501. 237987 PM x at 8.76E-OS 8.S1E-03 8.4 8.8 9.8 502 2398O8 PM a 8.77E-05 8.S1E-03 2102 1630 137.8 503 232584 PM a 8.82E-OS 8.53E-03 21.4 13.1 11.9 504 243993 PM a 8.82E-OS 8.53E-03 1946 118.3 117.0 505 54051 PM at PKNOX1 PBXknotted 1 homeobox 8.84E-05 8.53E-03 39.4 30.4 30.7

506 225522 PM a AAK1 AP2 associated kinase 1 8.97E-OS 8.64E-03 223.6 176.1 151.7 507 222667 PM s at ASH1L, ashl (absent, Small, or 9.02E-OS 8.67E-03 1637.7 1288.3 1282.8 homeotic)-like (Drosophila) 508 202822 PM a LPP LIM domain containing 9. OSE-OS 8.69E-03 371.8 281.4 299.5 preferred translocation partner in lipoma 509 242995 PM a 9.1OE-OS 8.7OE-03 59.4 38.9 36.7 510 243512 PM x a 911E-OS 8.7OE-03 36.0 22.1 22.O 511 243826 PM a 9.12E-OS 8.7OE-03 317.0 1814 215.2 512 201443 PM S a ATP6AP2 ATPase, H+ transporting, 9.16E-OS 8.72E-03 1784.1 2.195.2 217 O.S ysosomal accessory protein 2 513 243578 PM a 9.2OE-OS 8.73E-03 26.9 18.2 17.5 514 240971 PM X a 9.21E-OS 8.73E-03 215.1 1444 139.0 515 238853 PM a RAB3IP RAB3A interacting protein 9.23E-OS 8.73E-03 35.1 22.9 23.6 (rabin3) 516 221829 PM S a TNPO1 9.28E-OS 8.76E-03 1O3SO 8O3.O 842.O 517 242529 PM X a 9.3OE-OS 8.77E-03 34.6 23.5 22.3 518 239301 PM a 9.34E-OS 8.78E-03 226.9 128.8 139.8 519 1570194 PM x at - 9.38E-OS 8.81E-03 196.3 91.9 121.4 520 2.33867 PM a 949E-05 8.89E-03 863.1 SSS.6. S64.O 521 242479 PM S a 9.S2E-OS 8.90E-03 9.5 10.4 11.4 522 217679 PM X a 9.54E-OS 8.90E-03 680.8 483.9 S13.8 523 1559142 PM at MYST3 MYST histone 9.6OE-OS 8.94E-03 25.5 19.8 21.0 acetyltransferase (monocytic leukemia) 3 US 2017/O 137885 A1 May 18, 2017 40

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 524 209089 PM a RABSA RAB5A, member RAS 9.75E-05 9.06E-O3 740.4 904.4 9SO.S oncogene family 525 232372 PM a 9.84E-OS 9.13E-O3 23.3 17.3 17.1 526 218534 PM S at AGGF1 angiogenic factor with G 9.91E-OS 9.18E-O3 82.O 118.9 114.9 patch and FHA domains 1 527 1559723 PM S at - 9.99E-OS 9.2OE-03 20.1 14.8 14.3 528 232784 PM a O.OOO1 OOOO1 O.O0919631 68.2 51.7 46.1 529 242233 PM a O.OOO1 OOO81 O.O0919631 614.1 453.5 466.O 530 223662 PM X at DDX59 DEAD (Asp-Glu-Ala-Asp) O.OOO1 OO162 O.O0919631 129.3 106.9 114.9 box polypeptide 59 531 244865 PM a O.OOO1 OO377 O.O0919631 24.8 19.1 19.7 532 24.2121 PM a NCRNA00182 non-protein coding RNA O.OOO10040S O.O0919631 1332.1 853.7 927.4 82 533 202946 PM S at BTBD3 BTB (POZ) domain O.OOO100622 O.OO919889 26.6 42.1 44.6 containing 3 534 244611 PM a MED13 Mediator complex subunit O.OOO102003 O.OO928958 65.6 43.8 38.7 3 535 205992 PM S at IL15 interleukin 15 O.OOO102174 O.OO928958 177.2 292.0 335.6 536 242889 PM x at LOC645431 hypothetical LOC645431 O.OOO102186 O.OO928958 170.7 141.4 145.9 537 243030 PM a O.OOO102974 O.OO933895 384.8 242.9 256.3 538 242482 PM a PRKAR1A protein kinase, cAMP- O.OOO103274 O.OO933895 1312 79.8 9 O.S dependent, regulatory, type 1, alpha (tissue specific extinguisher 539 220085 PM a HELLS helicase, lymphoid-specific O.OOO103304 O.OO933895 18.5 15.4 12.7 54O 219017 PM a ETNK1 ethanolamline kinase 1 O.OOO103707 O.OO935802 52.2 83.1 91.3 541 24.0665 PM a O.OOO104299 O.OO93768 1121.4 732.2 726.7 542 2300.97 PM a O.OOO1043 O.OO93768 96.4 68.6 S8.9 543 237868 PM X at O.OOO104648 O.OO939.076 167.5 1231 138.3 544 201298 PM s at MOBKL1B MOB1, Mps One Binder O.OOO105824 O.OO947713 1271.1. 1594.O 1649.3 kinase activator-like 1B (yeast) 545 236931 PM at O.OOO106.187 O.OO947713 145.2 76.8 65.6 546 222230 PM s at ACTR1O actin-related protein 10 O.OOO1061.94 O.OO947713 641.3 778.2 745.3 homolog (S. cerevisiae) 547 217662 PM X at O.OOO106587 O.OO947997 49.5 41.1 43.3 548 224787 PM s at RAB18 RAB18, member RAS O.OOO106745 O.OO947997 233.3 359.4 359.2 oncogene family 549 240019 PM at O.OOO106882, O.OO947997 653.3 366.6 385.3 550 204771 PM s at TTF1 transcription termination O.OOO107004 O.OO947997 468.3 3644 376.O actor, RNA polymerase I 551 238875 PM at O.OOO109875 O.OO971 666 159.5 1143 108.4 552 213574 PM s at O.OOO11 O2S6 O.OO973.269 154O.S 1142.7 1168.0 553 1558237 PM x at O.OOO112606 0.0099.0882 275.2 205.9 217.7 554. 244771 PM at KBTBD12 kelch repeat and BTB O.OOO112658 0.0099.0882 11.O 9.1 102 (POZ) domain containing 2 555 239049 PM at O.OOO113136 0.00992O62 357.9 233.O 253.1 556 215191 PM at O.OOO113298 0.00992O62 300.6 196.1 185.8 557 226651 PM at HOMER1 homer homolog 1 O.OOO113403 0.00992O62 63.4 42.8 43.1 (Drosophila) 558 215383 PM x at SPG21 spastic paraplegia 21 O.OOO114.806 0.010O2S4 666.6 540.4 568.6 (autosomal recessive, Mast syndrome) 559 227435 PM a KIAA2O18 KIAA2O18 O.OOO115657 0.010O816 SO1.0 352.7 394.7 560 205104 PM a SNPH Syntaphilin O.OOO117244 0.0102017 21.9 17.7 17.0 561, 155.8569 PM at LOC100131541 Hypothetical O.OOO11856 0.0102806 104.4 51.7 55.9 LOC100131541 562 243404 PM a O.OOO11868 0.0102806 1984 140.6 145.0 563 220467 PM a O.OOO118879 0.0102806 2O5.4 130.1 107.4 564 211509 PM S at RTN4 reticulon 4 O.OOO119113 O.O102806 1430.3 1755.3 1868.7 565 204715 PM a PANX1 pannexin 1 O.OOO119206 0.0102806 16.5 22.6 21.9 566 235847 PM a O.OOO120325 O.O103588 329.6 175.4 160.4 567 239600 PM a O.OOO12O761 O.O10378 281.8 144.6 145.5 568 244457 PM a O.OOO121998 O.O104658 241.3 153.0 150.3 569 226140 PM S at OTUD1 OTU domain containing 1 O.OOO122S1 O.O104913 4O7.3 S38.5 585.7 570 227576 PM a O.OOO1232O8 O.O1 OS326 377.O 214.1 1923 571 242739 PM a O.OOO123432 O.O1 OS332 41.3 28.0 24.7 572 24.4625 PM a O.OOO123749 O.O105418 39.7 22.7 23.5 US 2017/O 137885 A1 May 18, 2017 41

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 573 228415 PM a AP1S2 adaptor-related protein O.OOO125275 O.O106532 141.1 213.5 223.3 complex 1, sigma 2 Subunit 574 214902 PM X at O.OOO1262O2 O.O106943 470.2 356.8 390S 575 241460 PM a OOOO126341 O.O106943 423.2 274.7 295.1 576. 1564733 PM at O.OOO126417 O.O106943 137.6 93.8 92.7 577 235959 PM a O.OOO126652 O.O106956 309.3 200.7 227.3 578 1556420 PM s at YPEL2 yippee-like 2 (Drosophila) O.OOO127836 O.O107739 110.9 77.0 79.7 579 243450 PM a O.OOO128021 O.O107739 51.7 31.2 30.3 580 234048 PM S at KIAA1632 KIAA1632 O.OOO128316 O.O1078O1 12.9 10.6 11.7 581 201057 PM s at GOLGB1 golgin B1 O.OOO129333 O.O108468 196.9 1492 148.0 582 242827 PM X at O.OOO130436 0.01092OS 345.7 226.7 1928 583 230607 PM a O.OOO131409 O.0109798 29.9 22.3 18.8 584 218379 PM a RBM7 RNA binding motif protein 7 O.OOO131656 0.0109798 249.9 336.2 329.5 585 241930 PM x at O.OOO1319.1 O.0109798 27.0 20.7 2O.O 586 2.35804 PM a O.OOO132O77 0.0109798 423 33.0 28.3 587 241688 PM a O.OOO132271 O.0109798 32.O 21.7 22.8 588 230970 PM a O.OOO133316 O.O110392 1228.2 700.6 742.7 589 235613 PM a O.OOO133562 O.O110392 113.6 774 73.3 590 214990 PM a PIGO phosphatidylinositol O.OOO133666 O.O110392 11.9 9.6 10.3 glycan anchor biosynthesis, class O 591 242349 PM a HECTD1 HECT domain containing 1 O.OOO134359 O.O110777 95.2 68.2 67.4 592 225204 PM a PPTC7 PTC7 protein phosphatase O.OOO134942 O.O11107 790.6 SS2.O 605.7 homolog (S. cerevisiae) 593 235660 PM a O.OOO1360S6 O.O111798 1303 89.4 97.7 594 216682 PM s at FAM48A Family with sequence OOOO136461 O.O111942 232.3 149.8 1654 similarity 48, member A 595 1556,373 PM a at - O.OOO136827 O.O112053 321.3 172.5 180.8 596 1556352 PM at O.OOO137SO3 O.O112418 256.9 139.8 1381 597 239655 PM a O.OOO13785 O.O112S13 11O.S 74.2 73.5 598 240600 PM a O.OOO138859 O.O113048 324.9 212.7 211.5 599 1556462 PM a at - O.OOO13897 0.0113048 99.4 618 42.5 600 1556323 PM at CELF2 CUGBP, Elav-like family O.OOO1396.28 O.0113223 1100.4 748.O 7S7.0 member 2 601 225207 PM a PDK4 pyruvate dehydrogenase O.OOO1396S O.0113223 85.6 214.9 1923 kinase, isozyme 4 602 235811 PM a O.OOO1401.31 O.011342S 8O2.0 498.S 381.6 603 226952 PM a EAF1 ELL associated factor 1 OOOO141842 (0.0114619 129.3 158.6 157.6 604 202484 PM S at MBD2 methyl-CpG binding O.OOO1448SS O.O11686 799.S 984.4 1005.3 domain protein 2 605 217803 PM a GOLPH3 golgi phosphoprotein 3 O.OOO146215 0.0117762 690.O 818.8 813.O (coat-protein) 606 213624 PM a SMPDL3A sphingomyelin O.OOO1471.9S O.O1183.56 113.S 213.6 238.0 phosphodiesterase, acid like 3A 607 229528 PM a SBNO1 strawberry notch homolog O.OOO1481.86 0.0118956 1776 129.9 24.2 1 (Drosophila) 603 230669 PM a RASA2 RAS p21 protein activator O.OOO14871 O.O1191.78 1010.8 776.3 762.2 2 609 242369 PM X at O.OOO148951 O.O119173 234.7 155.9 63.8 610 239978 PM a O.OOO149912 O.O11975 185.5 145.0 34.1 611 235841 PM a O.OOO150894 O.O119968 1821 93.8 O6.3 612 22.9457 PM a ANKHD1 ankyrin repeat and KH O.OOO150905 O.O119968 94.5 65.6 61.7 domain containing 1 613 24.0997 PM a O.OOO150923 O.O119968 25.9 20.3 22.3 614 1554595 PM at SYMPK symplekin OOOO151416 OO12O164 157.9 108.3 O7.O 615 201097 PM S at ARF4 ADP-ribosylatlon factor 4 O.OOO151957 O.O12O262 1063.S. 1248.9 1279.6 616 233319 PM X at O.OOO152O34 0.012O262 23.2 18.3 19.5 617 232834 PM a O.OOO153247 O.O121025 84.1 S2.9 40.6 618 225236 PM a RDM18 RNA binding motif protein O.OOO153692 O.O121151 104.6 1424 40.8 18 619 239285 PM a O.OOO1542O4 O.O121151 260.6 1842 59.7 620 239409 PM a O.OOO154229 O.O121151 694.8 433.8 443.4 621 213860 PM x at CSNK1A1 casein kinase 1, alpha 1 O.OOO154641 O.O121151 679.8 796.3 765.4 622 215600 PM X at FBXW12 F-box and WD repeat O.OOO154649 O.O121151 449.4 342.1 375.4 domain containing 12 623 234043 PM a O.OOO15SS23 O.O12164 16.1 11.7 11.8 624 238214 PM a LRRC69 leucine rich repeat O.OOO157072 O.O122546 85.9 62.5 59.4 containing 69 625 243170 PM a O.OOO1571.84 O.O122546 869.6 SOS.9 573.4 US 2017/O 137885 A1 May 18, 2017 42

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 626 241906 PM at O.OOO158212 O.O12315 315.8 1828 218.3 627 217713 PM X at O.OOO1590SS O.O123617 132.7 106.6 120.4 628 213404 PM S at RHEB Ras homolog enriched in O.OOO1596.25 0.01.23757 216.5 277.O 267.3 brain 629 1563130 PM a at - O.OOO159754. O.O123757 1298 89.9 95.1 630 213936 PM X at SFTPB surfactant protein B O.OOO16064 O.O124057 69.3 56.9 57.5 631 222380 PM S at PDCD6 Programmed cell death 6 O.OOO16065 O.O124057 244.5 160.8 1660 632 222313 PM at OOOO16118 OO124269 284.8 214.1 218.2 633 232420 PM X at LOC10O289341 Similar to hCG2022304 O.OOO162106 O.O12472 86.6 68.9 77.8 634 225,041 PM at MPHOSPH8 M-phase phosphoprotein 8 O.OOO162277 O.O12472 826.1 647.9 621.4 635 243559 PM at O.OOO163991 O.O12S745 23.6 6.6 16.1 636 201218 PM at CTBP2 C-terminal binding protein 2 O.OOO1641.26 O.O12S745 475.6 S89.0 644.6 637 244292 PM at O.OOO164428 O.O125778 107.0 69.3 60.4 638 232874 PM at DOCK9 dedicator of cytokinesis 9 O.OOO1653S O.O12628S 31.3 9.1 15.3 639 1565886 PM at O.OOO165997 O.O126581 151.6 99.6 94.8 640 208873 PM S at REEP5 receptor accessory protein O.OOO166895 O.O127067 449.8 656.5 674.1 5 641 242077 PM X at C6orf150 chromosome 6 open O.OOO167363 O.O12722S 1009.1 819.5 869.4 reading frame 150 642 214722 PM at NOTCH2NL notch 2 N-terminal like O.OOO1681O2 O.O127587 1850.6 1351.S 1425.5 643 1558O14 PM S at FAR fatty acyl CoA reductase 1 O.OOO169744 0.012845S 4.1.8 79.3 73.2 644 1563204 PM at ZNF627 Zinc finger protein 627 O.OOO169773 0.012845S 1O.S O.6 12.2 645 204181 PM S at ZBTB43 Zinc finger and BTB O.OOO170738 0.0128985 146.3 112.8 105.2 domain containing 43 646 241491 PM a O.OOO171717 O.O129524 25.9 8.5 18.7 647 206965 PM a KLF12 Kruppel-like factor 12 O.OOO173O42 O.O13O322 72.3 46.6 37.1 648. 1562364 PM at GVIN1 GTPase, very large O.OOO1746O4 O.O131295 43.6 29.8 27.8 interferon inducible 1 649 217810 PM X at LARS leucyl-tRNA synthetase O.OOO17SS17 O.O131.68 324.3 259.5 248.2 650 225890 PM a C20orf72 chromosome 20 open O.OOO175656 O.O131.68 91.3 269.4 253.2 reading frame 72 651 241041 PM a O.OOO176O27 O.O131755 68.1 70.3 79.7 652 226261 PM a ZNRF2 Zinc and ring finger 2 O.OOO176915 O.O132217 34.7 48.9 49.9 653 24O134 PM a O.OOO177936 O.O132776 45.1 82.6 89.0 654 213593 PM S at TRA2A transformer 2 alpha O.OOO1788OS O.O133221 1349.1 958.0 977.3 homolog (Drosophila) 655 244845 PM a O.OOO179762 O.O133567 283.3 150.4 159.3 656 236558 PM a O.OOO1798.18 O.O133567 68.5 97.3 92.2 657 239387 PM a O.OOO18O312 O.O13373 89.7 59.2 68.7 658 215378 PM a OOOO181169 O.O1341.61 79.3 46.5 53.2 659 204516 PM a ATXN7 ataxin 7 O.OOO181726 O.O13437 948.O 736.1 700.4 660 242337 PM a O.OOO183073 O.O13S161 53.1 102.2 105.5 661 1557707 PM at O.OOO1837 S O.O13S45S 71.2 S4.3 543 662 241065 PM X at CMAS Cytidine monophosphate O.OOO187162 0.01372OS 46.0 117.7 124.7 N-acetylneuraminic acid synthetase 663 1557814 PM a at - O.OOO18742 0.01372OS 53.0 95.7 119.2 664 1559249 PM at ATXN1 ataxin 1 O.OOO187463 0.01372OS 35.3 79.7 78.1 665 236474 PM at O.OOO187832 O.O1372OS 39.1 26.0 26.2 666 234762 PM X at NLN neurolysin O.OOO187929 O.O1372OS 416.0 322.3 333.7 (metallopeptidase M3 amily) 667 215529 PM x at DIP2A DIP2 disco-interacting O.OOO18854 0.01372OS 3.59.6 290.1 291.0 protein 2 homolog A (Drosophila) 668 208648 PM at VCP valosin-containing protein O.OOO1886.35 0.01372OS 264.7 1940 1924 669 225612 PM S at B3GNTS UDP-GlcNAc: beta Gal beta- O.OOO18864 O.O1372OS 155.2 206.5 290.7 1,3-N- acetylglucosaminyltransferase 5 670 234758 PM at O.OOO1888O3 0.01372OS 15.8 12.4 12.3 671 208857 PM S at PCMT1 protein-L-isoaspartate (D- O.OOO188939 O.O1372OS 532.7 785.1 766.5 aspartate) O methyltransferase 672 241438 PM at O.OOO189877 O.O137681 43.6 28.5 27.2 673 1558233 PM is at ATF1 activating transcription O.OOO192141 O.O139007 47.1 78.5 73.9 actor 1 674 240168 PM at XPO7 exportin 7 O.OOO192277 O.O139007 27.1 19.5 19.1 675 208662 PM S at TTC3 etratricopeptide repeat O.OOO192S68 O.O139011 470.2 3S4.O 31.1.1 domain 3 676 230629 PM S at EP4OO E1A binding protein p400 O.OOO192856 O.O139013 77.5 54.0 43.4 677 244610 PM X at O.OOO1949SS O.O13997 26.9 18.4 18.8 US 2017/O 137885 A1 May 18, 2017 43

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 678 229429 PM X at LOC728855 hypothetical LOC728855 O.OOO1950O3 3997 1167.6 986.3 93O.S 679 236829 PM at O.OOO195045 3997 1990 138.3 1436 68O 222326 PM at O.OOO196O28 40277 7O6.2 438.5 470.9 681 1556442 PM X at O.OOO196049 40277 333.7 272.2 2834 682 1569477 PM at O.OOO197297 40963 1208 59.0 S8.9 683 244046 PM at URGCP upregulator of cell O.OOO198236 41427 108.0 76.3 66.7 proliferation 684 1567044 PM S at O.OOO1987O3 41SS3 209.9 146.6 1594 685 1566491 PM at O.OOO1998.75 4.191 11.5 9.4 9.6 686 1559097 PM at C14Orf64 chromosome 14 open O.OOO199963 4.191 61.3 42.7 25.5 reading frame 64 687 1565079 PM at RPS16P5 ribosomal protein 516 O.OOO2OOO78 4.191 705.1 416.1 477.2 pseudogene 5 688 202710 PM at BET1 blocked early in transport OOOO2O1418 42653 91.6 1403 137.2 1 homolog (S. cerevisiae) 689 220071 PM X at HAUS2 HAUS augmin-like O.OOO2O1879 42772 2624 219.6 221.5 complex, Subunit 2 690 239274 PM at 43368 600.6 31 O.S 341.3 691 231927 PM at ATF6 activating transcription 44979 1920 140.O 146.2 factor 6 692 242361 PM at IMMT Inner membrane protein, O.OOO2099.17 47813 29.0 23.7 21.6 mitochondrial (mitofilin) 693 236368 PM at KIAAO368 KIAAO368 O.OOO210329 47889 93.7 59.9 62.1 694 241737 PM X at OOOO211224 48,304 S.O.3 35.9 33.5 695 235213 PM at ITPKB Inositol 14,5- O.OOO212S38 49012 224.7 157.1 139.1 trisphosphate 3-kinase B 696 1562280 PM at O.OOO213758 49652 43.1 26.7 27.3 697 236715 PM X at UACA uveal autoantigen with OOOO214698 50095 311.8 251.4 282.5 coiled-coil domains and ankyrin repeats 698 242558 PM at O.OOO215749 SO613 620.4 465.6 453.1 699 225957 PM at open O.OOO216336 50799 2095.9 1538.8 1569.1 reading frame 41 700 242494 PM at O.OOO216773 50799 28.0 18.8 19.4 701 1557238 PM S at OOOO216944 50799 59.0 41.6 41.6 702 200969 PM at SERP1 stress-associated O.OOO217306 SO836 236.0 362.5 361.3 protein 1 703 234033 PM at O.OOO218357 5135 2014 97.1 111.1 704 1556567 PM at NAP 1L4 nucleosome assembly O.OOO218709 51378 137.9 111.7 109.3 protein 1-like 4 705 244332 PM at O.OOO219503 51712 21.9 1S.O 17.2 706 201297 PM S at MOB KL1B MOB1, Mps One Binder O.OOO220874 52444 361.7 467.5 482.8 kinase activator-like 1B (yeast) 707 202511 PM s at ATGS ATG5 autophagy related 5 O.OOO2.21384 5258 92.5 138.8 132.5 homolog (S. cerevisiae) 708 240759 PM at O.OOO223975 54147 245.6 150.7 1444 709 200970 PM S at SERP 1 stress-associated O.OOO225987 SSO94 473.6 677.3 597.2 endoplasmic reticulum protein 1 710 1559687 PM at TMEM221 transmembrane protein O.OOO225987 SSO94 14.4 13.0 15.1 221 711 21O124 PM x at SEMA4F Sema domain, O.OOO227139 55.665 18.3 14.7 15.1 immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmi 712 202838 PM at FUCA1 fucosidase, alpha-L-1, O.OOO227972 335.3 478.9 SO9.8 tissue 713 222697 PM S at ABHD10 abhydrolase domain 33.7 S1.1 SO.2 containing 10 714 215067 PM X at PRDX2 peroxiredoxin 2 O.OOO229843 O.O156857 222.6 1804 172.9 715 232030 PM at KIAA1632 KIAA1632 O.OOO231SOS O.O157696 146.0 87.O 88.2 716 1556818 PM at O.OOO231721 O.O157696 256.0 175.5 1698 717 213684 PM S at PDLIMS PDZ and LIM domain 5 O.OOO233554 O.O1586.67 45.4 33.0 33.3 718 229268 PM at FAM1 OSB family with sequence O.OOO233799 O.O1586.67 109.1 80.0 8S.O similarity 105, member B 719 241223 PM x at O.OOO23.9453 O.O162279 97.7 75.5 834 720 1560259 PM at OOOO24O266 O.O162603 82.2 53.8 40.2 721 213473 PM at BRAP BRCA1 associated protein OOOO241741 O.O163375 474.O 4046 393.7 US 2017/O 137885 A1 May 18, 2017 44

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 722 221626 PM at ZNF506 Zinc finger protein 506 O.OOO242376 O.O163577 6S.O 46.8 47.9 723 233834 PM at O.OOO243937 O.O164403 126.5 7O.O 73.5 724 206792 PM x at PDE4C phosphodiesterase 4C, O.OOO245.343 O.O165122 484.6 390.8 415.9 cAMP-specific 725 24.1751 PM at OFD1 oral-facial-digital O.OOO246523 O.O165687 213.3 1342 138.4 syndrome 1 726 219695 PM at SMPD3 sphingomyelin O.OOO249284 O.O167312 13.0 12.O 17.6 phosphodiesterase 3, neutral membrane (neutral sphingomyelinase II) 727 2.32215 PM X at PRR11 proline rich 11 O.OOO2SO89 0.016795S S60.9 438.6 461.7 728 1569484 PM S at MDN1 MDN1, midasin homolog O.OOO2SO931 O.O16795S 19.2 12.8 12.9 (yeast) 729 243303 PM at O.OOO2S3404 O.O169377 255.0 170.9 1826 730 225697 PM at CDK12 cyclin-dependent kinase O.OOO2S3787 0.01694O1 256.4 204.5 211.2 12 731 1568.702 PM a at PAAF1 proteasomal ATPase- O.OOO2S533 0.01701.98 20.3 15.9 15.6 associated factor 1 732 225435 PM at SSR1 signal sequence receptor, O.OOO255878 O.O17033 234.7 1596 143.3 alpha 733 220969 PM S at O.OOO2S792 O.O17145S 84.5 55.9 53.7 734 232909 PM S at BPTF bromodomain PHD finger O.OOO260807 O.O173O36 394.O 315.2 313.4 transcription factor 735 230415 PM at O.OOO2610O8 O.O173O36 227.1 144.1 1343 736 241724 PM x at O.OOO264391 O.O17SO4 3O4 25.9 27.5 737 244061 PM at O.OOO265286 0.017539S 1448.2 941.9 1 O2S.S 738 239496 PM at O.OOO268384 O.O1772O3 66.1 49.8 47.6 739 240367 PM at O.OOO271372 O.O178933 18.6 15.2 14.7 740 240969 PM at O.OOO272419 0.0179381 22.1 16.6 16.O 741 244539 PM at O.OOO278311 O.O183013 256.0 173.7 154.7 742 1565913 PM at O.OOO280S3 O.O184224 116.1 60.3 69.1 743. 23.9545 PM at O.OOO281028 O.O1843O2 157.3 109.5 102.4 744 228590 PM at PTCD3 Pentatricopeptide repeat O.OOO281 682 0.0184332 167.3 129.6 109.1 domain 3 745 204038 PM S at LPAR1 lysophosphatidic acid O.OOO2823 19 O.O184332 11.6 13.0 16.O receptor 1 746 242146 PM at SNRPA1 Small nuclear O.OOO282356 O.O184332 1344 91.6 84.9 ribonucleoprotein polypeptide A 747 207654 PM X at DR1 down-regulator of O.OOO282S87 O.O184332 153.3 207.5 204.O transcription 1, TBP binding (negative cofactor 2) 748 213254 PM at TNRC6B trinucleotide repeat O.OOO285688 O.O185887 278.5 2146 213.3 containing 6B 749 1568,867 PM X at - O.OOO28.6168 0.0185887 11.3 9.4 9.1 750 240315 PM at O.OOO286463 0.0185887 67.1 48.5 44.3 751 224740 PM at CSOrf23 chromosome 5 open O.OOO286497 O.O185687 114.1 197.5 163.1 reading frame 43 752 235340 PM at GANC glucosidase, alpha; neutral O.OOO28733 O.O185987 9.4 8.1 9.3 C 753 226432 PM at ETNK1 ethanolamine kinase 1 O.OOO287446 0.0185987 58.4 111.9 97.8 754. 236462 PM at O.OOO287796 O.O18S987 45.8 32.3 31.5 755 232396 PM at O.OOO288551 O.O186228 611.0 4044 427.0 756 208185 PM x at O.OOO288946 0.0186236 24.9 19.3 20.3 757 241786 PM at O.OOO290S29 O.O187009 332.1 222.1 2S6.O 758 208286 PM X at POUSF1 POU class 5 homeobox 1 O.OOO294645 O.O188949 34.0 27.1 27.8 POUSF1B POU class 5 homeobox POUSF1P3 1B POU class 5 POUSF1P4 homeobox. 1 pseudogen 759 23.8350 PM at UBN2 ubinuclein 2 O.OOO2946.83 0.0188949 159.5 129.5 127.9 760 239451 PM at O.OOO294.888 O.O188949 63.5 46.9 48.3 761. 236930 PM at NUMB Numb homolog O.OOO29S483 0.0188949 387.S. 234.O 261.8 (Drosophila) 762 242268 PM at CELF2 CUGBP, Elav-like family O.OOO295958 O.O18894.9 1646.3 1171.9 1088.1 member 2 763 1556461 PM at O.OOO2961-54 O.O188949 27.6 17.7 15.6 764. 1560492 PM at O.OOO2962S6 O.O188949 27.0 19.7 2O2 765 227277 PM at MTDH metadherin O.OOO296841 O.O189074 167.6 134.6 123.8

US 2017/O 137885 A1 May 18, 2017 46

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 816 208097 PM S at TMX1 thioredoxin-related O.OOO346672 0.0207013 63.6 127.7 102.5 transmembrane protein 1 817 215268 PM at KIAAO754 KIAAO754 O.OOO3S3336 0.0210734 71.5 52.3 SO.4 818 217703 PM X at O.OOO36O795 O.O21492 55.9 48.0 49.6 819 238076 PM at GATAD2B GATA Zinc finger domain O.OOO362252 O.O21 S506. 296.9 221.6 231.6 containing 2B 820 22.3168 PM at RHOU ras homolog , O.OOO362992 O.O21 S506 128.2 217.8 211.7 member U 821 232814 PM X at C14orf153 Chromosome 14 open O.OOO363106 00215506 353.7 278.7 295.3 reading frame 153 822 244.185 PM at O.OOO366343 O.0217163 12O6 86.2 813 823 222489 PM S at WRNIP1 Werner helicase OOOO368949 O.O218442 119.2 158.8 143.9 interacting protein 1 824. 231825 PM X at ATF7IP activating transcription O.OOO370872 O.O219314 735.8 SS6.6 S65.4 factor 7 interacting protein 825 1556277 PM a at - O.OOO371726 O.O219553 332.1 97.4 223.8 826 211040 PM X at GTSE1 G-2 and S-phase O.OOO37274 0.021962 279.4 225.3 246.5 expressed 1 827 242225 PM a O.OOO373261 O.O21962 67.4 10.8 114.7 828 211559 PM S at CCNG2 cyclin G2 O.OOO37337 S O.O21962 72.3 S2.3 134.6 829 217331 PM a O.OOO373643 O.O21962 16.7 14.5 14.O 830 239234 PM a O.OOO378O38 0.0221936 233.6 47.9 150.2 831 235926 PM a O.OOO378.499 O.O221939 65.9 12.1 104.9 832 23O868 PM a O.OOO382228 O.O223843 17.2 83.3 82.9 833 244878 PM a O.OOO38266S O.O223843 46.5 29.9 28.0 834 233940 PM a O.OOO383892 O.O224291 39.0 3O.S 26.9 835 2360O2 PM a O.OOO387199 O.O225953 55.0 04.4 96.6 836 237330 PM a O.OOO388717 O.O226,567 4044 224.4 219.3 837 225793 PM a LIX1L, Lix1 homolog (mouse)-like O.OOO3924.46 0.0228467 485.3 425.6 383.2 838 240216 PM a O.OOO395157 0.022961 46.6 32.5 30.2 839 23.187 PM at C16orf53 chromosome 16 open O.OOO39576 O.O22961 81.8 44.8 146.6 reading frame 53 840 234649 PM a O.OOO395823 O.O22961 78.5 51.7 49.3 841 242074 PM a O.OOO397651 O.O23O396 45.7 13.1 99.5 842 231109 PM a O.OOO3994.17 O.O231145 778.5 455.6 469.9 843 239923 PM a O.OOO4OO186 0.023.1315 61S.S 352.9 368.1 844 201180 PM S at GNAI3 guanine nucleotide O.OOO404234 0.0233378. 830.7 1001.7 978.1 binding protein (G protein), alpha inhibiting activity polypeptide 3 845 202040 PM S at KDMSA lysine (K)-specific O.OOO405437 O.O233796 824.0 646.3 703.7 demethylase 5A 846 239969 PM at O.OOO4O6037 O.O23386S 89.6 62.7 62.6 847 228180 PM at O.OOO408895 O.O23SO42 202.3 158.S 146.2 848 232134 PM at O.OOO4O9046 0.0235042 121.3 96.1 88.1 849 1570.192 PM at O.OOO4101.78 O.O23S174 222.3 110.7 140.9 850 223547 PM at JKAMP JNK1 MAPK8-associated O.OOO41024 O.O23S174 57.3 84.1 82.3 membrane protein 851 228456 PM S at CDS2 CDP-diacylglycerol O.OOO412O23 O.O235756 473.4 361.8 388.5 LOC149832 synthase (phosphatidate cytidylyltransferase) 2 fif hypothetical pro 852 1561167 PM at O.OOO412223 O.O235756 318.7 1746 1803 853 237456 PM at O.OOO413833 0.0236399 197.6 102.4 107.6 854 215203 PM at GOLGA4 golgin A4 O.OOO415851 0.0237274 33.5 26.6 27.5 855 244473 PM at O.OOO417637 O.O23785 24.6 19.7 17.8 856 217745 PM S at NAASO N(alpha)-acetyltransferase O.OOO417837 O.O23785 342.9 454.8 420.4 50, NatE catalytic subunit 857 232096 PM X at OOOO423244 O.O24O647 132.7 93.5 97.3 858 2363.67 PM at SMG7 Smg-7 homolog, nonsense OOOO426413 O.O242038 60.3 43.6 39.9 mediated mRNA decay factor (C. elegans) 859 219099 PM at C12Orfs chromosome 12 open OOOO426684 O.O242038 143.5 195.8 1915 reading frame 5 860 239614 PM X at O.OOO428523 O.O242599 83.0 6.3.3 57.2 861 1565598 PM at O.OOO42946S O.O242599 219.4 108.9 116.5 862 244548 PM at O.OOO429SS2 O.O242599 989.0 S28.6 SSO.3 863 222133 PM S at PHF2OL1 PHD finger protein 20-like O.OOO42966S O.O242599 344.9 246.8 263.9 1 US 2017/O 137885 A1 May 18, 2017 47

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 864. 206095 PM S at SRSF10 serinefarginine-rich O.OOO43O876 O.O243OO1 169.2 26O.S 244.5 spiking factor 10 865 243325 PM at GSTK1 Glutathione S- O.OOO432321 O.O243534 48.8 34.7 36.0 kappa 1 866 32099 PM at SAFEB2 scaffold attachment factor O.OOO433362 O.O243839 252.4 1831 2O3.6 B2 867 1570200 PM at HELEB helicase (DNA) B OOOO434885 O.O244413 78.9 6O2 S2.9 868 238651 PM a O.OOO436948 0.024529 298.S. 217.3 217.3 869 236617 PM a O.OOO43989 O.0246657 18.3 12.2 13.4 870 240148 PM a MSH6 MutS homolog 6 (E. coli) O.OOO440S64 O.O246751 26.4 21.5 21.6 871 202874 PM S at ATP6V1C1 ATPase, H+ transporting, O.OOO441569 O.O24703 180.5 283.6 242.1 lysosomal 42 kDa, V1 subunit C1 872 225313 PM a C20orf177 chromosome 20 open O.OOO44279 0.0247389 212.6 288.7 286.2 reading frame 177 873 2371.89 PM a LOC10OSO6360 hypothetical O.OOO443225 O.O247389 3O.S 18.9 18.4 LOC10OSO 6360 874. 243691 PM a OOOO444048 O.O247564 30.8 21.6 24.6 875 209684 PM a RIN2 Ras and Rab Interactor 2 OOOO444718 O.O247648 136.4 227.4 238.7 876 244078 PM a O.OOO44521S O.O247648 35.5 26.5 25.4 877 240939 PM X at OOOO448669 O.O249274 29.4 21.3 21.6 878 239131 PM a OOOO4491.61 O.O249274 29.5 2O2 17.8 879 1560199 PM x at LOC728153 similar to FAM133B OOOO44992 O.O24.9411 4OO.O 271.5 281.7 protein 880 24O108 PM a O.OOO451383 0.0249938 167.6 119.5 119.7 881 239674 PM a O.OOO453OS O.O2SOS75 17.3 14.7 14.3 882 214948 PM S at TMF1 TATA element modulatory O.OOO454991 O.O2S1364 517.2 389.8 389.4 factor 1 883 234260 PM a O.OOO4S5932 O.O2S1599 105.2 74.3 73.8 884 1556925 PM at SMC3 Structural maintenance of O.OOO4590O8 O.O2S301 14.0 11.7 11.9 3 885 1558922 PM at O.OOO460623 O.O2S3613 116.9 86.3 78.3 886 215504 PM X at O.OOO4626SS O.O2S4445 705.6 S814 6O7.1 887 224986 PM S at PDPK1 3-phosphoinositide O.OOO464SSS O.O2SS2O1 313.O 372.9 393.7 dependent protein kinase 1 888 214100 PM x at NSUNSP1 NOP2/Sun domain family, O.OOO466365 0.02554.46 217.7 195.5 155.9 member 5 pseudogene 1 889 243458 PM at O.OOO467592 O.O2554.46 44.9 31.2 31.0 890 1558135 PM at TAF11 TAF11 RNA polymerase II, O.OOO46.7741 O.O2554.46 105.9 72.9 80.8 TATA box binding protein (TBP)-associated factor, 28 kDa 891. 211947 PM S at BAT2L2 HLA-B associated O.OOO467783 0.02554.46 394.8 277.9 283.8 transcript 2-like 2 892 24.4622 PM at BRWD1 Bromodomain and WD O.OOO468257 0.02554.46 44.1 32.7 32.9 repeat domain containing 1 893 233836 PM at TNRC6A trinucleotide repeat O.OOO46938 0.02554.46 19.5 15.2 15.5 containing 6A 894 1555.303 PM at O.OOO469387 O.O2554.46 1413 79.5 85.0 895 227026 PM at MPHOSPH8 M-phase phosphoprotein O.OOO469724 O.O2554.46 318.7 234.3 248.6 8 896 244607 PM at O.OOO469836 O.O2554.46 43.4 30.9 33.0 897 227905 PM S at AZI2 5-azacytidine induced 2 O.OOO470243 O.O2554.46 24.6 37.2 30.8 898 243300 PM at O.OOO472394 O.O2S6052 15.4 11.8 12.8 899 241891 PM at O.OOO472887 O.O2S6052 1177.4 796.8 777.5 900 222514 PM at RRAGC Ras-related GTP binding C O.OOO472935, O.O2S6052 6O7.8 722.1 6911 901 2196.58 PM at PTCD2 pentatricopeptide repeat O.OOO47383 O.O2S6252 618 52.7 44.8 domain 2 902 215092 PM s at NFAT5 nuclear factor of activated O.OOO474S41 O.O2S6352 205.3 133.5 151.1 T-cells 5, tonicity responsive 903 207078 PM at MED6 mediator complex subunit O.OOO47S119 O.O2S6S58 58.5 4.1.8 39.4 6 904 230608 PM at C1orf182 chromosome 1 open 0.00047.8577 0.025796 17.0 15.9 18.8 reading frame 182 905 1559101 PM at FYN FYN oncogene related to O.OOO48OO4S O.O2S8276 306.8 224.5 1849 SRC, FGR, YES US 2017/O 137885 A1 May 18, 2017 48

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR TX Gene p-value p-value Mean Mean Mean Probeset Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal

906 1562O59 PM at O.OOO480222 125.5 76.2 87.5 907 206233 PM a B4GALT6 UDP-Gal: betaGlcNAc beta O.OOO48.2556 9.9 11.3 11.9 1,4-, polypeptide 6 908 239571 PM a O.OOO484875 O.O26OOS3 352.5 248.8 249.2 909 1558469 PM at LPP LIM domain containing O.OOO48.5128 O.O26OOS3 17.7 14.0 12.8 preferred translocation partner in lipoma 2333O8 PM a COPB1 Coatomer protein O.00048,641 O.0260266 99.9 68.6 74.7 complex, Subunit beta 1 9 1 207499 PM x at UNC45A unc-45 homolog A O.OOO48.6594 O.0260266 23.4 19.1 20.4 (C. elegans) 241240 PM a O.OOO48833S O.0260911 245.3 151.5 1786 215604 O.OOO491.675 O.O262191 386.7 3O8.8 333.0 1568866 PM at OOOO491806 O.O262191 46.1 36.8 37.0 243801 PM x at OOOO494418 O.O26329S 38.4 31.2 31.7 224963 PM a SLC26A2 solute carrier family 26 OOOO4964.42 O.O264084 886 94.3 64.O (sulfate transporter), member 2 223289 PM S at USP38 ubiquitin specific O.OOO497818 O.O26432S 88.8 121.2 112.3 peptidase 38 226843 PM S at PAPD5 PAP associated domain OOOO498428 O.O26432S 449.5 361.7 348.9 containing 5 228471 PM a ANKRD44 ankyrin repeat domain 44 O.OOO498876 O.O26432S 2457.5 1972.3 2043.1 237588 PM a OOOO4.99064 O.O26432S 198.7 112.0 101.2 237185 PM a O.OOOSO1862 O.02654.42 106.8 41.3 58.3 1556416 PM S. at O.OOOSO2263 O.02654.42 49.8 39.0 35.8 239926 PM a O.OOOSOS191. O.O266645 82.1 45.7 55.2 231794 PM a CTLA4 cytotoxic T-lymphocyte O.OOOSOS633 O.O266645 13.8 13.0 11.5 associated protein 4 925 225366 PM a phosphoglucomutase 2 99.2 146.5 151.2 926 15577O6 PM at Zinc fingers and 38.1 24.1 25.8 2 927 1557 278 PM S. at TNPO1 Transportin 1 O.OOOS1016 O.O267982 SO.6 37.7 35.2 928 212907 PM a SLC30A1 solute carrier family 30 0.0005105.75 O.O267982 279.7 452.7 41.3.3 (Zinc transporter), member 1 929 228866 PM a O.OOOS1121 O.O267982 123.7 79.6 76.7 930 200047 PM S at YY1 transcription factor O.OOOS11468 O.O267982 947.2 1166.O 1192.6 931 214405 PM a O.OOOS12O36 O.O267991 378.5 258.8 245.1 932 204344 PM S at SEC23A Sec23 homolog A O.OOOS13855 O.O2686SS 18.8 25.8 22.9 (S. cerevisiae) 933 215592 PM a O.OOOS18172 O.O270383 99.2 6S.O 61.2 934 219947 PM a CLEC4A C-type lectin domain O.OOOS18808 O.O270383 908.1 1191.3 12O2.9 family 4, member A 935 209095 PM a DLD dihydrolipoamide O.OOOS18826 O.O270383 3.18.4 4431 4003 dehydrogenase 936 215888 PM a PDSSB PDS5, regulator of O.OOOS22684 O.O272103 137.4 96.3 92.6 cohesion maintenance, homolog B (S. cerevisiae) 937 206235 PM a LIG4 ligase IV, DNA, ATP O.O273436 15.7 21.8 19.5 dependent 938 222235 PM S at CSGALNACT2 chondroitin sulfater 0.0273925 309.6 499.7 460.3 N-acetytgalatosaminyltransferase 2 939 226587 PM at SNRPN Small nuclear 0.000528757 74.2 41.9 36.9 ribonucleoprotein polypeptide N 940 1556033 PM at FLJ39739 hypothetical FLJ39739 O.OOOS28966 229.2 2O5.4 172.5 941 218669 PM at RAP2C RAP2C, member of RAS O.OOOS32546 317.5 474.9 457.3 oncogene family 942 232190 PM x at LOC10O133445 hypothetical O.OOOS34373 O.O276416 33.7 28.3 LOC115110 LOC10O133445 hypothetical LOC115110 943 212921 PM at SMYD2 SET and MYND domain O.OOOS3853S O.O278274 54.8 41.5 34.4 containing 2 944 232266 PM x at CDK13 Cyclin-dependent kinase 0.000539275 O.O278.361 960.9 730.O 8O3.7 13 945 219027 PM S at myosin XA O.OOOS44917 57.5 46.0 47.1 946 1S60332 PM at O.OOOS4SS15 21.5 14.2 17.6 947 24O165 PM at O.OOOS46311 231.0 148.7 172.7 US 2017/O 137885 A1 May 18, 2017 49

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 948 231205 PM at O.OOOS46629 O.O28O839 440.9 251.8 278.3 949 241060 PM X at O.OOOS46958 0.028O839 29.1 20.6 17.6 950 226975 PM at RNPC3 RNA-binding region (RNP1, O.OOOS48452 O.O281.31 660.2 526.7 538.6 RRM) containing 3 951 226419 PM S at FLJ44342 hypothetical LOC645,460 O.OOOSS2685 0.02829 291.7 1954 218.9 952 203261 PM at DCTN6 dynactin 6 O.OOOSS2713 O.O2829 106.4 155.4 155.1 953 224990 PM at C4Orf34 chromosome 4 open O.OOOSS3439 O.O282974 129.9 172.5 1789 reading frame 34 954 227393 PM at ANO9 anoctamin 9 O.OOOSS4704 O.O283323 17.4 14.9 13.3 955 233099 PM at O.OOOSS6499 0.0283496 13.0 10.3 10.7 956 1559663 PM at O.OOOSS6916 0.0283496 36.6 21.5 23.0 957 203077 PM s at SMAD2 SMAD family member 2 O.OOOSS7342 0.0283496 109.8 133.3 139.1 958 232347 PM X at O.OOOSS7372 0.0283496 149.6 112.3 117.7 959 1559136 PM s at LOC100272228 hypothetical O.OOOSS7951 0.0283496 10.9 1O.S 9.5 LOC100272228 960 239333 PM X at GSTK1 glutathione S-transferase O.OOOS6OSO1 O.O284.495 225.0 175.7 187.6 kappa 1 961 244777 PM at DCP2 DCP2 decapping enzyme O.OOOS61209 O.O284S58 818.1 604.5 698.2 homolog (S. cerevisiae) 962 237953 PM at O.OOOS64728 O.O286O45 24.5 16.1 13.3 963 211084 PM X at PRKD3 protein kinase D3 O.OOOS6S658 0.0286218 44.2 35.8 34.1 964. 218012 PM at TSPYL2 TSPY-like 2 O.OOOSTO721 0.0288481 19.3 16.4 14.8 965 243646 PM at O.OOOS/2724 O.O2891.93 31.7 24.4 22.1 966 214594 PM X at ATP8B1 ATPase, O.OOOS/7893 O.O291,079 133.5 93.2 101.8 aminophospholipid transporter, class I, type SB, member 1 967 243216 PM X at O.OOOST8007 O.O291,079 125.1 103.4 101.7 968 221523 PM S at RRAGD Ras-related GTP binding D O.OOOS/82S1 O.O291,079 128.2 2O5.9 1911 969 1558.877 PM at O.OOOS/912S O.O291218 177.8 89.7 95.9 970 200071 PM at SMNDC1 Survival motor neuron O.OOOS82434 O.O292484 S63.2 694.7 713.O domain containing 1 971. 204681 PM S at RAPGEFS Rap guanine nucleotide O.OOOS82843 O.O292484 9.3 9.6 11.3 exchange factor (GEF) 5 972 239721 PM at O.OOOS844S1 O.O2928.39 143.4 96.3 95.6 973 217102 PM at LOC10O28.7076 Similar to malignancy- O.OOOS85345 O.O2928.39 10.7 9.3 9.9 associated protein 974. 215232 PM at ARHGAP44 Rho GTPase activating O.OOOS853S3 O.O2928.39 12.7 11.1 13.1 protein 44 975 232340 PM at LOC38.8889 hypothetical LOC388.889 O.OOOS89789 O.O294389 69.9 55.0 48.8 976 244358 PM at O.OOOS89852 O.O294389 304.7 149.5 155.6 977 226833 PM at CYB5D1 cytochrome b5 domain O.OOOS9026S O.O294389 21.1 16.7 16.5 containing 1 978 234731 PM at O.OOOS91523 O.O294.715 801.1 622.O 673.2 979 2391.63 PM at UBE2B ubiquitin-conjugating O.OOOS93286 O.O295292 442.8 263.6 337.4 enzyme E2B (RAD6 homolog) 980 242735 PM X at ELF2 E74-like factor 2 (ets O.OOOS96326 O.O296SO2 207.9 156.9 168.0 domain transcription factor) 981 234621 PM at O.OOOS99272 O.O297358 18.9 12.7 13.6 982 242031 PM at O.OOOS994O1 O.O297358 55.6 42.O 32.3 983 235647 PM at AP4S1 Adaptor-related protein O.OOOS99879 0.0297358 66.O 49.9 48.6 complex 4, sigma 1 Subunit 984 2228.70 PM S at B3GNT2 UDP-GlcNAc: beta Gal beta- O.OOO6O1513 O.O297865 115.6 176.2 1940 1,3-N- acetylglucosaminyltransferase 2 985 220546 PM at MLL myeloid/lymphoid or O.OOO602412 O.O298.007 88.2 69.7 61.7 mixed-lineage leukemia (trithorax homolog, Drosophila) 986 2.14052 PM X at BAT2L2 HLA-B associated O.OOO6O3S16 O.O298251 78.2 55.7 57.5 transcript 2-like 2 987 230590 PM at O.OOO60448S O.O2983O3 4745 243.9 242.2 988 218404 PM at SNX10 Sorting nexin 10 O.OOO6051.46 O.O298.303 975.9 1292.9 1317.3 989 236755 PM at O.OOO605459 O.O298.303 81.1 57.7 62.3 990 1560171 PM at O.OOO6O7629 O.O299 78.4 64.9 SO.2 991 242374 PM at O.OOO6081 O.O299 105.3 744 69.9 992 201435 PM S at EIF4E eukaryotic translation O.OOO60956S O.O29922 1311 1928 172.8 initiation factor 4E US 2017/O 137885 A1 May 18, 2017 50

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 993 218627 PM at DRAM1 DNA-damage regulated O.OOO60977S O.O29922 117.1 152.4 1844 autophagy modulator 1 994 1560552 PM a at - O.OOO612413 O.O3OO212 23.0 16.5 15.4 995 216187 PM X at O.OOO613591 O.O3OO487 1334.9 1072.4 1127.7 996 234753 PM X at O.OOO61778S O.O3O2237 17.6 13.7 15.4 997 232556 PM at OOOO623426 O.O3O4281 32.8 24.8 23.5 998 214705 PM at INADL InaD-like (Drosophila) OOOO624089 O.O3O4281 27.6 18.1 16.2 999 207112 PM S at GAB1 GRB2-associated binding O.OOO6241.39 O.O3O4281 11.9 13.5 14.0 protein 1 000 223886 PM S at RNF146 ring finger protein 146 OOOOS24461 O.O3O4281 469.8 S81.7 633.1 OO1 225117 PM at KIAA1267 KIAA1267 O.OOO629473 O.O30596S 708.1 567.5 592.4 002 227268 PM at RNFT1 ring finger protein, O.OOOS3O131 O.O30596S 1OOO 1628 165.7 transmembrane 1 OO3 235328 PM at PLXNC1 Plexin C1 O.OOO63O3S4 O.O30596S 27.6 20.9 19.8 004 222103 PM at ATF1 activating transcription O.OOO63O428 O.O30596S 1216 2033 1971 factor 1 005 235084 PM X at O.OOOS31188 O.O.306029 680.3 S21.1 S48.9 006 200056 PM S at C1D C1D nuclear receptor O.OOO633O3 O.O.306.617 383.0 SO19 499.8 corepressor 007 218178 PM S at CHMP1B chromatin modifying O.OOO63573 O.O3O7619 413.1 622.1 593.8 protein 18 008 201876 PM a PON2 paraOXonase 2 O.OOO642O18 O.O31 O3S3 64.4 83.3 103.8 009 227412 PM a PPP1R3E protein phosphatese 1, O.OOO643748 O.O310881 42.O 31.4 27.0 regulatory (inhibitor) subunit 3E 010 1560680 PM at O.OOO647985 0.0312507 27.6 24.2 21.1 011 226712 PM a SSR1 signal sequence receptor, O.OOO648398 0.0312507 146.7 108.2 101.4 alpha 012 220843 PM S at DCAF13 DDB1 and CUL4 associated O.OOO6491 08 0.031254 14.9 12.4 11.O factor 13 013 243808 PM a O.OOO652146 O.O313693 42.7 31.9 26.9 014 218738 PM S at RNF138 ring finger protein 138 O.OOO6SS843 O.O31516 346.9 514.4 498.2 O15 204185 PM X at PPID peptidylprolyl D O.OOO65830S 0.0316032 235.6 29O.S 285.7 O16 241081 PM a O.OOO660309 O.O316682 19.2 14.2 13.5 O17 242851 PM a KIAA1919 KIAA1919 O.OOO661733 O.O.316927 43.6 31.9 32.3 018 209066 PM X at UQCRB ubiquinol-cytochrome c O.OOO662121 O.O.316927 17O.O 360.1 345.4 reductase binding protein O19 238970 PM a O.OOO664525 O.O317609 155.2 114.4 96.2 02O 216197 PM a ATF7IP activating transcription O.OOO664849 O.O317609 1434 109.2 98.8 factor 7 interacting protein O21 221834 PM a LONP2 Lon peptidase 2, O.OOO666.186 O.O.317936 451.8 354.8 312.9 peroxisomal 022 219876 PM S at GOLGA2B golgin A2 family, member O.OOO669S47 O.O319227 12.9 10.7 11.9 B O23 1556568 PM a at - O.OOO671247 O.O319431 107.8 74.O 74.O 024 215269 PM a TRAPPC10 trafficking protein particle O.OOO671285 0.0319431 259.6 180.1 1804 complex 10 O25 24.0568 PM a O.OOO674356 O.O32O579 23.8 17.8 13.6 026 236437 PM a O.OOO678439 O.O322206 1546 89.5 113.1 027 240690 PM a O.OOO67947 O.O322269 102.0 59.2 58.4 O28 242505 PM a O.OOO680O31 O.O322269 30.2 22.9 22.5 029 210711 PM a NCRNA00260 non-protein coding RNA O.OOO680577 O.O322269 89.5 63.5 51.5 260 O30 229491 PM a NHEDC2 Na+ H+ exchanger domain O.OOO681217 O.O322269 21.2 18.7 15.6 containing 2 O31 241997 PM a O.OOO687S 66 O.O.324957 1402 105.5 97.8 O32 1563509 PM at O.OOO693415 O.O326067. 1276.9 893.8 849.1 033 203693 PM S at transcription factor 3 O.OOO694O69 O.O326067 129.9 171.1 1790 O34 203594 PM a RTCD1 RNA terminal phosphate O.OOO694477 O.O326067 149.6 205.7 170.5 cyclase domain 1 O35 229398 PM a RAB18 RAB18, member RAS O.OOO694934 O.O326067 414.7 289.6 309.1 oncogene family O36 218465 PM a TMEM33 transmembrane protein O.OOO69S471 O.O326067 77.1 113.0 13 O.S 33 O37 236155 PM a ZCCHC6 Zinc finger, CCHC domain O.OOO69S476 O.O326067 1242.2 877.5 826.6 containing 6 O38 2095.10 PM a RNF139 ring finger protein 139 O.OOO695929 O.O326067 3874 514.6 4814 O39 1564443 PM at DLEU2 Deleted in lymphocytic O.OOO6968O2 O.O326067 20.6 14.3 14.7 leukemia 2 (non-protein coding) US 2017/O 137885 A1 May 18, 2017 51

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 040 208137 PM X at ZNF611 Zinc finger protein 611 O.OOO697333 O.O326067 75.5 58.4 59.9 041 234148 PM a O.OOO697378 O.O326067 24.2 18.6 17.1 042 243064 PM a O.OOO697497 O.O326067 44.8 31.5 33.5 043 201730 PM S at TPR translocated O.OOO697945 O.O326067 759.5 569.8 580.7 region (to activated MET Oncogene) 044 2396.29 PM a CFLAR CASPB and FADD-like O.OOO699042 O.O3262S6 1603.S 1034.2 1151.O apoptosis regulator 04.5 242320 PM a O.OOO7O1964 O.O327287 327.6 186.6 1913 046 230229 PM a DLG1 Discs, large homolog 1 O.OOO702654. O.O327287 1626 1348 11O.S (Drosophila) O47 225997 PM a MOBKL1A MOB1, Mps One Binder O.OOO703244 O.O327287 86.8 151.6 1SO.O kinase activator-like 1A (yeast) 048 239724 PM a O.OOO7O3974 O.O327314 423 28.3 30.1 049 236160 PM a TRIP11 thyroid O.OOO7O6422 O.O327917 67.5 49.3 45.3 interactor 11 O50 236386 PM a LOC10OSO6SO1 hypothetical O.OOO706617 O.O327917 81.6 57.5 59.8 LOC10OSO6SO1 051 231896 PM S at DENR density-regulated protein O.OOO70898 O.O328.701 279.2 383.3 376.1 O52 203159 PM a GLS 0.000712753 0.03.29977 271.6 224.4 196.8 O53 225400 PM a TSEN15 tRNA splicing 0.000713875 0.03.29977 25.4 36.7 28.3 endonuclease 15 homolog (S. cerevisiae) 054 212234 PM a ASXL1 additional sex combs like 1 O.OOO71392 O.O329977 55.3 47.0 41.6 (Drosophila) 055 237337 PM a O.OOO714441 O.O329977 59.0 43.2 42.O O56 217534 PM a FAM49B family with sequence O.OOO717444 0.0331009 138.0 82.9 86.4 similarity 49, member B 057 238,544 PM a O.OOO71842 0.0331009 724 39.7 35.5 O58 233430 PM a TBC1D22B TBC1 domain family, O.OOO718714 O.O331009 28.4 22.4 19.9 member 22B 059 221155 PM X at O.OOO722OOS 0.0332211 62.O 46.7 52.O O6O 244233 PM a C18orf10 chromosome 18 open O.OOO723209 O.O332264 17.8 14.4 14.9 reading frame 10 O61 1558711 PM at FAM13AOS FAM13A opposite strand O.OOO723485 0.0332264 SS8.S. 363.4 368.1 (non-protein coding) 062 202714 PM s at KIAAO391 KIAAO391 O.OOO730644 0.033.5236 13.5 12.3 11.1 O63 1565703 PM at SMAD4 SMAD family member 4 O.OOO733O37 O.O335891 43.4 30.8 28.9 064. 216000 PM a O.OOO733449 O.O335891 33.8 28.8 24.2 O65 225651 PM a UBE2E2 ubiquitin-conjugating O.OOO73S351 O.O336446 178.7 226.O 265.1 enzyme E2E 2 (UBC4/5 homolog, yeast) 066 209566 PM a INSIG2 insulin induced gene 2 O.OOO737382 O.O336959 51.0 88.7 79.6 067 234135 PM X at O.OOO737857 0.0336959 51.0 S1.9 54.6 O68 212908 PM a DNAJC16 DnaJ (Hsp40) homolog, O.OOO74O783 O.O337979 225.1 1882 173.3 Subfamily C, member 16 O69 212158 PM a SDC2 Syndecan 2 O.OOO741594 O.O.338O32 20.7 2O.S 34.6 O70 242652 PM a O.OOO743OS 0.0338277 13.5 11.6 11.6 O71 24.0478 PM a O.OOO743S2 O.O.338277 176.2 1292 132.6 O72 44790 PM S at C13orf18 chromosome 13 open O.OOO744289 0.0338311 452.2 473.1 696.4 reading frame 18 O73 233270 PM x at O.OOO746251 O.O.338887 83.1 61.5 62.7 074 239740 PM a ETV6 ets variant 6 O.OOO7S3532 O.O341875 97.5 60.9 66.4 O75 215588 PM x at RIOK3 RIOkinase 3 (yeast) O.OOO754615 O.O342O48 473.9 368.9 409.2 O76 202536 PM a CHMP2B chromatin modifying O.OOO7SS843 O.O342286 111.7 1634 167.2 protein 2B 077 243963 PM a SDCCAG8 Serologically defined colon O.OOO758,246 O.O34298 234.5 183.6 179.2 cancer antigen 8 O78 222378 PM a O.OOO758.784 O.O34298 39.0 22.5 24.9 O79 215553 PM x at OOOO760604 O.O343484 21.9 17.8 18.8 O80 239651 PM a ANAPCS anaphase promoting O.OOO7629O3 O.O3442O3 27.5 20.7 21.2 complex subunit 5 O81 1562528 PM at O.OOO764376 O.O344549 97.0 67.3 41.5 O82 239748 PM x at OCLAD1 OCIA domain containing 1 O.OOO766272 O.O345084 930.4 716.6 775.3 O83 238595 PM a O.OOO771117 O.O346946 269.3 167.7 171.4 O84 240465 PM a C4Orf32 chromosome 4 open O.OOO7729 O.O347427 2O.O 15.6 15.2 reading frame 32 O85 236327 PM a O.OOO7736S1 O.O347444 157.1 119.1 121.3 086 243410 PM a O.OOO774723 O.O347605 70.9 55.2 50.7 O87 232588 PM a STAG1 stromal antigen 1 O.OOO776932 O.O348.276 55.5 40.O 36.5 US 2017/O 137885 A1 May 18, 2017 52

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 088 242457 PM at O.OOO779275 O.O3490OS 137.5 64.9 58.7 O89 207953 PM at O.OOO78O244 0.03491.18 18.6 14.9 14.7 O90 215287 PM at LOC10O288939 Similar to hCG1987955 O.OOO782993 O.O3SOO27 238.6 180.7 179.6 O91 1560794 PM at O.OOO787684 O.O3S1801 13.2 10.4 11.3 O92 232565 PM at 0.000790598. O.O352779 36.6 28.1 25.2 093 222169 PM X at SH2D3A SH2 domain containing 3A O.OOO793,064 O.O3S3556 14.2 12.6 11.8 O94 244868 PM at O.OOO7942S2 O.O3S3762 33.5 22.8 22.1 095 201311 PM S at SH3BGRL SH3 domain binding O.OOO797O82 O.O3S4698 830.9 1084.3 1071.6 glutamic acid-rich protein like O96 1568.815 PM a at DDX50 DEAD (Asp-Glu-Ala-Asp) O.OOO798O4 O.O3S48 122.3 86.7 91.9 box polypeptide 50 O97 227163 PM at GSTO2 glutathione S-transferase O.OOO814O76 O.O3616 14.7 12.5 13.5 Omega 2 O98 212460 PM at C14orf147 chromosome 14 open O.OOO82O682 0.03642O2 90.2 137.8 1343 reading frame 147 O99 1569053 PM at AP3M2 adaptor-related protein O.OOO82218 O.O364535 20.4 17.2 16.8 complex 3, mu 2 subunit OO 2424.07 PM at OOOO82641 0.0365795 537.1 400.3 365.6 O1 239946 PM at O.OOO826524 O.O.365795 317.5 187.7 1889 O2 215070 PM X at RABGAP1 RAB GTPase activating O.OOO827856 O.O366052 11.5 9.7 10.3 protein 1 O3 233884 PM at HIVEP3 human immunodeficiency O.OOO832SO4 O.O367699 31.8 25.8 18.1 virus type I enhancer binding protein 3 04 217843 PM s at MED4 mediator complex subunit O.OOO833O89 O.O367699 196.9 248.0 257.6 4 OS 238944 PM at ZNF404 Zinc finger protein 404 O.OOO835718 O.O.36852S 34.7 24.3 23.2 O6 1557688 PM at O.OOO837S7S O.O36901 546.6 3.14.2 328.6 07 23O885 PM at SPG7 spastic paraplegia 7 (pure O.OOO838.625 O.O369139 372.5 277.2 282.1 and complicated autosomal recessive) 08 221268 PM S at SGPP1 sphingosine-1-phosphate O.OOO839S43 O.O3692S3 25.1 41.9 39.5 phosphatase 1 09 244581 PM a O.OOO84432 O.O370975 29.7 22.6 21.0 10 215626 PM a O.OOO846447 O.O371575 13.3 11.3 10.4 11 218446 PM S at FAM18B1 family with sequence O.OOO848.307 O.O371994 68.2 108.6 120.4 similarity 18, member B1 12 203414 PM a MMD monocyte to macrophage O.OOO849S71 O.O371994 452.7 71.2.2 689.2 differentiation-associated 13 237218 PM a O.OOO849691. O.O371994 82.8 53.8 54.7 14 222553 PM x at OXR1 oxidation resistance 1 O.OOO85174 O.O372556 100.8 160.4 169.3 15 242824 PM a O.OOO854784 O.O373427 34.5 24.5 23.7 16 206551 PM X at KLHL24 kelch-like 24 (Drosophila) O.OOO855873 O.O373427 211.6 156.3 174.8 17 210260 PM S at TNFAIP8 tumor necrosis factor, O.OOO856O31 O.O373427 528.5 780.3 666.8 alpha-induced protein 8 18 242156 PM a O.OOO86286 O.O375636 15.8 11.6 11.5 19 244571 PM S at TTC12 Tetratricopeptide repeat O.OOO863136 O.O375636 14.5 11.4 11.2 domain 12 20 233302 PM a O.OOO8634O6 O.O375636 217.7 146.6 75.8 21 1558236 PM at O.OOO866834 0.0376791 287.5 22O.O 226.6 22 212887 PM a SEC23A Sec23 homolog A O.OOO87OO7 O.O377662 162.7 225.6 212.1 (S. cerevisiae) 23 208694 PM a PRKDC protein kinase, DNA- O.OOO87O39 O.O377662 310.8 1942 2002 activated, catalytic polypeptide 24, 239917 PM a VPS8 Vacuolar protein sorting 8 O.OOO87152 0.0377705 261.2 1740 187.7 homolog (S. cerevisiae) 25 228.645 PM a SNEHG9 Small nucleolar RNA host O.OOO872O38 0.0377705 23.9 21.1 17.5 gene 9 (non-protein coding) 26 23.6007 PM a AKAP10 A kinase (PRKA) anchor O.OOO873781. O.O3781 24 759.7 S82.O 627.1 protein 10 27 234.604 PM a O.OOO876SO4 O.O37896S 76.3 38.0 39.8 28 244290 PM a O.OOO882117 O.O38O845 21.3 1S.O 15.4 29 203983 PM a TSNAX translin-associated factor O.OOO882415 0.038O845 239.3 365.9 3745 X 30 225519 PM a PPP4R2 protein phosphatase 4, O.OOO885487 0.0380901 2S8.8 3704 427.5 regulatory Subunit 2 31 227766 PM a UG4 ligase IV, DNA, ATP- O.OOO88588 O.O380901 22.7 37.2 39.7 dependent US 2017/O 137885 A1 May 18, 2017 53

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 32 242646 PM at O.OOO88S928 O.O380901 249.4 1935 181.7 33 215750 PM at KIAA1659 KIAA1659 protein O.OOO886213 O.O380901 21.6 16.9 15.5 34 225222 PM at HLAT1 hippocampus abundant O.OOO8868O1 O.O380901 479.9 S84.O 600.6 transcript 1 35 240238 PM at O.OOO887234 0.0380901 116.7 78.0 73.5 36 243876 PM at O.OOO889423 O.O381SOS 23.3 18.7 17.0 37 216263 PM s at NGDN neuroguidin, EIF4E binding O.OOO890647 O.O381694 25.4 20.3 18.6 protein 38 215330 PM at O.OOO895O74 O.O383.06 43.2 27.1 23.7 39 1561720 PM at RECQL5 RecQ protein-like 5 O.OOO8954O7 O.O383.06 15.4 12.6 12.4 40 232583 PM at O.OOO897151 O.O383382 247.3 1647 142.8 41 1558996 PM at FOXP1 orkhead box P1 O.OOO897734 O.O383382 243.0 177.1 166.9 42 215615 PM X at O.OOO900021 O.O384022 14.7 12.6 13.6 43 238800 PM S at ZCCHC6 Zinc finger, CCHC domain O.OOO901O4S O.O3841.23 561.9 379.1 373.7 containing 6 44 217856 PM at RBM8A RNA binding motif protein O.OOO902O61 O.O38422 240.2 196.3 196.1 8A 45 208370 PM S at RCAN 1 regulator of calcineurin 1 O.OOO904627 O.O384976 56.1 81.4 72.8 46 222262 PM S at ETNK1 ethanolamine kinase 1 O.OOO905546 O.O38SO31 34.9 47.7 SO.2 47 224870 PM at KIAAO114 KIAAO114 O.OOO910077 O.O38.662 132.2 114.3 77.9 48 244490 PM at O.OOO914O68 O.O387977 17.0 15.1 12.5 49 233223 PM at O.OOO916204 0.0388545 229.8 126.8 132.5 50 241294 PM at O.OOO917347 O.O38.8566 78.9 57.4 53.2 51 237119 PM at O.OOO917848 0.0388S 66 275.7 172.7 157.4 52 54.632 PM at THADA thyroid adenoma O.OOO918721 0.0388S98 65.8 S4.9 46.8 associated 53 215151 PM at DOCK10 dedicator of cytokinesis 10 O.OOO919627 O.O388644 68.3 52.4 43.4 54 222719 PM S at PDGFC platelet derived growth O.OOO923078 O.O38.9764 1O.O 11.9 12.8 factor C 55 231890 PM at O.OOO9299.08 O.O3923O8 91.O 61.5 63.0 56 1560706 PM at O.OOO934795 O.O394O27 813.7 489.7 487.1 57 1562236 PM at MYST4 MYST histone O.OOO935599 O.O394O27 16.7 14.7 13.4 acetyltransferase (monocytic leukemia) 4 58 37079 PM at NUS1P3 nuclear undecaprenyl O.OOO9369S4 O.O394257 9.2 10.9 10.2 pyrophosphate synthase 1 homolog (S. cerevisiae) pseudogene 3 59 24.1331 PM a SKAP2 Src kinase associated O.OOO937938 O.O39433 24.9 16.4 22.9 phosphoprotein 2 60 2091.87 PM a DR1 down-regulator of O.O3O939306 0.039456S 334-6 S22.1 505.2 transcription 1, TBP binding (negative cofactor 2) 61 2281.81 PM a SLC30A1 solute carrier family 30 O.OOO940396 O.O394683 27.7 39.3 38.1 (Zinc transporter), member 1 62 226901 PM a C17orf58 chromosome 17 open O.OOO942438 O.O395199 19.8 26.8 25.8 reading frame 58 63 39313 PM at WNK1 WNK lysine deficient O.OOO944928 O.O395903 113.9 8O.S 75.3 protein kinase 1 64 242279 PM a O.OOO947662 O.O396562 124.3 86.5 82.8 65 2231.34 PM a BBX bobby Sox homolog O.OOO9481.29 O.O396562 S94.6 470.1 457.6 (Drosophila) 66 204738 PM S at KRIT1 KRIT1, ankyrin repeat O.OOO950724 O.O39.7306 41.2 41.2 34.O containing 67 233914 PM S at SBF2 SET binding factor 2 O.OOO95246 O.O397369 221.5 144.0 159.3 68 2394.49 PM at O.OOO952SO4 O.O397369 37.2 22.9 23.0 69 1561166 PM a at - O.OOO9567S7 O.O398802 30.6 21.5 21.2 70 235786 PM at O.OOO963166 0.04.0113 228.1 176.8 16S.S 71 1568986 PM x at PIGT phosphatidylinositol O.OOO967O31 O.O4O2396 22.7 18.0 19.7 glycan anchor biosynthesis, class T 72 233800 PM at O.OOO969773 0.0403.192 207.8 148.8 142.8 73 208663 PM S at TTC3 tetratricopeptide repeat O.OOO9774.41 O.O405812 4S4S 378.8 313.8 domain 3 74 1556646 PM at O.OOO97774 0.04.05812 104.7 78.1 73.O 75 213852 PM at RBM8A RNA binding motif protein O.OOO9786.67 O.O405851 408.4 313.7 313.5 US 2017/O 137885 A1 May 18, 2017 54

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 76 210145 PM at PLA2G4A phospholipase A2, group O.OOO984.729 O.O408018 SO.8 84.4 84.4 IVA (cytosolic, calcium dependent) 77 225770 pM at RSPRY1 ring finger and SPRY O.OOO98857S O.O408945 233.6 2O3.8 1933 domain containing 1 78 234981 PM X at CMBL carboxymethylenebutenolidase O.OOO988861 O.O40894S 1572.4 1302.O 1387.2 homolog (Pseudomonas) 79 235444 PM at FOXP1 forkhead box P1 O.OOO990226 O.O408945 426.6 299.7 316.1 80 218595 PM S at HEATR1 HEAT repeat containing 1 O.OOO990634 0.0408945 131.9 97.8 101.0 81 242874 PM at O.OOO991162 O.O408945 32.6 23.7 18.1 82 228315 PM at ZMAT3 Zinc finger, matrin-type 3 O.OOO992797 0.04O9273 651.6 S38.8 S16.1 83 215757 PM at PRKDC Protein kinase, DNA- O.OOO998OO1 O.O41107 29.5 15.8 17.5 activated, catalytic polypeptide 84 215597 PM X at O.OO1 OO129 O.O412O77 13.8 11.9 12.2 85 1555842 PM at CYTH2 cytohesin 2 O.OO10O876 O.O4148 15.2 12.0 12.1 86 1556.305 PM at O.0010118 O.O4157 4004 248.7 281.5 87 1569597 PM at O.OO1O1421 O.O416339 53.3 47.0 34.4 88 232614 PM at O.00101542 (0.0416485 1342 69.5 48.3 89 206821 PM X at AGFG2 Arf6AP with FG repeats 2 O.OO101641 O.O41654 11.O 11.1 12.4 90 229078 PM S at KIAA1704 if KIAA1704 i? hypothetical O.OO10206S O.O417784 128.1 106.6 89.3 LOC100507773 LOC100507773 91 1559822 PM S at MTDH metadherin O.OO102116 O.O417784 135.0 117.7 99.5 92 206567 PM S at PHF2O PHD finger protein 20 O.OO102394 O.O41857 379.0 287.3 287.7 93 218496 PM at RNASEH1 ribonuclease H1 O.OO102602 O.O419069 100.7 86.O 68.6 94 214917 PM at PRKAA1 protein kinase, AMP- O.OO10283 O.041.964.8 148.0 103.7 1054 activated, alpha 1 catalytic Subunit 95 215063 PM X at LRRC40 leucine rich repeat O.OO 103399 0.0421379 415.2 351.3 361.9 containing 40 96 217982 PM S at MORF4L1 mortality factor 4 like 1 O.OO 103427 O.0421379 2083.6 2398.1 2340.4 97 201769 PM a CLINT1 clathrin interactor 1 O.OO 103627 O.O421841 427.8 S69.7 594.9 98 244687 PM a DBT dihydrolipoamide O.OO 103809 O.0422064 49.O 41.3 34.O branched chain transacylase E2 99 221264 PM S at TARDBP TAR DNA binding protein O.OO 103855 0.0422064 4O6.9 328.6 302.5 200 241242 PM a O.OO104186 0.04230S6 1984 130.9 143.4 201 215310 PM a APC adenomatous polyposis O.OO104337 O.0423316 227.1 157.6 168.5 coil 202 238231 PM a NFYC Nuclear transcription O.OO104517 O.0423427 98.2 66.4 62.2 factor Y. gamma 203 238863 PM x at O.OO104538 0.0423427 20.3 16.7 17.3 204 1561310 PM at O.OO10478 O.0424054 10.7 9.4 10.1 205 2.38560 PM a CALCOCO2 calcium binding and O.OO 10503 O.O424713 146.3 944 98.3 coiled-coil domain 2 206 243546 PM a O.OO 105.358 0.042S687 95.8 69.2 64.2 207 244674 PM a O.OO 105727 O.O426823 33.6 22.0 23.0 208 236321 PM a FAM2OOB family with sequence O.OO 105871 O.O427051 75.1 108.0 114.6 similarity 200, member B 209 203628 PM a IGF1R insulin-like growth factor 1 O.OO106O19 O.O427294 442.5 240.2 246.7 receptor 210 244312 PM a O.OO106163 O.O4276O2 414.4 295.2 313.4 211 215589 PM a O.OO10636 O.O427784 15.4 12.4 11.4 212 203283 PM S at HS2ST1 heparan sulfate 2-O- O.OO1064O4 O.O427784 46.3 55.0 61.5 Sulfotransferase 1 213 217873 PM a CAB39 calcium binding protein 39 O.OO106547 O.O42788 901.3 1106.4 1107.1 214 243423 PM a O.OO106721 O.O42788 115.9 86.4 73.8 215 218195 PM a C6orf211 chromosome 6 open O.OO106818 O.O42788 1938 286.2 2.78.4 reading frame 211 216 216751 PM a O.OO106819 O.O42788 19.1 15.7 15.7 217 226119 PM a PCMTD1 protein-L-isoaspartate (D- O.OO106929 O.O42788 363.2 622.9 612.1 aspartate) O methyltransferase domain containing 1 218 240621 PM a O.OO10696 O.O42788 21.6 18.0 18.0 219 236610 PM a O.OO107052 O.O42788 43.8 30.3 26.5 220 1555446 PM S at TRAPPC10 trafficking protein particle O.OO107.184 O.O42788 270.7 178.4 175.9 complex 10 221 238468 PM a TNRC6B trinucleotide repeat O.OO107218 O.O42788 494.2 355.2 363.6 containing 6B US 2017/O 137885 A1 May 18, 2017 55

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 222 222699 PM S at PLEKHF2 pleckstrin homology O7435 O.04281.28 69.9 110.8 101.8 domain containing, family F (with FYVE domain) member 2 223 233193 PM X at INTS4 integrator complex O7456 O.04281.28 13.9 11.9 12.5 subunit 4 224 227270 PM at FAM2OOB family with sequence O.0431514 64.3 91.5 106.1 similarity 200, member B 225 217653 PM X at O8483 O.0431514 47.2 37.5 39.9 226 212126 PM at CBXS chromobox homolog 5 O8729 O.043214 156.4 112.9 124.7 227 240326 PM at O8962 O.O43238S 1823 103.5 119.O 228 232307 PM at O8968 O.O43238S 113.5 64.6 59.1 229 239232 PM at MSI2 Musashi homolog 2 O9848 O.O435522 39.6 28.7 28.2 (Drosophila) 230 1552343 PM S at PDE7A phosphodiesterase 7A 09961 O.O435615 51.0 35.9 35.9 231 1557553 PM at PPP1R12B protein phosphatase 1, O324 O.0436698 182.7 94.7 102.2 regulatory (inhibitor) subunit 12B 232 236814 PM at MDM4 Mdm2. binding protein 0.559 O.O437273 1429.5 1127.2 1112.4 homolog (mouse) 233 234428 PM at O.O437389 13.1 1O.O 1O.S 234 222640 PM at DNA(cytosine-5-)- O.O437741 93.3 73.9 71.7 methyltransferase 3 alpha 235 212027 PM at RNA binding motif protein O.OO 16S O.O440516 702.5 556.5 S4O.7 25 236 210561 PM S at WSB1 WD repeat and SOC5 box 1899 O.O441141 991.O 1310.4 1331.4 containing 1 237 1570O89 PM at 224 O.O441774 24.2 20.6 18.8 238 241913 PM at 2241 O.O441774 56.1 35.6 34.1 239 202194 PM at TMED5 transmembrane emp24 2677 705.1 1045.9 972.3 protein transport domain containing 5 240 207630 PM S at CREM cAMP responsive element 2709 28.1 37.5 39.2 modulator 241 237839 PM a 3444 26.4 15.7 13.6 242 226276 PM a TMEM167A transmembrane protein 3S46 426.3 579.1 594.3 167A 243 234609 PM a 4012 23.3 16.4 16.3 244 1570210 PM X at PPP6R2 protein phosphatase 6, 4O73 37.7 28.3 27.6 regulatory Subunit 2 245 232628 PM a 4327 O.O447326 334.1 2O2.5 202.2 246 203921 PM a CHST2 carbohydrate (N- 4386 O.O447326 235.8 301.3 363.2 acetylglucosamine-6-O) Sulfotransferase 2 247 225700 PM a GLCCI1 glucocorticoid induced 4929 O.O449089 39.4 29.6 27.0 transcript 1 248 222589 PM a NLK nemo-like kinase 5377 O.O4498.44 118.3 159.O 1603 249 235894 PM a 5378 O.O4498.44 117.3 86.7 98.0 250 241993 PM X at 5399 O.O4498.44 389.1 290.4 301S 251 233473 PM X at SS84 974.O 689.3 713.7 252 224984 PM a NFAT5 nuclear factor of activated 6222 857.3 694.2 743.5 T-cells 5, tonicity responsive 253 1570531 PM at 6466 12.4 1O.S 12.O 2S4 234326 PM a 656 337.1 1948 209.7 255 222444 PM a ARMCX3 armadillo repeat 6672 24.2 32.1 37.0 containing, X-linked 3 243792 PM X at PTPN13 Protein tyrosine 703 O.0454.022 19.1 15.6 16.6 phosphatase, non receptor type 13 (APO 1/CD95 (Fas)-associated phospha 1257 205202 PM at PCMT1 protein-L-isoaspartate (D- O.OO117229 O.045443.3 SO9.3 727.1 742.4 aspartate) O methyltransferase 1258 243739 PM at O.OO117713 62.6 40.9 40.3 1259 215000 PM S at FEZ2 fasciculation and O.OO118371 286.2 368.4 385.7 elongation protein zeta 2 (Zygin II) 12SO 1569815 PM X at STRN striatin, calmodulin 28.4 19.4 2O.O binding protein US 2017/O 137885 A1 May 18, 2017 56

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 261 207365 PM X at USP34 ubiquitin specific 1908 258.2 201.7 2O6.2 peptidase 34 262 205849 PM S at UQCRB ubiquinol-cytochrome c 1916.2 1514 304.8 294.7 reductase binding protein 263 210743 PM S at CDC14A CDC14 cell division cycle 194OS O.0460669 21.4 17.3 14.7 14 homolog A (S. cerevisiae) 264 237180 PM a PSME4 Proteasome (prosome, 19818 O.O461896 133.8 95.9 109.5 macropain) activator subunit 4 26S 206056 PM X at SPN sialophorin 2OOS3 422.4 352.8 366.3 2S6 234159 PM a 20174 82.6 57.7 55.6 267 224104 PM a 2O531 9.8 9.7 11.1 268 219694 PM a FAM1OSA family with sequence 2O711 123.2 175.8 167.3 similarity 105, member A 269 237184 PM a 209 O.0464218 26.6 2O2 19.7 270 204011 PM a SPRY2 sprouty homolog 2 21023 O.0464218 11.O 14.5 13.6 (Drosophila) 271 218303 PM X at KRCC1 lysine-rich coiled-coil 1 21087 O.0464218 165.2 258.0 2S3.6 272 1559391 PM S at 21924 O.0467059 740.8 414.6 457.1 273 225837 PM a C12Orf32 chromosome 12 open 22486 O.0468.451 36.3 53.4 40.6 reading frame 32 274 232469 PM X at C1orf191 chromosome 1 open 2259 O.0468.451 92.0 77.4 71.O reading frame 191 275 237216 PM a 22711 O.0468.451 23.5 17.6 17.0 276 1559282 PM at 22737 O.0468.451 28.0 21.0 21.3 277 1554148 PM a at solute carrier family 33 22768 O.0468.451 14.7 20.1 16.8 (acetyl-CoA transporter), member 1 278 228793 PM a jumonji domain containing 1C 22969 O.O468593 994.7 644.1 725.0 279 242611 PM a 23041 O.O468593 16.4 13.4 13.5 28O 230086 PM a ormin binding protein 1 23107 O.O468593 18.6 1S.O 14.5 281 215212 PM a 2319 O.O468593 122.8 79.5 79.0 282 23.0099 PM a 23347 O.O468824 370.8 2750 2S1.1 283 232555 PM a CAMP responsive element 24O92 O.O471288 1517.2 924.2 1042.4 binding protein 5 284 241036 PM a 24392 224.0 169.5 158.1 285 230270 PM a PRP38 pre-mRNA 24844 806.4 593.9 635.5 processing factor 38 (yeast) domain containing B 286 235730 PM a 25167 O.0474262 239.8 1743 1928 287 234423 PM x at 2S281 O.O47432S 280.4 230.9 229.0 288 224751 PM a PL-5283 PL-5283 protein 25969 O.O47656 617.3 876.2 848.8 289 241368 PM a PLINS perilipin 5 26593 O.O478549 123.5 84.5 136.3 290 232284 PM a PSMD6 Proteasome (prosome, 2684 O.O4791.11 1982 124.3 1236 macropain) 26S Subunit, non-ATPase, 6 291 233909 PM a 27099 O.O479718 12.7 10.8 10.8 292 213164 PM a solute carrier family 5 27396 O.0480466 613.O 462.3 491.5 (sodium/myo-inositol cotransporter), member 3 293 1553644 PM at chromosome 14 open 27584 O.0480603 1O.S 10.1 11.7 reading frame 49 294 24.1750 PM X at 27776 O.O4.81155 109.8 72.7 81.1 295 1560926 PM at 27908 O.048.128 249.4 159.7 191.7 296 1559589 PM a at 285.15 O.O4831.51 28.9 21.7 22.7 297 237626 PM at 29452 O.0486.338 295.5 211.O 216.1 298 226353 PM at SPPL2A peptidase 30512 O.04899.43 789.5 991.8 943.1 like 2A 299 211277 PM x at APP amyloid beta (A4) 3O823 O.O490732 24.3 21.9 21.7 precursor protein 1569450 PM at CAP2A2 capping protein (actin 31042 O.O49.1176 30.2 21.4 23.8 filament) muscle Z-line, alpha 2 301 225600 PM at chromosome 8 open 31519 59.8 94.1 96.O reading frame 83 206154 PM at RLBP1 retinaldehyde binding 31658 O.0492727 12.5 11.O 12.4 protein 1 303 1561633 PM at HMGA2 high mobility group AT 323.18 O.O494817 12.7 11.4 10.8 hook 2 US 2017/O 137885 A1 May 18, 2017 57

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 1304 207436 PM X at KIAAO894 KIAAO894 protein O.OO132539 O.O495263 3S4.6 306.9 318.7 1305 1557350 PM at G3BP1 GTPase activating protein O.OO132688 O.O49544 44.8 32.4 29.4 (SH3 domain) binding protein 1 1306 202169 PM S at AASDHPPT aminoadipate- O.OO132799 O.O495474 178.6 260.1 242.2 semialdehyde dehydrogenase phosphopantetheinyl transferase 3.07 232210 PM at O.OO132904 O.O4954.87 391.2 221.5 144.3 308 1558691 PM a at DOCK4 dedicator of cytokinesis 4 O.OO133158 0.0496054 13.8 12.1 11.3 309 209833 PM at CRADD CASP2 and RIPK1 domain O.OO133577 O.O4967 35.8 45.8 42.O containing adaptor with death domain 310 1554963 PM at O.OO133636 O.O4967 13.8 11.1 11.8 311 234131 PM at O.OO133696 O.O4967 106.2 76.1 76.5 312 1559054 PM a at - O.OO133739 O.O4967 68.0 47.8 50.7 313 242467 PM at O.OO1340O2 O.O4969.08 280.3 218.5 215.2 314 238733 PM at O.OO134142 O.O496908 143.7 88.7 105.1 315 221808 PM at RAB9A RAB9A, member RAS O.OO134149 0.049 6908 307.4 375.4 369.8 oncogene family 316 201830 PM S at NET1 neuroepithelial cell O.OO1342O3 O.O4969.08 18.7 24.9 18.2 transforming 1 317 217016 PM X at TMEM212 transmembrane protein O.OO134421 O.O497337 18.0 14.8 17.0 212 318 212721 PM at SREK1 splicing regulatory O.OO134616 O.O497681 105.3 175.8 182.7 glutamineflysine-rich protein 1 319 224105 PM X at O.OO1348O8 O.O498O13 56.2 47.9 514 320 232978 PM at O.OO135736 O.OSO1061 27.9 24.4 19.4 321 236370 PM at O.OO136O23 O.OSO1741 40.7 30.8 28.3 322 208.246 PM X at O.OO1364S4 O.OSO295 1858.8 1458.O 1576.1 323 239701 PM at O.OO136972 O.OSO4477 2O2.0 111.2 112.8 324 224644 PM at O.OO13769 O.OSO6184 521.7 670.3 638.6 325 212408 PM at TOR1AIP1 torsin A interacting O.OO137762 O.OSO6184 1217.4 1446.6 1448.5 protein 1 326 205998 PM X at CYP3A4 cytochrome P450, family O.OO137763 O.OSO6184 21.6 18.8 2O6 3, Subfamily A, polypeptide 4 327 224416 PM S at MED28 mediator complex subunit O.OO1378S1 O.OSO6184 66.6 85.5 90.3 28 328 220694 PM at ASAP1-IT ASAP1 intronic transcript O.OO137967 O.OSO6229 3.14.9 1611 1893 (non-protein coding) 329 1556728 PM at O.OO138078 O.OSO62SS 75.9 54.2 47.9 330 236417 PM at O.OO138772 O.OSO8134 1883 1242 115.5 331 205401 PM at AGPS alkylglycerone phosphate O.OO138799 O.OSO8134 26.7 36.6 28.6 synthase 332 1561130 PM at C12Orfs1 chromosome 12 open O.OO139089 O.OSO8306 29.8 22.8 23.3 reading frame 51 333 220410 PM S at CAMSAP1 calmodulin regulated O.OO139091 O.OSO8306 21.8 16.6 16.2 spectrin-associated protein 1 334 219095 PM at JMJD7-PLA264B JMJD7-PLA2G4B O.OO139159 O.OSO830S 25.6 20.9 2O2 PLA2G4B readthrough if phospholipase A2, group IVB (cytosolic) 335 209096 PM at UBE2V2 ubiquitin-conjugating O.OO139729 O.OS1 OOO6 89.4 132.O 126.3 enzyme E2 variant 2 336 218559 PM S at MAFB v- O.OO140241 O.O511491 592.3 883.7 939.1 musculoaponeurotic fibrosarcoma oncogene homolog B (avian) 337 242793 PM at O.OO140523 O.OS12136 SO.O 32.8 31.7 338 242008 PM at O.OO140833 O.OS12S16 1505.6 1047.9 1116.4 339 228913 PM at LOC10O190939 hypothetical O.OO140855 O.OS12516 42.8 29.7 29.3 LOC10O190939 340 223336 PM S at RAB18 RAB18, member RAS O.OO140948 O.OS12516 229.6 362.7 345.9 oncogene family 341 225147 PM at CYTH3 cytohesin 3 O.OO141048 O.OS12516 32.7 36.9 45.9 342 208278 PM S at O.OO141367 O.OS13293 53.2 31.8 33.6 343 233678 PM at O.OO141576 O.OS13669 14.5 12.9 12.1 US 2017/O 137885 A1 May 18, 2017 58

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 344 244357 PM at O.OO141804 O.O514113 621.3 320.1 324.5 345 240205 PM X at O.OO141966 O.O514318 115.2 85.3 88.1 346 226493 PM at KCTD18 potassium channel O.OO142551 O.OS16054 121.5 1616 157.9 tetramerisation domain containing 18 347 216745 PM X at O.OO142692 O.OS16181 39.0 32.O 34.4 348 233.007 PM at O.OO142903 O.OS162 60.1 43.8 43.0 349 1568594 PM S at TRIMS2 tripartite motif-containing O.OO143095 O.OS162 92.5 86.8 71.2 52 350 1554564 PM a at SPPL3 signal peptide peptidase 3 O.OO143162 O.OS162 29.5 23.7 24.3 351 225210 PM s at FAM103A1 family with sequence O.OO143168 O.OS162 444.6 SOO.7 S22.9 similarity 103, member A1 352 243587 PM X at O.OO143227 O.OS162 85.5 61.O 59.5 353 1563.075 PM S at - O.OO143366 O.OS16319 678.1 437.5 494.O 354 236703 PM at NTSC2 5'-nucteotidase, cytosolic O.OO143781 O.OS17431 425.1 268.3 297.8 II 355 239227 PM at O.OO144381 O.OS19158 65.8 36.7 38.9 356 244.165 PM at C10orf18 open O.OO144474 O.OS19158 1616 97.3 90.3 reading frame 18 357 231087 PM at O.OO144663 O.O.5.19454 35.7 30.6 25.4 358 1560928 PM at LOC151657 hypothetical protein O.OO144829 O.OS19667 42.O 32.2 31.3 LOC151657 359 232031 PM S at KIAA1632 KIAA1632 O.OO145151 O.OS2O286 33.8 24.3 24.O 360 1570.108 PM at O.OO145234 O.OS2O286 33.3 24.4 24.3 361. 203883 PM S at RAB11FIP2 RAB11 family Interacting O.OO145364 O.OS2O286 433.2 330.8 343.2 protein 2 (class I) 362 230489 PM a CD5 CD5 molecule O.OO14S462 0.0520286 41.7 37.5 23.5 363 242136 PM X at MGC70870 C-terminal binding protein O.OO14SSS3 O.OS2O286 35.7 42.5 47.0 2 pseudogene 364. 235288 PM a O.OO145642 O.OS2O286 209.1 145.5 158.8 365 243016 PM a O.OO145891 O.OS2O78 26.2 19.4 17.0 366 222720 PM X at C1orf27 chromosome 1 open O.OO145994 O.OS2O78 12.3 15.7 1S.O reading frame 27 367 236607 PM a O.OO146319 O.OS2145 86.5 64.5 64.7 368 213056 PM a FRMD4B FERM domain containing O.OO146422 O.O52145 75.3 96.5 1286 4B 369 1557895 PM at FLJ35934 FLJ35934 O.OO146SO3 O.OS2145 25.2 18.1 18.2 370 218059 PM a ZNF706 Zinc finger protein 706 O.OO147057 0.0523O4 824.7 1059.4 921.0 371 2383O3 PM a STT3B STT3, subunit of the O.OO147382 O.OS23813 57.8 43.7 37.9 oligosaccharyltransferase complex, homolog B (S. cerevisiae) 372 2051.40 PM a FPGT fucose-1-phosphate O.OO147672 O.OS24307 29.9 47.3 47.5 guanylyltransferase 373 227916 PM X at EXOSC3 exosome component 3 O.OO147736 O.OS24307 219.2 27S.O 268.7 374 201973 PM s at C7orf28B if chromosome 7 open O.OO148545 O.OS26794 809.5 979.5 9014 CCZ1 reading frame 28B if CC21 vacuolar protein trafficking and biogenesi 375 209455 PM at FBXW11 F-box and WD repeat O.OO149798 O.O530851 129.5 1SO.O 146.2 domain containing 11 376 201865 PM X at NR3C1 nuclear receptor Subfamily O.OO1500O8 O.OS31209 2013.9 1715.9 1694.7 3, group C, member 1 () 377 209228 PM X at TUSC3 tumor Suppressor O.OO15O159 O.OS31358 9.4 8.9 10.1 candidate 3 378 240498 PM at O.OO15055 O.OS32708 54.8 29.9 31.3 379 230987 PM at O.OO150865 O.OS33O82 264.9 153.4 172.8 380 240626 PM at O.OO150978 O.OS3309S 15.1 12.7 12.6 381 231069 PM at O.OO15111 O.OS3313S 36.6 28.9 29.9 382 214553 PM s at ARPP19 cAMP-regulated O.OO15131 O.OS3313S 24.5 36.0 33.9 phosphoprotein, 19 kDa 383 1561060 PM at O.OO151345 O.OS3313S 11.6 9.9 10.9 384 242256 PM X at - O.OO151427 O.OS3313S 34.1 26.5 31.1 385 233017 PM x at O.OO151651 O.OS33487 1415 120.1 130.7 386 208073 PM X at TTC3 tetratricopeptide repeat O.OO151746 O.OS33487 378.1 3OO.S 254.2 domain 3 387 223.809 PM at RGS18 regulator of G-protein O.OO152O81 O.O534279 1124.9 1686.1 1664.1 signaling 18 388 236546 PM at O.OO152367 O.OS34898 15.1 12.3 13.2 389 1557300 PM S at - O.OO152S25 O.OS34991 45.8 33.1 31.9 US 2017/O 137885 A1 May 18, 2017 59

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR TX Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 390 232744 PM X at 52613 O.OS34991 147.6 89.9 84.2 391 238783 PM at TMEM161B transmembrane protein 5277 0.05351.56 158.6 125.3 119.1 161B 392 218107 PM at WDR26 WD repeat domain 26 53315 826.4 974.5 1036.8 393 1558732 PM at MAP4K4 mitogen-activated protein 53377 244.7 1544 1744 kinase kinase kinase kinase 4 394 229360 PM at ZNF28OB Zinc finger protein 28 OB 53,761 O.OS37469 15.3 12.5 12.1 395 225324 PM at CRLS1 cardiolipin synthase 1 S4301 O.OS3897 61.9 108.9 91.7 396 2098.93 PM S at FUT4 4 S4586 O.OS394OS 54.5 81.2 64.4 (alpha (1,3) fucosyltransferase, myeloid-specific) 397 1567045 PM at S4647 O.OS394OS 33.2 24.5 25.5 398 227986 PM a ZNF343 Zinc finger protein 343 S482 O.OS39622 17.5 14.0 14.8 399 239788 PM a 54997 0.05397 34.9 25.6 2SO 400 241851 PM X at hypothetical SSO64 0.05397 29.1 20.7 22.3 LOC10O130429 232375 PM a SS84 O.OS41008 468.2 2949 276.6 217346 PM a LOC10O2931.60 peptidyl-prolyl cis-trans 55947 O.OS41008 55.0 46.5 47.8 PPIA isomerase A-like if peptidylprolyl isomerase A (cyclophilin 403 226941 PM a ATF6 activating transcription 55955 O.OS41008 622.1 497.8 535.6 factor 6 404 212749 PM S at RCHY1 ring finger and CHY Zinc 55965 O.OS41008 1973 276.9 253.5 finger domain containing 1 40S 201944 PM a HEXB hexosaminidase B (beta 55995 O.OS41008 847.7 10613 1043.5 polypeptide) 4O6 1570227 PM at 56173 O.0541241 27.0 22.6 22.1 407 217152 PM a 56.614 O.OS42135 158.2 111.O 105.3 4.08 211374 PM X at S6833 O.OS42135 26.8 21.7 22.9 409 210438 PM X at TROVE2 TROVE domain family, S6842 O.OS42135 693.6 597.4 559.3 member 2 222942 PM S at TIAM2 T-cell lymphoma invasion 56876 O.OS42135 90.6 SO.1 and metastasis 2 236883 PM at 572O6 O.OS42719 205.7 153.4 1499 216006 PM at 57268 O.OS42719 1086 68.0 73.3 s 1556.359 PM at Chromosome 6 open 57408 O.OS42724 54.2 4O.S 41.7 reading frame 89 242171 PM at 57492 O.OS42724 15.5 12.6 13.4 s 236941 PM at open 57693 O.OS43003 11O.S 74.9 75.2 reading frame 30 232769 PM at 57796 O.OS43003 44.4 27.0 34.9 s 212132 PM at LSM14A LSM14A, SCD6 homolog A S8O11 O.OS43067 314.5 358.5 375.3 (S. cerevisiae) 224642 PM at FYTTD1 forty-two-three domain 58105 O.OS43067 44.2 63.9 56.4 containing 1 201312 PM S at SH3 domain binding S8149 O.OS43057 2316.5 2827.1 28SS.1 glutamic acid-rich protein like 420 228654 PM a SPIN4 spindlin family, member 4 S9134 O.OS45691 24.3 41.3 45.5 421 232580 PM X at 5921 O.OS45691 129.6 96.6 94.3 422 205175 PM X at ZNF222 Zinc finger protein 222 59338 O.OS45691 19.6 24.1 25.3 423 208866 PM a CSNK1A1 casein kinase 1, alpha 1 S94OS O.OS45691 4O16 342.0 314.O 424 218365 PM S at DARS2 aspartyl-tRNA synthetase 59473 O.OS45691 16.4 17.2 14.5 2, mitochondrial 425 236254 PM a vacuolar protein sorting O.OS47633 1169.4 933.1 958.7 13 homolog 8 (yeast) 426 244691 PM a SETD5 SET domain containing 5 60515 O.05484.86 22.0 17.4 15.7 427 1557529 PM at C12Orfs1 chromosome 12 open 6064 O.OS48529 58.8 46.9 44.1 reading frame 51 428 228454 PM a LCOR ligand dependent nuclear 61199 0.0550052 7034 514.4 559.2 receptor compressor 429 243554 PM a 61638 O.OSS1164 777 53.9 S4.3 430 221509 PM a DENR density-regulated protein 62004 O.OSS1499 219.1 296.9 302.8 431 237703 PM a 62O3 O.OSS1499 40.8 29.4 30.2 432 205994 PM a ELK4 ELX4, ETS-domain protein O.OSS1499 10.3 11.5 10.7 (SRF accessory protein 1) US 2017/O 137885 A1 May 18, 2017 60

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 433 227.046 PM at SLC39A11 solute carrier family 39 O.OO162189 O.OSS1499 624 87.O 777 (metal ion transporter), member 11 434 240527 PM at O.OO162319 O.OSS1556 71.1 52.2 S4.9 435 240154 PM at O.OO163371 O.OSS4633 1222.2 811.2 806.3 436 1564773 PM X at - O.OO1634.52 O.OSS4633 2O.O 17.0 16.3 437 232341 PM x at HABP4. hyaluronan binding O.OO163784 O.OSSS373 28.7 20.8 19.4 protein 4 438 215595 PM X at O.OO163972 O.OSSS623 29.2 23.4 25.2 439 224452 PM S at C7orf70 chromosome 7 open O.OO164229 O.OSSS72S 244.O 320.1 298.0 reading frame 70 440 243709 PM a SLC38A9 solute carrier family 38, O.OO16423 0.0555725 76.1 54.1 57.5 member 9 441 2365.92 PM a O.OO164591 O.OSS6184 119.9 56.1 57.6 442 236453 PM a O.OO164594 O.OSS6184 10.7 11.7 14.4 443 242111 PM a METTL3 methyltransferase like 3 O.OO166042 O.O56.0644 33.3 25.6 23.6 444 1560445 PM X at ARHGEF1 Rho guanine nucleotide O.OO16618 O.056.0644 93.5 71.O 75.4 exchange factor (GEF) 1 445 239175 PM a O.OO166259 O.OS 6.0644 S33.1 407.2 435.4 446 243414 PM a PPIL2 Peptidylprolyl isomerase O.OO16666 O.OS61576 36.8 31.1 27.5 (cyclophilin)-like 2 447 232659 PM a O.OO166766 0.0561576 4.1.8 27.6 27.2 448 201816 PM S at GBAS glioblastoma amplified O.OO167064 O.OS62191 322.9 439.5 389.3 Sequence 449 225332 PM a LOCA29082 Hypothetical protein O.OO16728 O.OS62S3 684.2 S69.3 S32.4 LOCA29032 450 242106 PM a O.OO167411 O.OS62S82 52.7 30.1 31.5 451. 239173 PM a INADL InaD-like (Drosophila) O.OO167659 O.OS63027 22.4 16.8 14.6 452 1562194 PM at O.OO1681.48 O.OS64239 389.6 24O.S 242.9 453 205931 PM S at CREBS cAMP responsive element O.OO16834 O.OS64239 1458.6 94.9.7 1263.1 binding protein 5 454 203347 PM S at MTF2 metal response element O.OO16846.7 O.OS64239 34.7 52.O 50.7 binding transcription factor 2 455 244181 PM a O.OO16858 O.OS64239 82.8 618 58.4 456 217586 PM X at O.OO168599 O.OS64239 23.3 18.5 19.1 457 233369 PM a O.OO168731 O.OS64293 589.3 362.9 442.4 458 22.3169 PM S at RHOU ras homolog gene family, O.OO169034 O.OS6SO86 11.3 14.8 15.3 member U 459 232796 PM a O.OO1695SS O.OS66272 15.9 12.8 12.3 460 212250 PM a MTDH metadherin O.OO169897 O.OS66921 268.8 395.3 343.4 461 227017 PM a ERICH1 glutamate-rich 1 O.OO169982 0.0566921 183.7 214.7 242.6 462. 1569730 PM at HEATRAB2 HEAT repeat family O.OO170215 O.OS6731 11.5 1O.O 10.8 member 7B2 463 240446 PM a O.OO170444 O.OS67SS1 33.7 25.2 26.O 464. 23.9892 PM a O.OO17053 0.0567551 48.7 38.8 35.8 465 240052 PM a ITPR1 Inositol 1,4,5-triphosphate O.OO170637 0.0567551 105.7 71.7 73.7 receptor, type 1 466 244100 PM a O.OO171135 0.056882 29.4 22.5 23.2 467 242608 PM X at FAM161B Family with sequence O.OO171743 O.OS 69937 603.O 486.0 517.6 similarity 161, member B 468 216022 PM a O.OO171835 O.OS 69937 16.0 13.4 12.6 469 238436 PM S at ZNF805 Zinc finger protein 805 O.OO171856 O.OS 69937 1432 124.8 102.8 470 2007S3 PM X at SRSF2 serinefarginine-rich O.OO171939 O.OS 69937 162.S 218.7 1971 spiking factor 2 471 213922 PM a TTBK2 tau tubulin kinase 2 O.OO172865 O.OS726.17 164.7 119.5 127.7 472 226729 PM a USP37 ubiquitin specific O.OO1730S6 O.OS72706 3S.O 32.9 26.6 peptidase 37 473 204483 PM a ENO3 enolase 3 (beta, muscle) O.OO173146 O.OS72706 15.3 13.5 12.9 474. 24.0260 PM a O.OO1732S8 O.OS72706 45.6 34.2 31.8 475 220720 PM X at MZT2B mitotic spindle organizing O.OO173362 O.OS72706 150.8 118.6 118.7 protein 2B 476 1562529 PM S at - O.OO173646 0.05732SS SO8.3 342.7 224.4 477 1564736 PM a at CASP12 caspase 12 O.OO173894 O.OS73685 10.3 10.3 12.O (gene pseudogene) 478 2285.16 PM at CDAN1 congenital O.OO174063 0.0573854 51.1 445 38.4 dyserythropoietic anemia, type I 479 241995 PM at DGUOK deoxyguanosine kinase O.OO174243 O.OS74059 37.8 28.6 28S 480 244594 PM X at O.OO17S136 O.OS761.59 78.1 59.4 61.6 US 2017/O 137885 A1 May 18, 2017 61

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 481. 212190 PM a SERPINE2 Serpin peptidase inhibitor, O.OO175198 0.05761.59 25.8 26.4 36.5 clade E (nexin, plasminogen activator inhibitor type 1), me 482 243474 PM a O.OO175235 0.05761.59 147.6 84.9 88.8 483 216278 PM a O.OO175491 O.OS76612 38.8 34.0 28.3 484 234118 PM a O.OO175682 0.0576836 12.4 9.6 1O.O 485 242983 PM a O.OO17S796 O.OS76836 37.0 31.1 27.2 486 213956 PM a CEP350 centrosomal protein O.OO176171 0.0577677 154.O 117.9 111.9 350 kDa 487 232626 PM a O.OO176762 0.0578856 24.1 17.2 20.6 488 23.6005 PM a O.OO176768. O.OS78856 23.9 18.0 16.5 489 222336 PM a C4Orf34 chromosome 4 open O.OO177041 O.OS7931.5 22.6 15.2 17.7 reading frame 34 490 21.3317 PM a CLICS chloride intracellular O.OO177146 0.057931.5 14.6 12.5 11.7 channel 5 491 231377 PM a CXOrf6S chromosome X open O.OO177794 O.OS80906 87.7 64.8 56.2 reading frame 65 492 215852 PM x at C20orf117 chromosome 20 open O.OO177871 O.OS80906 13.9 12.2 12.5 reading frame 117 493 239778 PM X at O.OO17819 O.OS81223 67.7 45.2 46.6 494. 242732 PM a O.OO1784.84 O.OS81223 38.6 24.2 2S.O 495 227523 PM S at PHF2OL1 PHD finger protein 20-like O.OO1784.87 O.OS81223 1104.7 904.2 90S.O 1 496 232344 PM a O.OO178515 O.OS81223 112.5 76.2 76.8 497 205438 PM a PTPN21 protein tyrosine O.OO178672 0.0581223 9.7 9.7 11.6 phosphatase, non receptor type 21 498 244208 PM a O.OO1787S6 O.OS81223 26.7 18.7 19.4 499 243860 PM a O.OO1788O3 O.OS81223 157.5 104.9 113.1 500 1561139 PM at O.OO179722 O.OS835.49 31.0 24.3 24.3 501. 231304 PM a PPP3R2 protein phosphatase 3, O.OO179758 O.OS835.49 9.5 9.1 10.6 regulatory Subunit B, beta 502 230777 PM is at PRDM15 PR domain containing 15 O.OO17995 O.0583.783 43.9 35.9 33.0 503 242664 PM a O.OO18OSO6 O.OS84844 11.6 9.9 9.6 504 233399 PM X at ZNF252 Zinc finger protein 252 O.OO180517 O.OS84844 73.9 59.8 63.5 505 1566166 PM at O.OO181697 O.OS88276 27.6 21.2 20.1 506 238,548 PM a O.OO181899 O.OS88287 20.6 15.4 16.4 507 225O16 PM a APCDD1 adenomatosis polyposis O.OO182182 0.0588.287 15.8 18.2 22.O coil down-regulated 1 508 244032 PM a O.OO182239 O.OS88287 17.7 14.9 14.6 509 202026 PM a SDHD Succinate dehydrogenase O.OO1822S6 O.OS88287 4036 505.0 S10.6 complex, Subunit D, integral membrane protein 510 232466 PM a CUL4A Cullin 4A O.OO1823O4 O.OS88287 16.7 16.3 13.3 511 221566 PM S at NOL3 nucleolar protein 3 O.OO182839 O.O589481 1O.O 10.4 11.8 (apoptosis represser with CARD domain) 512 1560342 PM at O.OO182916 0.0589481 51.7 32.7 34.1 513 240593 PM X at O.OO183593 O.OS911. 67 21.4 14.8 15.7 514 242968 PM at O.OO183682 0.05911. 67 3S4.7 260.4 265.7 515 219892 PM at TM6SF1 trans membrane 6 O.OO184024 O.O591877 295.4 4O2.3 432.6 Superfamily member 1 516. 230747 PM S at TTC39C etratricopeptide repeat O.OO18479 O.OS93924 72.8 57.6 45.9 domain 39C 517 239223 PM S at FBXL20 F-box and leucine-rich O.OO184921 O.OS93924 124.3 87.3 81.9 repeat protein 20 518 243819 PM at O.OO185026 O.OS93924 593.4 471.6 404.2 519 22.7133 PM at FAM199X amily with sequence O.OO18569 O.OS94225 120.2 146.3 158.7 similarity 199, X-linked 520 1557239 PM at BBX bobby Sox homolog O.OO185785 O.OS94225 55.9 38.2 37.6 (Drosophila) 521 23O350 PM at O.OO185917 O.OS94225 255.5 1951 1849 522 221547 PM at PRPF18 PRP18 pre-mRNA O.OO185948 O.OS94225 6S.O 88.7 82.7 processing factor 18 homolog (S. cerevisiae) 523 214101 PM S at NPEPPS Aminopeptidase O.OO186O2 O.OS94225 12O2 81.0 813 puromycin sensitive 524 221613 PM S at ZFAND6 Zinc finger, AN1-type O.OO186232 O.OS94225 479.2 S78.4 589.9 domain 6 US 2017/O 137885 A1 May 18, 2017 62

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 525 223288 PM a USP38 ubiquitin specific O.OO186358 0.0594225 1794 221.9 237.O peptidase 38 526 239258 PM a O.OO186474 O.OS94225 176.4 111.1 121.8 527 239096 PM a O.OO186551 O.OS94225 21S.O 167.5 1873 528 81811 PM at O.OO186608 O.OS94225 55.3 41.5 40.7 529 231149 PM S at ULK4 unc-51-like kinase 4 O.OO18674 O.OS94225 17.7 13.3 13.1 (C. elegans) 530 236664 PM a AKT2 V-akt murine thymoma. O.OO186813 O.OS94225 28.9 24.1 22.8 viral oncogene homolog 2 531 226322 PM a TMTC1 transmembrane and O.OO186893 O.OS94225 46.2 92.9 143.5 tetratricopeptide repeat containing 1 532 207923 PM X at PAX8 paired box. 8 O.OO186921 O.OS94225 10.9 9.3 10.3 533 244682 PM a CAMSAP1 calmodulin regulated O.OO186949 O.OS94225 13.5 10.9 11.9 spectrin-associated protein 1 534 243612 PM a NSD1 nuclear receptor binding O.OO187215 O.OS946.09 148.1 110.2 117.1 SET domain protein 1 535 23 2205 PM a O.OO187314 O.OS946.09 53.3 39.8 39.2 536 2391.86 PM a MGC39372 Serpin peptidase inhibitor, O.OO18809 O.OS96684 32.5 21.0 20.9 clade B (ovalbumin), member 9 pseudogene 537 240351 PM a O.OO188672 0.0598141 18.5 14.8 15.3 538 209363 PM S at MED21 mediator complex subunit 21 O.OO189018 0.059861 22.3 31.2 25.3 539 236216 PM a O.OO189247 O.OS9861 76.6 423 45.1 540 207730 PM x at O.OO18927 O.OS9861 S28.9 425.8 47S.O 541 210942 PM S at ST3GAL6 ST3 beta-galactoside O.OO189461 O.OS9861 77.6 113.7 1249 alpha-2,3- 6 542 203102 PM s at MGAT2 mannosyl (alpha-1,6-)- O.OO189569 O.OS9861 302.8 410.8 387.O glycoprotein beta-1,2-N- acetylglucosaminyltransferase 543 215057 PM a LOC100272228 hypothetical O.OO189599 O.OS9861 49.5 34.6 35.9 LOC100272228 544 1569871 PM at LMF1 ipase maturation factor 1 O.OO18968 O.OS9861 29.9 23.1 24.2 545 2.35990 PM a LOC10O130987 similar to hCG1815675 O.OO1901S2 O.O599711 24.4 19.1 19.4 546 222752 PM S at TMEM2O6 transmembrane protein O.OO1904O6 OO6OO124 69.6 103.3 105.9 2O6 547 242311 PM X at O.OO190812 OO600907 46.6 38.8 40.4 548 232150 PM a O.OO190901 OO600907 688.6 493.5 539.7 549 231247 PM S at LOCA2782O Hypothetical protein O.OO191175 0.06O1381 87.O 61.5 68.7 LOC72782O 550 227626 PM a PAQR8 progestin and adipoCR O.OO191435 0.0601495 171.2 132.9 117.8 receptor family member VIII 551 212449 PM s at LY PLA1 ySophospholipase 1 O.OO191734 OO601495 730.3 1021.2 965.O 552 235616 PM a TSHZ2 eashirt Zinc finger O.OO1917S1 OO601495 16.9 12.5 12.9 homeobox2 553 225445 PM a UBN2 ubinuclein 2 O.OO191834 OO601495 220.9 171.9 1866 554. 234151 PM a O.OO191915 OO60149S 1955.4 1313.1 1262.3 555 208661 PM S at TTC3 etratricopeptide repeat O.OO191952 OO601495 3.29.1 269.7 222.6 domain 3 556 242195 PM x at NUMBL numb homolog O.OO192097 OO6O1562 61O.S. 523.6 SSO.S (Drosophila)-like 557 2294.83 PM at O.OO192SO3 OO6O238 251.4 176.O 178.2 558 24.1268 PM X at O.OO192669 O.O6O238 544 45.1 46.7 559 243153 PM at CDK5RAP2 CDK5 regulatory subunit O.OO192729 OO6O238 19.2 16.9 1S.O associated protein 2 560 208.610 PM S at SRRM2 serinefarginine repetitive O.OO1930O3 OO60285 1239.8 918.2 933.7 matrix 2 561 238159 PM at O.OO1932O6 OO602852 48.9 31.9 34.6 562 204028 PM S at RABGAP1 RAB GTPase activating O.OO1932S1 OO602852 2684 228.4 239.8 protein 1 563. 219463 PM at C20orf103 chromosome 20 open O.OO19351 O.0603273 18.6 20.4 26.O reading frame 103 564. 23.0998 PM at O.OO19380S OO603S03 176.2 124.6 145.8 565 219471 PM at C13orf18 chromosome 13 open O.OO193993 OO603S03 336.4 358.O 496.3 reading frame 18 566 244434 PM at GPR82 6 protein-coupled O.OO194032 OO603S03 15.5 18.4 28.1 receptor 82 567 1564424 PM at O.OO194O79 0.06O3S03 18.0 14.4 14.5 US 2017/O 137885 A1 May 18, 2017 63

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 568 201100 PM S at USP9X ubiquitin specific O.OO194416 OO6036O3 1396.1 1129.4 1179.O peptidase 9, X-linked 569 1569409 PM x at - O.OO194437 OO603603 111.5 87.2 89.8 57O 244726 PM at O.OO194483 OO603603 253.6 152.8 152.8 571 1552370 PM at C4Orf33 chromosome 4 open O.OO195O1 O.0604854 27.3 40.9 41.9 reading frame 33 572 220113 PM X at POLR1B polymerase (RNA) I O.OO1954.33 OO605705 74.9 59.3 62.8 polypeptide 8, 128 kDa 573 226035 PM at USP31 ubiquitin specific O.OO195533 OO605705 38.0 29.3 27.7 peptidase 31 574 244019 PM at O.OO196O76 O.O606,229 SO.9 34.0 34.4 575 241686 PM X at O.OO1961.2 O.O606,229 33.2 27.5 29.5 576 220768 PM S at CSNK1 G3 casein kinase 1, gamma 3 O.OO1961.26 OO606,229 51.2 73.4 78.2 577 214241 PM at NDUFB8 NADH dehydrogenase O.OO1962 O.O606,229 102.2 85.3 72.9 (ubiquinone) 1 beta Subcomplex, 8, 19 kDa 578 216524 PM X at O.OO196509 OO606799 222.8 180.3 1983 579 215110 PM at MBL1P mannose-binding lectin O.OO1968S9 OO607495 9.7 9.2 10.4 (protein A) 1, pseudogene 580 222983 PM S at PAIP2 poly(A) binding protein O.OO1978O3 OO610O22 946.3 1132.8 1164.7 interacting protein 2 581 224.584 PM at C20orf50 chromosome 20 open O.OO198O83 OO61OS14 1214.2 1518.9 1382.1 reading frame 30 582 1555392 PM at LOC10O128868 Testin-related protein TRG O.OO198345 OO61092 196.5 140.7 1413 583 1562736 PM at LHX9 LIM homeobox 9 O.OO1994.67 0.0613988 8.3 8.3 93 584 217743 PM s at TMEM3OA transmembrane protein O.OO199593 0.0613988 434.6 564.3 616.8 3OA 585 217985 PM s at BAZ1A bromodomain adjacent to O.OO1999.06 OO614563 1612.3 1280.7 1389.1 Zinc finger domain, 1A 586 210539 PM at TTLL5 tubulin tyrosine ligase-like O.OO200268 OO615287 16.5 12.6 13.6 family, member 5 587 229364 PM at O.OO2OO899 0.0616837 68.1 48.3 42.9 588 225507 PM at SFRS1B splicing factor, O.OO2O1916 OO619569 1153.7 931.O 862.7 arginine?serine-rich 18 589 211893 PM X at CD6 CD6 molecule O.OO2O2S31 OO62O482 17.9 17.1 12.7 590 1566959 PM at O.OO2O2S47 OO62O482 1936 105.4 107.9 591 241920 PM X at SPG11 spastic paraplegia 11 O.OO2O2662 OO62O482 28.0 22.0 22.2 (autosomal recessive) 592 221071 PM at O.OO2O2821 OO62O482 38.7 29.4 29.0 593 233411 PM at O.OO2O28S O.O62O482 1930 137.8 99.2 594 1557684 PM at ZNF286A Zinc finger protein 28.6A O.OO2O3O37 OO62O664 28.6 25.6 2O.S 595 240775 PM at O.OO2O3278 O.O62O778 21.6 15.4 15.8 596 231288 PM at CCDC88C coiled-coil domain O.OO2O3329 OO62O778 97.8 81.1 68.8 containing 88C 597 224933 PM S at JMJD1C jumonji domain containing 1C O.OO2O3726 OO6216 2710.7 1952.4 2061.8 598 235927 PM at XPO1 exportin 1 (CRM1 O.OO2O4212 0.0622693 169.3 129.5 108.4 homolog, yeast) 599 200829 PM X at ZNF2O7 Zinc finger protein 207 O.OO2O4523 O.O623252 4923 6OO.O 596.9 600 225239 PM at O.OO2O4808 OO623651 1535.8 882.2 876.O 601 224838 PM at FOXP1 orkhead box P1 O.OO2O491 O.O623651 11614 888.0 915.3 602 202540 PM S at HMGCR 3-hydroxy-3- O.OO2O5127 0.0623922 117.9 1448 1636 methylglutaryl-CoA reductase 603 210905 PM X at POUSF1P4 POU class 5 homeobox 1 O.OO2OSSS8 OO624.842 12.7 1O.S 11.1 pseudogene 4 604 226,566 PM at FAM102B amily with sequence O.OO2O580S 0.06252O3 155.4 219.4 221.5 similarity 102, member B 605 221756 PM at PIK3IP1 phosphoinositide-3-kinase O.OO2O6058 0.0625582 315.4 242.7 1870 interacting protein 1 606 241988 PM X at O.OO2O683 0.0627535 3O.S 22.7 21.8 607 200777 PM s at BZW1 basic and O.OO2O7SO6 OO628699 590.6 782.6 676.4 W2 domains 1 608 214402 PM S at SFI1 Sfil homolog, spindle O.OO2O7518 OO628699 30.9 25.5 22.7 assembly associated (yeast) 609 1556203 PM a at SRGAP2 SLIT-ROBO Rho GTPase O.OO2O76SS OO628699 246.0 183.7 157.1 activating protein 2 610 232184 PM at ALS2 amyotrophic lateral O.OO2O773 O.O628699 9.5 10.3 11.4 Sclerosis 2 (juvenile) 611 218659 PM at ASXL2 additional sex combs like 2 O.OO2O7993 OO6291 OS 485.2 373.S. 403.3 (Drosophila) US 2017/O 137885 A1 May 18, 2017 64

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 612 233289 PM at O.OO2O8249 OO629488 66.7 49.3 45.9 613 204137 PM at GPR137B G protein-coupled O.OO2O8751 OO630614 106.7 150.6 169.9 receptor 137B 614 226050 PM at TMCO3 transmembrane and O.OO2O9242 OO6317OS 2S3.6 311.O 353.6 coiled-coil domains 3 615 224377 PM S a RAB18 RAB18, member RAS O.OO2O964 O.O632399 367.1 499.6 S15.7 oncogene family 616 216695 PM S a TNKS tankyrase, TRF1- O.OO2O9731 OO632399 13.0 11.1 11.9 interacting ankyrin-related ADP-ribose polymerase 617 205586 PM x a VGF VGF nerve growth factor O.OO21O124 OO632482 11.1 9.6 9.6 inducible 618 1556657 PM at O.OO210147 OO632482 221.5 133.9 124.3 619 202147 PM S a IFRD1 Interferon-related O.OO210148 OO632482 283.9 372.9 436.2 developmental regulator 1 620 200098 PM S a ANAPCS anaphase promoting O.OO211129 OO63SO42 688.6 614.3 556.9 complex subunit 5 621 204403 PM X a FAM115A family with sequence 0.00212582 0.0538777 28.1 24.0 25.7 similarity 115, member A 622 1561263 PM at C1OTNF3 C1q and tumor necrosis O.OO212633 OO638777 14.6 12.3 11.9 factor related protein 3 623 209442 PM X a ANK3 ankyrin 3, node of Ranvier O.OO212886 OO639143 29.8 18.7 16.4 (ankyrin G) 624 232646 PM at TTC17 Tetratricopeptide repeat O.OO2132O1 OO63969S 37.5 27.3 26.4 domain 17 625 213615 PM at LPCAT3 Lysophosphatidylcholine O.OO213472 OO64O114 21.7 19.8 16.8 acyltransferase 3 626 212642 PM S at HIVEP2 human immunodeficiency O.OO213796 OO64059 75.5 55.7 55.2 virus type 1 enhancer binding protein 2 627 235740 PM a MCTP1 multiple C2 domains, O.OO213967 OO64059 109.0 168.0 163.5 transmembrane 1 628 221145 PM a O.OO214126 OO64059 10.9 10.3 12.1 629 236924 PM a O.OO214209 OO64059 45.1 3O4 28.4 630 1560443 PM at O.OO214288 OO64059 246.7 1SO.8 169.6 631 244301 PM a O.OO21528 O.O6431 61 8.9 1O.O 10.1 632 225992 PM a MLLT10 myeloid/lymphoid or O.OO215843 O.O64396S S1.9 74.9 64.5 mixed-lineage leukemia (trithorax homolog, Drosophila); translocate 633 221786 PM a C6orf120 chromosome 6 open O.OO215863 OO64396S 162.4 223.2 214.2 reading frame 120 634 1552711 PM a at CYB5D1 cytochrome b5 domain O.OO216069 O.O64396S 36.4 28.8 28.9 containing 1 635 242844 PM a O.OO216O78 O.O64396S 14.6 17.7 20.8 636 207892 PM a CD4OLG CD40 ligand O.OO216866 OO645919 2O.O 16.4 14.5 637 237442 PM a O.OO217083 0.064617 671.6 SO2.7 S22.2 638 242428 PM a DCUN1D1 DCN1, defective in cullin O.OO217479 0.06469S4 1841 113.6 122.7 neddylation 1, domain containing 1 (S. Cere-isiae) 639 1561927 PM at C3orf16 chromosome 3 open O.OO21.8042 OO648233 14.2 12.1 12.O reading frame 16 640 215435 PM at O.OO218.988 OO6SO184 213.7 1316 158.6 641 235798 PM at TMEM17OB transmembrane protein O.OO219052 OO6SO184 362.9 561.8 S38.5 17OB 642 222654 PM at IMPAD1 inositol monophosphatase O.OO219198 OO6SO184 25.7 37.4 38.8 domain containing 1 643 235984 PM at O.OO219232 OO6SO184 296.8 235.1 242.2 644 24.0156 PM at O.OO22O135 0.065246S 131.5 63.9 72.5 645 232991 PM at O.OO220964 OO6S4524 85.9 59.2 56.7 646 1569759 PM at O.OO221902 OO656903 14.9 12.1 12.9 647 221617 PM at TAF9B TAF9B RNA polymerase II, O.OO222895 OO659442 2042 144.2 146.6 TATA box binding protein (TBP)-associated factor, 31 kDa 648 229872 PM S at LOC10O132999 hypothetical O.OO223246 OO659972 943.4 778.9 743.2 LOC10O132999 649 218718 PM at PDGFC platelet derived growth O.OO223345 OO659972 71.4 106.8 129.1 factor C US 2017/O 137885 A1 May 18, 2017 65

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 650 1570439 PM at O.OO223 614 OO66O31 13.2 11.6 11.5 651 203139 PM a DAPK1 death-associated protein O.OO2238S2 OO66031 276.5 370.6 396.6 kinase 1 652 204177 PM S at KLHL20 kelch-like 20 (Drosophila) O.OO223866 OO66031 66.4 66.5 54.7 653 216245 PM a IL1RN interleukin 1 receptor O.OO224247 OO661033 10.3 10.2 11.7 antagonist 654 202381 PM a ADAM9 ADAM metallopeptidase O.OO224445 OO661217 95.2 1291 153.8 domain 9 655 226976 PM a KPNA6 karyopherin alpha 6 O.OO224819 OO661919 295.4 248.6 243.4 (importin alpha 7) 656 205540 PM S at RRAGB Ras-related GTP binding B O.OO224968 OO661957 14.5 18.0 16.1 657 215349 PM a BT8D18 BTB (POZ) domain O.OO22S6O1 OO663004 25.3 19.4 20.4 containing 18 658 210281 PM S at ZMYM2 Zinc finger, MYM-type 2 O.OO225691 OO663OO4 268.8 1994 179.7 659 242645 PM a O.OO225732 OO663004 57.4 45.6 41.4 660 234044 PM a O.OO226424 OO6646.36 163.7 91.1 94.7 661 226829 PM a AFAP1L2 actin filament associated O.OO226642 OO664876 1O.S 12.2 11.2 protein 1-like 2 662 2031.65 PM S at SLC33A1 solute carrier family 33 O.OO22697 O.O665403 13.4 19.3 17.2 (acetyl-CoA transporter), member 1 663 233816 PM at O.OO227095 OO665403 282.3 144.3 154.1 664 226556 PM at MAP3K13 mitogen-activated protein O.OO227425 OO665,672 34.7 51.5 48.3 kinase kinase kinase 13 665 242390 PM at O.OO22746 O.O665,672 113.8 82.3 74.1 666 214295 PM at KIAAO485 hypothetical LOC57235 O.OO227737 OO665968 20.7 15.3 16.3 667 1557436 PM at XKR6 XK, Kell blood group O.OO227948 OO665968 12.9 11.O 11.1 complex subunit-related family, member 6 668 226858 PM at CSNK1E casein kinase 1, epsilon O.OO2281 61 OO665968 24.3 23.7 19.4 669 2394.04 PM at O.OO228336 OO665968 371.8 2SO.2 266.3 670 202713 PM S at KIAAO391 KIAAO391 O.OO22846S OO665968 177.0 1498 131.3 671 244772 PM at O.OO2284.94 OO665968 49.5 39.5 37.8 672 203123 PM S at SLC11A2 solute carrier family 11 O.OO22866S OO665968 72.9 56.7 49.0 (proton-coupled divalent metal ion transporters), member 2 673 203007 PM X at LY PLA1 lysophospholipase I O.OO228.733 OO665958 SS6.2 723.5 626.O 674 217671 PM at O.OO228791 OO665958 88.4 62.1 55.2 675 236119 PM S at SPRR2G Small proline-rich protein O.OO229039 O.O66609 12.O 10.8 10.4 2G 676 225876 PM at NIPAL3 NIPA-like domain O.OO229168 0.066609 168.8 142.1 113.1 containing 3 677 222432 PM S at CCDC47 coiled-coil domain O.OO229.243 O.O66609 149.3 1699 192.9 containing 47 678 228738 PM at D2HGDH D-2-hydroxyglutarate O.OO229436 OO666.253 28.1 25.3 20.3 dehydrogenase 679 230712 PM at NBPF1 neuroblastoma breakpoint O.OO2296S O.O666477 157.3 107.3 103.5 family, member 1 680 242780 PM at WAPA VAMP (vesicle-associated O.OO229898 OO666526 60.8 41.4 47.4 membrane protein)- associated protein A, 33 kDa 681 1553107 PM S at C5orf24 chromosome 5 open O.OO23OO72 OO666525 130.7 108.4 108.2 reading frame 24 682 203885 PM at RAB21 RAB21, member RAS O.OO230077 O.OS66526 1842 236.8 24O.O oncogene family 683 243005 PM at O.OO2306S O.0667789 43.4 32.7 3O.O 684 222307 PM at LOC28.2997 hypothetical LOC282997 O.OO231381 OO659231 100.3 68.8 65.1 685 243182 PM at O.OO231423 O.O669231 135.3 83.7 81.2 686 228249 PM at C11orf74 chromosome 11 open O.OO231604 OO66.9358 13.3 15.3 17.3 reading frame 74 687 225228 PM at DRAM2 DNA-damage regulated O.OO23257 O.O671751 111.9 158.2 147.6 autophagy modulator 2 688. 204594 PM S at SMCR7L Smith-Magenis syndrome O.OO23287 OO672219 90.8 78.2 67.1 chromosome region, candidate 7-like 689 238393 PM at O.OO233582 OO673875 10.2 8.6 9.2 690 217945 PM at BTBD1 BTB (POZ) domain O.OO233926 OO674236 226.9 290.8 294.2 containing 1 US 2017/O 137885 A1 May 18, 2017 66

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 691 226939 PM at CPEB2 cytoplasmlc O.OO233984 OO674236 263.3 395.7 474.O polyadenylation element binding protein 2 692 227116 PM at MON1B MON1 homolog B (yeast) O.OO234772 0.0675747 296.8 367.9 364.O 693 242759 PM at O.OO234837 0.0675747 31.3 25.3 24.O 694 1553352 PM X at ERVWE1 endogenous retroviral O.OO234941 0.0675747 18.5 15.5 19.6 family W., env(C7), member 1 695 1566889 PM at THADA Thyroid adenoma O.OO235063 0.0675747 21.6 17.7 16.3 associated 696 226426 PM a ADNP activity-dependent O.OO235345 OO6761.59 1732 140.4 137.5 neuroprotector homeobox 697 243296 PM a NAMPT Nicotinamide 0.002355.57 O.O6.76369 6234.7 4363.4 SOO1.5 phosphoribosyltransferase 698 232330 PM a OO676674 353.4 276.0 237.6 699 2301.47 PM a coagulation factor II OO677822 8.9 9.8 10.3 (thrombin) receptor-like 2 700 227752 PM a SPTLC3 serine O.OO236,684 OO678239 9.6 9.4 10.7 palmitoyltransferase, long chain base subunit 3 701 242297 PM a RREB1 ras responsive element O.OO23.6765 OO678239 263.6 209.9 2O3.7 binding protein 1 702 223391 PM a SGPP1 sphingosine-1-phosphate O.OO23695 OO67837 98.1 146.7 1444 phosphatase 1 703 215612 PM a O.OO2383OS 39.4 30.1 28.8 704 1570078 PM a at DOCKS dedicator of cytokinesis 5 O.OO238372 238.5 134.7 1301 705 226085 PM a CBXS chromobox homolog 5 O.OO238S25 45.1 32.5 29.3 706 237943 PM a O.OO238947 206.3 121.3 134.9 707 241159 PM X at O.OO239578 34.0 28.0 27.2 708 1555561 PM a at UGGT2 UDP-glucose glycoprotein O.OO240013 8.8 1O.S 9.9 2 709 225.040 PM 5 at RPE ribulose-5-phosphate-3- O.OO241.37 O.O687956 66.9 108.6 104.9 epimerase 710 1570335 PM at O.OO241,512 O.O687956 1S.O 12.2 12.1 711 201534 PM S at UBL3 ubiquitin-like 3 O.OO241611 O.O687956 333.0 456.3 410.9 712 1557283 PM a at ZNF519 Zinc finger protein 519 O.OO241.71 O.O687956 1S.O 12.1 11.7 713 237544 PM at O.OO242O71 O.O688581 256.5 186.1 171.6 71.4 238888 PM at O.OO242768 O.O6901 61 126.5 88.2 9 O.S 715 232763 PM at TLN1 Talin 1 O.OO243337 O.O69137 68.8 423 S2.9 716 236645 PM at LOC10OSO6312 hypothetical O.OO243477 O.O69137 176.O 119.5 113.9 LOC10OSO 6312 717 218482 PM at ENY2 enhancer of yellow 2 O.OO244156 O.O692326 279.5 381.1 398.2 homolog (Drosophila) 718 237176 PM at O.OO244236 O.O692326 755.4 544.8 580.0 719 226176 PM S at Us P42 ubiquitin specific O.OO24424 O.O692326 250.5 2OO.O 196.3 peptidase 42 720 211139 PM S at NAB1 NGFI-A binding protein 1 1224 87.3 88.4 (EGR1 binding protein 1) 721 202647 PM S at NRAS neuroblastoma RAS viral SO4 71.1 64.3 (v-ras) oncogene homolog 722 201653 PM at CNIH cornichon homolog 395.5 S42.O 471.3 (Drosophila) 723 201800 PM S at OSBP oxysterol binding protein 145.1 13 O.S 123.8 724 234565 PM X at 23.7 2O.O 20.8 725 242235 PM X at S14.7 396.2 447.4 726 239063 PM at O.OO246405 O.O69563 23.6 21.9 15.8 727 228660 PM X at SEMA4F Sema domain, O.OO246807 O.0696004 17.0 14.8 14.1 immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmi 1728 1569041 PM at O.OO246823 O.0696004 15.9 12.4 13.4 1729 229773 PM at SNAP23 Synaptosomal-associated O.OO24732 O.O697OO2 176.6 119.6 128.5 protein, 23 kDa 1730 221735 PM at WDR43 WD repeat domain 48 O.OO247658 0.0697551 383-4 349.4 325.4 1731 228902 PM at NUP214 nucleoporin 214 kDa O.OO248O86 O.O698.353 74.2 97.1 99.1 1732 200833 PM S at RAP1B RAP1B, member of RAS O.OO248892 O.O70O217 2219.0 3O42.4 2647.5 oncogene family 1733 228512 PM at PTCD3 Pentatricopeptide repeat O.OO24.9085 O.O700356 85.7 69.5 61.6 domain 3 1734 232653 PM at O.OO2496.28 2002 122.6 134.9

US 2017/O 137885 A1 May 18, 2017 68

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 780 238459 PM X at SPATAS spermatogenesis O.OO26484 O.O724992 9.8 9.2 1O.S associated 6 781. 212852 PM 5 at TROVE2 TROVE domain family, O.OO26SOS6 O.O72S176 1001.7 839.5 867.1 member 2 782 236963 PM at O.OO26S2O7 O.O72S182 22.9 15.9 15.2 783 1560771 PM at O.OO265437 O.O72S4O4 10.6 9.6 11.4 784 232500 PM at RALGAPA2 Ral GTPase activating O.OO26S586 O.O72S4O4 8443 SS2.7 S63.1 protein, alpha Subunit 2 (catalytic) 785 214188 PM at HEXIM1 Hexamethylene bis- O.OO2673O8 O.O729698 92.1 62.O 69.8 acetamide inducible 1 786 22.5225 PM at LOCA29082 Hypothetical protein O.OO2681.23 O.O731513 816.1 728.6 684.3 LOCA29082 787 214925 PM S at SPTAN1 spectrin, alpha, non- O.OO268359 O.O731748 18.5 14.9 13.7 erythrocytic 1 (alpha fodrin) 788 210619 PM S at HYAL1 hyaluronoglucosaminidase 1 O.OO268625 O.O732O63 123 12.5 14.6 789 225785 PM at REEP3 receptor accessory protein O.OO269026 O.O732746 1SS.S. 216.8 220.9 3 790 203248 PM at ZNF24 Zinc finger protein 24 O.OO269663 O.O734O71 25.1 32.1 31.7 791 236946 PM at O.OO27OO89 O.O734562 35.5 25.9 29.2 792 224667 PM X at ANAPC16 anaphase promoting O.OO27O145 O.O734562 965.2 789.1 852.8 complex subunit 16 793 2025.38 PM S at CHMP2B chromatin modifying O.OO271151 O.O736886 261.4 335.9 311.5 protein 2B 794 225774 PM a RSPRY1 ring finger and SPRY O.OO2.71833 O.O738328 79.8 108.0 94.2 domain containing 1 795 219482 PM a SETD4 SET domain containing 4 O.OO272S31 O.O739812 48.4 43.1 36.7 796 216107 PM a LOC10O1295.03 hypothetical O.OO272787 0.074OO94 11.O 10.6 12.2 LOC10O129SO3 797 243931 PM a O.OO273O33 O.O740349 1040.1 794.8 804.1 798 220603 PM S at MCTP2 multiple C2 domains, O.OO273533 O.O741293 33O.O 339.S 465.8 transmembrane 2 799 243361 PM a SREK1 splicing regulatory O.OO274347 O.O7428OS 44.4 35.3 35.6 glutamineflysine-rich protein 1 800 225484 PM a TSGA14 estis specific, 14 O.OO274396 O.O7428OS 39.7 33.5 29.7 801 244249 PM a O.OO2.74878 O.O743697 31.1 22.7 25.8 802. 218474 PM S at KCTDS potassium channel O.OO275283 O.O744379 1419 2102 182.5 etramerisation domain containing 5 803 205277 PM a PRDM2 PR domain containing 2, O.OO27S856 O.O744924 102.5 78.6 66.3 with ZNF domain 804 221013 PM S at APOL2 apolipoprotein L, 2 O.OO276OS4 O.O744924 25.7 21.7 20.9 805 2208.63 PM a MIP major intrinsic protein of O.OO276.109 OO744924 10.7 11.O 12.3 ens fiber 806 2.16555 PM a C22Orf30 chromosome 22 open O.OO276119 O.O744924 334.7 263.2 302.6 reading frame 30 807 203132 PM a RB1 retinoblastoma 1 O.OO276249 O.O744924 123S 169.0 178.7 808 228613 PM a RAB11FIP3 RAB11 family interacting O.OO2772S1 O.O747213 88.9 6O.O S2.1 protein 3 (class II) 809 24.1588 PM a O.OO277SO7 O.O747489 18.3 15.8 14.4 810 242216 PM a O.OO279169 O.O751551 41.1 31.4 28.1 811 243442 PM X at O.OO279361 O.O751652 35.2 29.8 31.8 812 238860 PM a C6orf130 chromosome 6 open O.OO280S6S O.O754475 145.8 1208 112.2 reading frame 130 813 217164 PM a O.OO281545 O.O756693 3.09.4 245.1 197.5 814 225501 PM a XPNPEP3 X-prolylaminopeptidase O.OO281717 O.O756.738 133.0 96.7 98.4 (aminopeptidase P) 3, putative 815 23O324 PM a O.OO2824O9 O.O7S7882 1236 91.1 88.4 816 210266 PM S at TRIM33 tripartite motif-containing O.OO2824S4 O.O7S7882 891.O 758.8 761.0 33 817 231302 PM a O.OO282886 0.0758491 137.7 86.O 97.4 818 1557733 PM a at - O.OO283O39 O.O758491 55.2 30.3 27.6 819 204325 PM S at NF1 O.OO28319.5 O.O758491 11.3 9.6 9.6 820 204226 PM a STAU2 staufen, RNA binding O.OO2833S3 O.O758491 41.7 62.6 57.3 protein, homolog 2 (Drosophila) 821 1556053 PM at DNAJCT DnaJ (Hsp40) homolog, O.OO283528 O.O758491 263.2 2114 219.2 Subfamily C, member 7 US 2017/O 137885 A1 May 18, 2017 69

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 822 204165 PM at WASF1 WAS , O.OO283615 O.O758491 20.1 23.2 32.O member 1 823 232304 PM at PELI1 Pellino homolog 1 O.OO283972 O.O759029 1637.9 1045.8 1096.8 (Drosophila) 824 221841 PM S at Kruppel-like factor 4 (gut) O.OO284676 O.O76.0384 365.1 487.7 S28.4 825 2424.40 PM at O.OO284916 0.076.0384 3O.O 19.9 20.9 826 239726 PM at O.OO2.84947 0.076.0384 40.2 26.5 21.4 827 1563320 PM at O.OO285747 O.O761441 26.6 21.5 21.1 828 242854 PM X at DLEU2 deleted in lymphocytic O.OO285768 O.O761441 1616 12S.O 112.2 leukemia 2 (non-protein coding) 829 224645 PM at EIF4EBP2 eukaryotic translation O.OO285812 O.O761441 2102 1745 159.1 initiation factor 4E binding protein 2 830 203496 PM S at MED1 mediator complex subunit O.OO28.614 O.O761498 1719 145.5 134.9 1 831 1553282 PM at C21orf128 chromosome 21 open O.OO286146 (O.O761498 9.6 9.2 8.6 reading frame 128 832 242070 PM at LOCA28485 hypothetical LOC728485 O.OO286444. O.O761872 10.9 11.4 12.7 833 227208 PM at CCDC84 coiled-coil domain O.OO28.6599 O.O761872 216.6 174.9 1688 containing 84 834 1557797 PM a at - O.OO2868O8 O.O762012 3.09.O 22O.S 223.1 835 210820 PM X at COQ7 coenzyme Q7 homolog, O.OO287385 O.O762.795 13.0 16.6 17.4 ubiquinone (yeast) 836 231775 PM at TNFRSF1 OA tumor necrosis factor O.OO287422 O.O762.795 1806 145.4 125.6 receptor Superfamily, member 10a 837 219520 PM S at WWC3 WWC family member 3 O.OO287674 0.0762.795 756.O 570.8 589.3 838 228983 PM at 0.00287729 O.O762795 33.4 25.1 27.5 839 207761 PM S at METTL7A methyltransferase like 7A O.OO287972 O.O763O24 1051.S 1303.3 1344.O 840 218873 PM at GON4L gon-4-like (C. elegans) O.OO28832 O.O763331 142.0 122.9 109.0 841 242357 PM X at O.OO2884.74 0.0763331 19.9 16.4 16.2 842 236493 PM at NKAPP1 NFKB activating protein O.OO288558 O.O763331 17.0 14.8 13.7 pseudogene 1 843 233775 PM x at LOC10O289.333 Hypothetical protein O.OO289763 O.O766103 769.1 631.O 679.7 LOC10O28.9333 844 222930 PM S at AGMAT agmatine O.OO29O397 O.O767363 14.1 13.0 11.6 () 845 217885 PM at IPO9 importin 9 O.OO290642 O.O767594 227.8 183.0 1713 846 244354 PM at LOC10O288939 Similar to hCG1987955 O.OO291439 O.O768.645 262.1 2116 206.8 847 240410 PM at O.OO291445 O.O768.645 252.9 1930 1891 848 230018 PM at DPP9 dipeptidyl-peptidase 9 O.OO291513 O.O768.645 49.O 42.2 46.2 849 217579 PM X at O.OO291.77S O.O768919 217.6 178.8 1861 850 218337 PM at FAM16OB2 family with sequence O.OO292O68 0.0769276 53.1 SO.8 43.0 similarity 160, member B2 851 225232 PM at MTMR12 myotubularin related O.OO292317 O.O769515 3OSO 361.8 389.4 protein 12 852. 243677 PM at GORASP1 Golgi reassembly stacking O.OO293066 0.0771071 9.7 10.1 10.9 protein 1, 65 kDa 853 225446 PM at BRWD1 bromodomain and WD O.OO293424 O.O771219 47.9 62.2 47.6 repeat domain containing 1 854 241727 PM X at DHFRL1 dihydrofolate reductase- O.OO293439 O.O771219 82.O 68.9 70.9 like 1 855 210285 PM X at WTAP Wilms tumor 1 associated O.OO294.086 O.O772SO3 944 149.5 115.1 protein 856 232432 PM S at SLC3OAS solute carrier family 30 O.OO294546 O.O773294 79.1 113.1 86.3 (Zinc transporter), member 5 857 238694 PM at DGKE diacylglycerol kinase, O.OO294979 O.O774O14 27.3 22.0 18.3 epsilon 64 kDa 858 1558.142 PM at TNRC6B trinucleotide repeat O.OO295374 0.077.4477 435.3 330.1 377.1 containing 6B 859 1569296 PM a at LOC4.93754 RAB guanine nucleotide O.OO295656 0.077.4477 28.2 22.8 22.7 exchange factor (GEF) 1 pseudogene 860 217970 PM S at CNOT6 CCR4-NOT transcription O.OO295761 O.O774477 69.0 101.6 83.5 complex, Subunit 6 861 1558289 PM at RFT1 RFT1 homolog 0.00295791 0.077.4477 22.6 19.9 18.4 (S. cerevisiae) US 2017/O 137885 A1 May 18, 2017 70

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 862 1570496 PM at 0.00295955 O.O77449 14.2 12.3 12.4 863 1552652 PM at HPS4 Hermansky-Pudlak O.OO2962O3 O.O774723 16.6 14.0 14.6 syndrome 4 864 155.3466 PM at chromosome X open O.OO297091 0.07761.65 10.4 9.4 9.3 reading frame 59 865 1557486 PM at 0.07761.65 13.7 10.8 11.7 866 201417 PM at SOX4 SRY (sex determining 0.07761.65 1223 169.0 185.8 region Y)-box 4 867 208772 PM at ANKHD1 if ankyrin repeat and KH O.OO29.7453 0.07761.65 546.6 459.2 414.6 ANKHD1-EIF4EBP3 domain containing 1 ANKHD1-EIF4EBP3 readthrough 868 207133 PM X at alpha-kinase 1 0.00297,551 0.07761.65 217.3 1736 1811 869 1560512 PM at 0.0029797 O.O776842 18.8 13.9 12.4 870 238.064 PM at O.OO298875 O.O778785 669.2 441.3 S12.2 871 1559949 PM at O.OO2993 O.O779476 38.0 26.2 3O.O 872 236116 PM at O.OO3OOO46 O.O781001 26.7 21.8 2O.O 873 223871 PM X at Inhibitor of growth family, O.OO3OO704 O.0782296 22.2 18.5 20.9 member 5 874 1561606 PM at 11.8 11.5 13.3 875 222345 PM at O.O787613 11.6 10.7 9.9 876 212079 PM S at myeloid/lymphoid or 0.0787729 155.0 119.7 104.9 mixed-lineage leukemia (trithorax homolog, Drosophila) 877 244579 PM at 0.0787729 397.7 26O.S 288.6 878 244168 PM S at ULK4 unc-51-like kinase 4 0.0787729 2O.S 16.5 16.7 (C. elegans) 879 204842 PM x at PRKAR2A protein kinase, cAMP 0.0787729 S35.4 456.5 466.2 dependent, regulatory, type II, alpha 880 2097.04 PM at MTF2 metal response element 0.0787729 37.4 53.0 48.2 binding transcription factor 2 881 1555908 PM at FAM120A family with sequence O.0788074 14.4 15.8 17.8 similarity 120A 882 243178 PM at O.078.9333 1388.5 913.1 948.5 883 2063O8 PM at TRDMT1 tRNA aspartic acid O.078.9333 16.4 21.0 20.6 methyltransferase 1 884 217971 PM at MAPKSP1 MAPK scaffold protein 1 O.OO3OS191. O.078.9333 366.5 SO4.9 497.5 885 226808 PM at ZNF862 Zinc finger protein 862 O.OO305746 O.O790349 392.1 3O8.8 321.6 886 243988 PM at O.OO306374 O.O791106 13.0 10.8 11.0 887 232232 PM S at SLC22A16 solute carrier family 22 O.OO306384 O.O791106 30.7 45.8 53.9 (organic cation carnitine transporter), member 16 888 232532 PM at QRICH2 glutamine rich 2 O.O791106 11.5 11.3 10.3 889 215854 PM at O.O791106 18.7 14.7 15.3 890 236919 PM at O.O7914SS 24.1 18.3 18.2 891 202069 PM S at IDEH3A isocitrate dehydrogenase O.O791944 63.0 85.5 79.3 3 (NAD+) alpha 892 212818 PM S at ASB1 ankyrin repeat and SOCS O.O793,069 52.1 47.2 41.4 box-containing 1 893 203440 PM at CDH2 cadherin 2, type 1, N O.O793,069 11.9 11.5 16.O cadherin (neuronal) 894 233326 PM at CCDC39 coiled-coil domain O.O795902 9.0 8.8 10.4 containing 39 895 225956 PM at chromosome 5 open O.O79.5981 1312.0 1010.4 1112.8 reading frame 41 896 242875 PM at O.O797794 2O7.1 137.4 142.5 897 215208 PM X at Ribosomal protein L35a O.O799079 777 61.4 64.7 898 244035 PM at O.O799079 66.4 42.O 31.3 899 226379 PM S at C19Crf25 open O.OO311564 O.O799079 16.9 14.6 14.8 reading frame 25 900 219345 PM at BOLA1 bol A homolog 1 (E. coli) O.OO311784 O.O799079 35.6 37.0 29.7 901 202195 PM S at TMED5 transmembrane emp24 O.OO311821 O.O799079 81.8 107.9 107.9 protein transport domain containing 5 902 1560861 PM at O.O799079 12.6 11.O 1O.S 903 240528 PM S at EXOC4 exocyst complex O.O799079 47.4 42.9 33.2 component 4 US 2017/O 137885 A1 May 18, 2017 71

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 904 243295 PM at RBM27 RNA binding motif protein O.OO312686 342.8 282.8 2886 27 905 1557235 PM at LOC1001280O2 Hypothetical O.OO312941 9.2 9.5 1O.S LOC1001280O2 906 1557246 PM at KIDINS220 kinase D-interacting O.OO313O29 347.0 245.O 265.2 substrate, 220 kDa 907 220349 PM S at ENGASE endo-beta-N- O.OO314235 O.O802887 63.2 48.8 42.8 acetylglucosaminidase 908 200732 PM S at PTP4A1 protein tyrosine O.OO314386 O.O802887 3.10.1 384.3 363.2 phosphatase type IVA, member 1 240016 PM at O.OO314629 117.2 79.4 76.8 222393 PM S at NAASO N(alpha)-acetyltransferase O.OO315072 118.2 157.8 139.5 50, NatE catalytic subunit 232586 PM X at olfactory receptor, family O.OO315151 0.08O3577 25.8 24.5 7, Subfamily E, member 126 pseudogene 212500 PM at ADO 2-aminoethanethiol O.OO315656 O.08.04444 63.4 94.0 88.7 (cysteamine) dioxygenase 240613 PM at JAK1 Janus kinase 1 O.OO316752 18.1 13.9 1S.O 215577 PM at O.OO3176O1 22.3 17.0 16.7 231235 PM at NKTR natural killer-tumor O.OO317914 12O6 88.6 75.7 recognition sequence 213566 PM at 6-Sep septin 6 O.OO318269 O.0809166 261.2 200.3 18O.O g g 237317 PM at O.OO318339 O.0809166 26.6 24.2 19.8 220925 PM at NAA35 N(alpha)-acetyltransferase O.OO319274 O.08 1119 1118 106.3 90.3 35, NatC auxiliary subunit 214016 PM S at LOC10OSO6168 hypothetical O.OO319481 O.08 1222 8734 726.2 724.4 SFPQ LOC100506168 //? splicing factor proline:glutamine rich 920 232371 PM a 7-Mar Membrane-associated ring O.OO319954 O.08 1484 101.0 98.8 finger (C3HC4) 7 921 1557504 PM at 2322 26.5 19.4 2O2 922 223328 PM a ARMC10 armadillo repeat 2322 131.8 172.1 139.9 containing 10 923 218516 PM S at IMPAD1 inositol monophosphatase O.OO32O72 2322 18.5 25.3 24.2 domain containing 1 924 233674 PM a O.OO320811 2322 170.7 95.5 91.3 925 219485 PM S at PSMD10 proteasome (prosome, O.OO321022 2322 213.8 289.3 263.O macropain) 26S Subunit, non-ATPase, 10 926 231316 PM a O.OO321081 O.08 2322 78.9 65.9 S8.9 927 233333 PM X at AVIL advillin O.OO321.804 O.08 2981 32.2 24.6 26.4 928 1563502 PM at ZDHHC2 Zinc finger, DHHC-type O.OO321858 O.08 2981 29.9 23.3 20.9 containing 2 929 212098 PM a LOC151162 hypothetical LOC151162 /// O.OO321918 O.08 2981 284.9 209.3 215.4 MGATS mannosyl (alpha-1,6-)- glycoprotein beta-1,6-N- acetyl-glucosa 930 1551652 PM at BECN1 Beclin 1, autophagy O.OO322009 O.08 2981 1S.O 12.6 13.4 related 931 201339 PM S at SCP2 sterol carrier protein 2 O.OO322271 O.08 3062 379.6 SO4.O 439.2 932 236066 PM at O.OO322375 O.08 3062 30.3 27.6 24.5 933 22O127 PM S at FBXL12 F-box and leucine-rich O.OO322582 O.08 3164 97.4 121.1 111.0 repeat protein 12 934 206748 PM S at SPAG9 sperm associated antigen O.OO3231SS O.08 4O13 23.2 17.0 18.7 935 211795 PM S at FYB FYN binding protein O.OO3232S3 O.08 4O13 44805 3726.3 3726.9 936 218313 PM S at GALNT7 UDP-N-acetyl-alpha-D- O.OO3241.16 O.08 5764 2134 276.0 290.7 galactosamine: polypeptide N-acetylgalactosaminyltransferase 7 (Gal 937 1564753 PM at O.OO324528 O.08 591 12.9 10.7 11.8 938 226,544 PM x at MUTED muted homolog (mouse) O.OO324648 O.08 591 343.5 298.8 31O.S 939 228.097 PM at MYLIP myosin regulatory light O.OO324676 O.08 591 1294 87.6 80.9 chain interacting protein 940 224047 PM at O.08 766 8.6 8.4 9.5 941 242352 PM at NIPBL Nipped-B homolog O.08 766 1020.9 8O8.3 835.7 (Drosophila) 942 227121 PM at O.OO326653 O.08 961 67.1 48.7 47.0 US 2017/O 137885 A1 May 18, 2017 72

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 943 232174 PM at O.OO327857 O.O821646 369.3 203.O 212.O 944 230526 PM at LOC100131096 hypothetical O.OO32788 O.O821646 85.3 79.7 62.4 LOC100131096 945 244347 PM at O.OO328111 O.O821646 37.1 25.3 24.O 946 1562591 PM a at OFCC1 orofacial cleft 1 candidate O.OO3281.39 O.O821646 10.8 9.9 11.4 1 947 243608 PM at COG2 component of oligomeric O.OO328.364 O.O821787 33.9 27.7 25.7 golgi complex 2 948. 207027 PM at HGFAC HGF activator O.OO33O422 O.O826S13 1O.O 9.8 10.9 949 235513 PM at O.OO330961 O.O827436 296.4 212.1 239.3 950 23O821 PM at ZNF148 Zinc finger protein 148 O.OO331765 O.O829024 90.4 79.7 67.9 951 237591 PM at NCRNA00173 non-protein coding RNA O.OO33227 O.0829809 623.6 365.2 524.8 173 952 215207 PM X at NUS1 nuclear undecaprenyl O.OO332421 O.O829809 26.O 34.8 32.8 NUS1P3 pyrophosphate synthase 1 homolog (S. cerevisiae) if nuclear undec 953 1560395 PM at O.OO333835 O.O832578 11.3 9.8 9.4 954 232587 PM a EML4 echinoderm microtubule O.OO333872 O.O832578 42.6 32.3 28.3 associated protein like 4 955 234059 PM a O.OO334O76 O.O832661 10.7 9.3 0.4 956 220618 PM S at ZCWPW1 Zinc finger, CW type with O.OO334668 0.083371 15.6 12.7 4.0 PWWP domain 1 957 238735 PM a O.OO336694. O.O838328 34.3 26.7 23.4 958 1562O28 PM at CCND3 Cyclin D3 O.OO337137 O.O839003 15.6 11.7 1.9 959 1565689 PM at 0.00337532 0.08395.57 46.8 35.6 37.0 960 217344 PM a FDPS farnesyl diphosphate O.OO338219 O.O840837 9.4 9.9 0.7 Synthase 961. 214719 PM a SLC46A3 solute carrier family 46, O.OO338423 O.O84O91S 419.8 342.3 348.5 member 3 962 233439 PM a LETM1 leucine zipper-EF-hand O.OO338.723 O.O840983 13.4 12.3 1.6 containing transmembrane protein 1 963 203803 PM a PCYOX1 prenylcysteine oxidase 1 O.OO33906 O.O840983 20.7 18.8 S.6 964. 239296 PM a O.OO339.104 O.O840983 104.3 66.O 80.3 965 213351 PM S at TMCC1 transmembrane and O.OO339141 O.O84O983 446.1 281.1 3114 coiled-coil domain family 1 966 237181 PM a O.OO339341 O.O841051 27.0 19.7 7.2 967 231016 PM S at ARNT Aryl hydrocarbon receptor O.OO339928 O.O842O78 21.4 21.6 26.7 nuclear translator 968 233713 PM a O.OO34O118 O.O84212 65.9 51.2 43.3 969 220735 PM s at SENP7 SUMO1/sentrin specific O.OO341419 O.O844912 12.4 17.4 6.1 peptidase 7 970 221904 PM a FAM131A family with sequence O.OO341688 O.O845149 125.6 1523 169.4 similarity 131, member A 971. 218292 PM s at PRKAG2 protein kinase, AMP- O.OO3423S3 O.O846231 78.7 107.9 1OO.2 activated, gamma 2 non catalytic subunit 972 210810 PM S at SLC6AS solute carrier family 6 O.OO342473 O.O846231 10.4 9.2 9.9 (neurotransmitter transporter, ), member 5 973 240865 PM a O.OO3436SS O.O848722 29.3 22.0 17.9 974. 233656 PM S at VPS54 vacuolar protein sorting O.OO344O76 O.O849061 72.2 119.2 100.9 54 homolog (S. cerevisiae) 975 244813 PM a O.OO344188 O.O349061 19.5 15.2 15.1 976 211565 PM a SH3GL3 SH3-domain GRB2-like 3 O.OO344315 O.O849061 10.8 11.8 12.9 977 214321 PM a NOV nephroblastoma O.OO34S461 O.O851.456 77.2 88.5 1636 overexpressed gene 978 222266 PM a C19orf2 Chromosome 19 open O.OO345958 O.O851917 321.2 256.1 2O6.O reading frame 2 979 239307 PM a LOC10OSO9703 hypothetical O.OO345998. O.O851917 2SS.S 1554 188.5 LOC10OSO9703 98.0 200624 PM S at MATR3 matrin 3 O.OO347416 O.O854977 255.1 378.0 322.4 981 222048 PM a CRYBB2P1 crystallin, beta B2 O.OO34836 O.O856867 30.4 25.6 23.7 pseudogene 1 982 226756 PM a O.OO348.639 O.O857087 53.5 77.9 91.O 983 239391 PM a FAM12OAOS Family with sequence O.OO3488O1 O.O857087 53.8 43.6 SO.8 similarity 120A opposite strand US 2017/O 137885 A1 May 18, 2017 73

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR - TX - Gene p-value p-value Mean Mean Mean Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 984 211764 PM S at UBE2D1 ubiquitin-conjugating O.OO3494.14 O.O857522 1682.5 2015.O 21923 enzyme E2D 1 (UBC4/5 homolog, yeast) 985 222835 PM at THSD4 thrombospondin, type I, O.O857522 10.6 9.8 11.2 domain containing 4 986 232313 PM at TMEM132C transmembrane protein O.O857522 11.7 11.O 12.5 132C 987 230735 PM at 921.5 683.6 628.9 988 1555536 PM at anthrax toxin receptor 2 65.7 55.0 53.3 989 241905 PM at Phosphoinositide-3- 127.2 95.1 96.4 kinase, class 2, alpha polypeptide 990 201784 PM S at C11orf58 chromosome 11 open 484.3 641.2 610.2 reading frame 58 991 203224 PM a RFK riboflavin kinase 0.0035.255 127.7 179.7 175.5 992 1566897 PM at 0.00352577 4.O.S 30.3 28S 993 233598 PM a C20orf187 chromosome 20 open O.OO3S2604 9.3 9.4 10.3 reading frame 187 994 212519 PM a UBE2E1 ubiquitin-conjugating O.O863142 694.7 905.4 845.O enzyme E2E 1 (UBC4/5 homolog, yeast) 995 2101.19 PM a KCNJ15 potassium inwardly O.O863142 2213.3 1462.5 1794.1 rectifying channel, Subfamily J, member 15 996 241932 PM a O.O863346 27.5 20.4 2O2 997 230261 PM a ST8 alpha-N-acetyl O.O863346 223.7 281.2 329.5 neuraminide alpha-2.8- sialyltransferase 4 998 204725 PM S at NCK1 NCK adaptor protein 1 O.O865436 62.3 93.1 83.9 999 235965 PM a O.O865688 8.7 9.1 1O.S 2OOO 210368 PM a PCDHGA8 protocadherin gamma O.O868851 12.4 10.6 11.6 Subfamily A, 8 2001 231107 PM a 0.00357367 O.O870236 47.2 37.3 35.4 2002 234439 PM a O.OO3S897 0.0873.703 11.5 1O.O 1O.O 2003 243869 PM a O.OO35929 O.O874O45 214.O 1836 147.6 2004 235766 PM X at RAB27A RAB27A, member RAS O.OO3S9922 O.O8751.46 1165.1 1438.S 1374.3 oncogene family 2005 242853 PM a O.OO36O722 O.0876653 52.3 38.3 41.2 2006 40446 PM at PHF1 PHD finger protein 1 O.OO3.6114 O.O876843 263.3 227.3 227.3 2007 244646 PM a O.OO36116 O.O876843 113.5 85.O 87.2 2008 232097 PM a TOX4 TOX high mobility group O.OO361452 0.0877115 159.7 112.9 128.3 box family member 4 2009 217877 PM S at GC-rich promoter binding O.OO3S1929 0.0877835 327.8 387.8 381.1 protein 1-like 1 2010 1557452 PM at O.OO362626 O.O879088 46.4 33.4 36.8 2011 222214 PM at O.OO364195 O.O882453 40.O 27.0 26.2 2012 220918 PM at chromosome 21 open O.OO364716 O.O883276 364.2 2949 224.1 reading frame 96 2013 155.2563 PM a at O.00365851 O.O88558S 14.2 12.3 11.9 2014 1568857 PM a at NBR1 Neighbor of BRCA1 gene 1 O.OO366SO7 O.O886732 1348 97.1 98.6 2015 15575O1 PM a at O.OO366836 O.O887088 38.9 31.1 30.6 2016 222182 PM S at CNOT2 CCR4-NOT transcription O.OO367216 O.O887566 466.6 388.5 4O2.9 complex, Subunit 2 2017 1560144 PM at O.OO367869 O.O888704 9.5 9.1 102 2018 202704 PM at TOB1 transducer of ERBB2, 1 O.OO368242 O.O8891 64 337.2 449.9 4-SS.S 2019 223490 PM S at EXOSC3 exosome component 3 O.OO368,908 O.O890331 60.7 88.7 71.7 2020 228.027 PM at GPRASP2 G protein-coupled O.OO369478 O.089126S 11.1 10.3 9.4 receptor associated Sorting protein 2 2021 225805 PM at heterogeneous nuclear O.OO369714 O.O891393 22.1 31.7 25.1 ribonucleoprotein U (scaffold attachment factor A) 2022 228628 PM at SRGAP2P1 SLIT-ROBO Rho GTPase O.OO371487 O.O894886 461.9 362.6 338.6 activating protein 2 pseudogene 1 2023 225,023 PM at GOPC golgi-associated PDZ and O.OO37153 O.O894886 33.6 42.6 42.5 coiled-coil motif containing 215169 PM at solute carrier family 35, O.OO372164 O.O89597 157.6 108.2 117.3 member E2 US 2017/O 137885 A1 May 18, 2017 74

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 2025 23O856 PM at O.OO372727 O.O896.882 113.2 84.2 84.6 2026 208669 PM S at EID1 EP300 interacting inhibitor O.OO373918 O.O899183 SS3.2 801.6 679.5 of differentiation 1 2027 203226 PM S at TSPAN31 tetraspanin 31 O.OO374052 O.O899183 64.9 90.1 76.5 2028 243765 PM at O.OO37SOO4 O.0901027 19.5 17.2 16.2 2029 1562468 PM at O.OO376362 O.O903403 24.4 17.4 17.0 2030 209076 PM s at WDR45L WDR45-like O.OO376364 O.O903403 1423 1628 167.8 2031. 24.1543 PM at O.OO376716 O.O9038O3 10.4 9.4 11.0 2032 1559201 PM a at - O.OO3784OS O.O906794 6.13.6 450.2 499.4 2033 224796 PM at ASAP1 Arf6AP with SH3 domain, O.OO378.442 O.O906794 1795.7 1328.9 1478.4 ankyrin repeat and PH domain 1 2034 233041 PM X at O.OO378521 O.O906794 855.4 706.6 739.4 2035 232597 PM x at SRSF2IP serinefarginine-rich O.OO378854 0.090698 766.8 615.4 6213 splicing factor 2, interacting protein 2036 217550 PM a ATF6 activating transcription O.OO378.971 O.O90698 2204 149.4 2006 factor 6 2037 233476 PM a O.OO3796SS O.0908171 420.4 284.9 2931 2038 1554559 PM at GPR62 G protein-coupled O.OO382185 O.091.3775 13.4 11.6 12.1 receptor 62 2039 217654 PM a CFLAR CASP8 and FADD-like O.OO38248.1 O.O914OO6 42.1 26.0 26.3 apoptosis regulator 2040 224674 PM a TTYH3 tweety homolog 3 O.OO3826S7 O.O914OO6 31.7 4O.S 41.7 (Drosophila) 2041 232773 PM a O.OO383.209 OO91467 107.9 81.8 78.2 2042 242232 PM a O.OO383319 O.O91467 27.9 19.9 2O.O 2043 2392.24 PM a FBXL20 F-box and leucine-rich O.OO383498 0.091467 38.6 31.3 31.1 repeat protein 20 2044 1552714 PM at CREG2 cellular repressor of E1A- O.OO385834 0.0919468 10.2 9.7 11.5 stimulated genes 2 2045 22.5677 PM a BCAP29 B-cell receptor-associated O.OO386O12 O.O919468 49.1 69.2 74.5 protein 29 2046 238886 PM a TMED10 transmembrane emp24- O.OO386O76 O.O919468 45.5 32.9 33.1 like trafficking protein 10 (yeast) 2047 237426 PM a SP100 SP100 nuclear antigen O.OO386.538 0.0919651 344.2 223.2 258.5 2048 239431 PM a TICAM2 .. toll-like receptor adaptor O.OO386718 O.0919651 42.O 59.7 60.8 TMED7-TICAM2 molecule 2 TMED7 TICAM2 readthrough 2049 243013 PM a O.OO386719 O.0919651 68.1 53.2 48.5 2050 236612 PM a O.OO3.87911 O.O92128 14.2 12.0 13.1 2051 222582 PM a PRKAG2 protein kinase, AMP- O.OO3.87911 O.O92128 158.1 1948. 206.7 activated, gamma 2 non catalytic subunit 2052 227205 PM a TAF1 TAF1 RNA polymerase II, O.OO387971 O.O92128 45.6 6O.O 51.5 TATA box binding protein (TBP)-associated factor, 250 kDa 2053 23.6836 PM a O.OO388617 O.O922O81 85.6 72.4 6O.O 2054 201375 PM S at PPP2CB protein phosphatase 2, O.OO388,709 OO922O81 410.6 SO7.3 496.6 catalytic subunit, beta isozyme 2055 209130 PM a SNAP23 synaptosomal-associated O.OO389024 O.O922O81 1604.7 1776.S 1930.4 protein, 23 kDa 2056 224177 PM s at CXorf26 chromosome X open O.OO389364 O.O922O81 51.1 76.8 57.5 reading frame 26 2057 202505 PM a SNRPB2 Small nuclear O.OO3894.63 O.O922O81 392.0 SO8.O 467.4 ribonucleoprotein polypeptide B 2058 1570.124 PM at O.OO389516 O.O922O81 11.6 10.6 12.2 2059 231968 PM a UGGT1 UDP-glucose glycoprotein O.OO3896.33 O.O922O81 302.7 247.7 259.2 glucosyltransferase 1 2060 222631 PM a P4K2B phosphatidylinositol 4- O.OO390047 O.O922427 42.2 64.7 62.O kinase type 2 beta 2061. 23.5805 PM a O.OO390158 0.0922427 48.0 30.8 32.9 2062 230582 PM a HECA Headcase homolog O.OO390887 O.0923703 15.5 13.2 13.6 (Drosophila) 2063. 223011 PM S at OCLAD1 OCIA domain containing 1 O.OO391.975 O.O92S82S 608.3 727.8 657.3 2064 232135 PM a SAP3OL SAP30-like O.OO3928.04 O.O927333 309.6 233.1 2S2.6 US 2017/O 137885 A1 May 18, 2017 75

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 206S 206366 PM X at XCL1 chemokine (C motif) O.OO393296 O.O928.045 205.2 302.0 368.0 ligand 1 2066 226368 PM at CHST11 carbohydrate (chondroitin O.OO395067 0.0931773 1079.8 818.7 836.O 4) sulfotransferase 11 2067 205068 PM S at ARHGAP26 Rho GTPase activating O.OO396416 0.0933895 1314.3 888.0 1031.9 protein 26 2068. 204037 PM at LPAR1 lysophosphatidic acid O.OO396S14 0.0933895 20.3 23.4 27.6 receptor 1 2069 206499 PM S at RCC1 regulator of chromosome O.OO3957S9 O.O933895 24.4 32.1 25.4 condensation 1 2070 239955 PM at O.OO3968S9 O.O933895 166.5 1214 113.9 2071 222728 PM S at TAF1D TATA box binding protein O.OO397247 O.O933895 591.6 472.2 470.7 (TBP)-associated factor, RNA polymerase I, D, 41 kDa 2072 228.787 PM S at BCAS4 breast carcinoma O.OO39.7319 O.O933895 24.3 22.9 19.6 amplified sequence 4 2073 212802 PM S at GAPVD1 GTPase activating protein O.OO397442 0.0933895 482.4 412.6 428.7 and VP59 domains 1 2074 2235O1 PM at TNFSF13B tumor necrosis factor O.OO397788 O.O933895 2123.6 2619.4 2925.4 (ligand)Superfamily, member 13b 2075 241425 PM at NUPL1 nucleoporin like 1 O.OO397867 O.O933895 SO6.9 376.8 4O6.3 2076 208853 PM S at CANX calnexin O.OO398O28 O.O933895 142.7 1938 170.5 2077 1557813 PM at O.OO398,075 0.0933895 161.6 103.7 117.7 2078 225626 PM at PAG1 phosphoprotein O.OO3987O8 O.O934.504 1834.4 1353.6 1349.3 associated with glycosphingolipid microdomains 1 2079 AFFX-r2-P1-cre-5 at - O.OO398.718 O.O.934SO4 101.55.6 98.61.1 10591.3 2080 225,091 PM at ZCCHC3 Zinc finger, CCHC domain O.OO4OO6SS O.O938S92 106.6 132.3 117.4 containing 3 2081 233669 PM S at TRIMS4 tripartite motif-containing O.OO4O1166 0.0939338 12.0 10.7 11.8 S4 2082 218325 PM S at DIDO1 death inducer-obliterator O.OO4O1405 O.O9394.46 122.7 106.7 98.9 2083 1558.486 PM at ZNF493 Zinc finger protein 493 O.OO4O2O68 O.O94OS46 404.2 284.3 271.1 2084 219715 PM s at TDP1 tyrosyl-DNA O.OO4O2SS9 O.O.941242 51.5 46.8 39.4 phosphodiesterase 1 2085 1554806 PM a at FBXO8 F-box protein 8 O.OO402917 O.O941438 64.3 91.0 72.2 2086 215545 PM a O.OO4O3O29 O.O941438 69.3 56.4 55.5 2087 232835 PM a O.OO4036 O.O941915 361.6 219.4 215.7 2088 229556 PM a LOC10O2888.93 hypothetical O.OO40362 O.O941915 12.6 14.9 16.1 LOC10O2888.93 2089 221883 PM a PKNOX1 PBXknotted 1 homeobox O.OO404237 O.O942721 67.9 514 46.6

2090 241018 PM a TMEM59 transmembrane protein O.OO4047O2 O.O942721 52.1 39.9 37.4 59 2091 224673 PM a LENG8 eukocyte receptor cluster O.OO404728 O.O942721 30.1 22.9 22.0 (LRC) member 8 2092 211406 PM a ER3IP1 immediate early response O.OO404739 O.O942721 15.9 18.5 19.5 3 interacting protein 1 2093 201056 PM a GOLGB1 golgin B1 O.OO405091 O.O94309 89.6 70.1 71.1 2094. 217911 PM S at BAG3 BCL2-associated O.OO405374 O.O943.298 43.6 31.9 25.2 athanogene 3 2095 237107 PM a PRKRA protein kinase, interferon- O.OO4O7199 O.O946S79 56.7 37.6 39.8 inducible double stranded RNA dependent activator 2096 202442 PM a AP3S1 adaptor-related protein O.OO4O7287 O.O946S79 783.8 948.8 953.9 complex 3, sigma 1 Subunit 2097 203410 PM a AP3M2 adaptor-related protein O.OO4O7367 O.O946S79 58.6 45.9 40.2 complex 3, mu 2 subunit 2098 235985 PM a O.OO4O7823 O.O947187 110.9 84.1 75.6 2099 242371 PM x at O.OO408.809 OO94856 16.5 13.9 14.0 2100 2281.90 PM a ATG4C ATG4 autophagy related 4 O.OO408,993 0.094.856 51.6 70.4 78.4 CTR9 homolog C (S. cerevisiae) f/ Ctrg, Paf1/RNA polymerase II com 2101 203024 PM S at CSOrf15 chromosome 5 open O.OO4O9089 0.094.856 418.3 S4S.O 531.4 reading frame 15 US 2017/O 137885 A1 May 18, 2017 76

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR - SCAR - TX - Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 2102 202872 PM at ATP6V1C1 ATPase, H+ transporting, O.OO409559 O.O948SS 81.6 115.8 118.9 lysosomal 42 kDa, V1 subunit C1 2103 233496 PM S at CFL2 cofilin 2 (muscle) O.OO4O962 O.094.856 9.5 9.6 10.8 2104 202080 PM S at TRAK1 trafficking protein, kinesin O.OO4O9747 0.094.856 1354 1621 171.8 binding 1 2105 243262 PM at O.OO4O98O2 O.O94856 19.5 1S.O 15.8 2106 228087 PM at CCDC126 coiled-coil domain O.OO410O37 0.094.856 8O.O 119.2 136.9 containing 126 21.07 230630 PM at AK4 adenylate kinase 4 O.OO410166 O.O94856 14.0 12.2 13.2 2108 218494 PM s at SLC2A4RG SLC2A4 regulator O.OO410524 O.O948938 69.3 73.8 48.0 2109 211387 PM X at RNGTT RNA guanylyltransferase O.OO411271 O.O950213 24.5 19.9 22.1 and 5'-phosphatase 2110 230980 PM X at O.OO412014 O.O.951479 27.7 22.3 22.1 2111 236562 PM at ZNF439 Zinc finger protein 439 O.OO413239 O.O953856 25.7 36.6 43.4 2112 239848 PM at O.OO413966 0.09SSO82 24.9 18.6 18.5 2113 226459 PM at PIK3AP1 phosphoinositide-3-kinase O.OO415318 O.O957S98 2062.2 2494.4 2596.3 adaptor protein 1 2114 224837 PM at FOXP1 forkhead box P1 O.OO415683 0.0957598 688.1 567.3 535.8 2115 213500 PM at O.OO415703 0.0957598 75.5 61.9 62.1 2116 1556.178 PM X at TAF8 TAF8 RNA polymerase II, O.OO416O3S O.O957598 33.1 39.2 31.7 TATA box binding protein (TBP)-associated factor, 43 kDa 2117 204837 PM at MTMR9 myotubularin related O.OO416123 O.O957598 315.8 269.5 270.1 protein 9 2118 238812 PM at O.OO416236 0.0957598 153.0 105.4 101.1 2119 215127 PM s at RBMS1 RNA binding motif, single O.OO416626 O.O957867 2167.2 1825.2 2003.6 stranded interacting protein 1 2120 222202 PM at O.OO416849 O.O957867 11.O 9.9 11.2 2121 226438 PM at SNTB1 syntrophin, beta 1 O.OO41701 0.0957867 83.2 129.3 116.4 (dystrophin-associated protein A1, 59 kDa, basic component 1) 2122 222032 PM s at USP7 ubiquitin specific O.OO417139 O.O957867 22.9 18.3 2O.O peptidase 7 (herpes virus associated) 2123 2386.31 PM a ZNF140 Zinc finger protein 140 O.OO41831 O.O96O103 15.9 13.6 12.3 2124 218514 PM a C17orf71 chromosome 17 open O.OO419327 O.O96.1984 94.3 118.2 1113 reading frame 71 2125 213369 PM a CDHR1 cadherin-related family O.OO419612 O.O.96218S 11.9 10.8 12.3 member 1 2126 240737 PM a O.OO42OSSS O.O963894 143.2 116.6 115.7 2127 216626 PM a O.OO423185 O.O9694.66 11.9 10.1 102 2128 241351 PM a O.OO423575 0.0969903 48.6 39.4 37.1 2129 1554.964 PM X at - O.OO423798 0.0969958 13.8 11.O 11.9 2130 231601 PM a LOC10OSO7224 hypothetical O.OO42559 O.O9736O2 10.4 10.1 11.3 LOC10OSO7224 2131 200776 PM S at BZW1 basic leucine Zipper and O.OO426985 O.O975934 1964 240.6 239.9 W2 domains 1 2132 239861 PM a O.OO42701 O.O975934 360.5 261.9 284.1 2133 1561006 PM at O.OO427945 O.O977613 13.5 12.8 11.9 2134 242443 PM a EMLS Echinoderm microtubule O.OO428.213 O.O977766 25.4 18.7 18.7 associated protein like 5 2135 212078 PM S at MLL myeloid/lymphoid or O.OO42932 O.O97983S 186.7 143.2 117.3 mixed-lineage leukemia (trithorax homolog, Drosophila) 2136 215470 PM at GTF2H2B general transcription O.OO42.9999 O.O98O854 246.2 1846 138.8 factor IIH, polypeptide 2B 2137 224641 PM at FYTTD1 forty-two-three domain O.004301.69 O.O98O854 330.1 444S 371.2 containing 1 2138 209027 PM S at ABI2 abl-interactor 1 O.OO43OSO4 O.O981158 S37.3 673.6 648.2 2139 224698 PM at ESYT2 extended synaptotagmin- O.OO431319 O.O982SS6 437.9 373.9 323.4 like protein 2 2140 225783 PM at UBE2F ubiquitin-conjugating O.0043.1806 0.09832O6 262.9 338.1 367.5 enzyme E2F (putative) US 2017/O 137885 A1 May 18, 2017 77

TABLE 4-continued List of 2156 differentially expressed probesets between AR, SCAR and TX from a 3-way ANOVA stepup AR SCAR TX Gene p-value p-value Mean Mean Mean i Probeset ID Symbol Gene Title (Phenotype) (Phenotype) Signal Signal Signal 2141 230742 PM a O.OO432O39 O.O98321 1618 115.4 106.3 2142 232148 PM a NSMAF Neutral sphingomyelinase O.OO432334 0.098321 144.0 94.9 94.9 (N-SMase) activation associated factor 2143 24.4636 PM a O.OO432413 O.O98321 31.1 22.7 20.7 2144 244686 PM a TCOF1 Treacher Collins- O.OO433OOS O.O984O99 14.2 12.6 14.4 Franceschetti syndrome 1 2145 1569806 PM at O.OO4350O8 O.O987818 13.3 11.7 13.1 2146 235623 PM a ELP2 Elongation protein 2 O.OO435048 O.O987818 148.9 119.0 117.2 homolog (S. cerevisiae) 2147 222207 PM x at O.OO435892 O.O.989274 752.8 633.6 673.2 2148 202544 PM a GMFB glia maturation factor, O.OO436,196 O.O989SO3 350.5 476.6 471.2 beta 2149 1553176 PM at SH2D1B SH2 domain containing 1B O.OO436721 O.O990233 11.4 12.7 13.5 2150 243492 PM a THEM4 thioesterase Superfamily O.OO4372O6 O.O990871 28.2 20.9 17.9 member 4 2151 244-154 PM a DDHD1 DDHD domain containing O.OO437947 O.O992O89 83.5 83.9 1 2152 242946 PM a O.OO438297 O.O992421 2226.9 1788.3 1732.9 2153 232665 PM X at O.OO438865 O.O993245 17.4 14.9 16.1 2154 222035 PM S at PAPOLA poly(A) polymerase alpha O.OO44OO72 O.O99486S 299.9 376.9 346.1 2155 1566958 PM at O.OO44O104 O.O9948.65 15.9 12.8 13.8 2156 215978 PM X at ZNF721 Zinc finger protein 721 O.OO44O193 O.O99486S 1251.4 972.1 104.24

TABLE 5 Time to biopsy (days post transplant).

SCAR CAR TX

Mean 287.6 921.2 267.8 Range 8-748 15-2876 84-2228

TABLE 6 3-Way 1-Step Microarray Analysis (AR v. SubAR v. TX) using biopsy samples - Results Predicted

Real AR Bx TXBx SCAR Bx

AR Bx 16 O 4 TX Bx O 21 4 SCAR Bx 5 5 12 Positive Negative % Predictive Sensitivity Specificity Predictive Predicitve Method Classifies Accuracy (%) (%) Value (%) Value (%) AUC

Nearest Centroid TX w.S. AR 100% 100% 100% 100% 100% 1.OOO (1 Step Prediction) TX vs. SCAR 78% 81% 75% 84% 719 O.785 AR ws. SCAR 76% 76% 75% 80% 71% 0.768

TABLE 7 Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - first step (AR+ SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 211796 PM S at TRBC1 if receptor beta constant 1 if T cell receptor 4.15E-12 TRBC2 beta constant 2 US 2017/O 137885 A1 May 18, 2017 78

TABLE 7-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - first step (AR+ SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 213193 PM X at TRBC1 T cell receptor beta constant 1 3.16E-11 207238 PM S at PTPRC protein tyrosine phosphatase, receptor type, C 3.47E-11 204118 PM a CD48 CD48 molecule E-11 212587 PM S at PTPRC protein tyrosine phosphatase, receptor type, C 1 204655 PM a CCL5 chemokine (C-C motif) ligand 5 1 34210 PM at CD52 CD52 molecule 1 210915 PM X at TRBC2 T cell receptor beta constant 2 1 1405 PM i a CCL5 chemokine (C-C motif) ligand 5 1 1555759 PM a at CCL5 chemokine (C-C motif) ligand 5 1 204661 PM a CD52 CD52 molecule O 213539 PM a CD3D CD3d molecule, delta (CD3-TCR complex) 1.14E-10 204774 PM a EVI2A ecotropic viral integration site 2A 1.38E-10 226789 PM a EMB embigin 1.45E-10 212588 PM a PTPRC protein tyrosine phosphatase, receptor type, C 2.06E-10 205831 PM a CD2 CD2 molecule 2.1OE-10 224356 PM X at MS4A6A membrane-spanning 4-domains, Subfamily A, 2.11E-10 member 6A 206011 PM a CASP1 caspase 1, apoptosis-related peptidase 2.51E-10 (interleukin 1, beta, convertase) 223280 PM X at MS4A6A membrane-spanning 4-domains, Subfamily A, 3.37E-10 member 6A 229041 PM S at EST 4.24E-10 229041 PM S at 213566 PM at RNASE6 ribonuclease, RNase A family, kó 4.26E-10 213603 PM S at RAC2 ras-related C3 botulinum toxin substrate 2 (rho 4.52E-10 family, Small GTP binding protein Rac2) 210972 PM X at TRAC if T cell receptor alpha constant fif T cell receptor 4.73E-10 TRAJ17 alpha joining 17 if T cell receptor TRAV2O 211742 PM S at EVI2B ecotropic viral integration site 2B 4.95E-10 205488 PM a GZMA granzyme A (granzyme 1, cytotoxic T-lymphocyte- 5.04E-10 associated serine esterase 3) 202957 PM a HCLS1 hematopoietic cell-specific Lyn Substrate 1 6.04E-10 223922 PM X at MS4A6A membrane-spanning 4-domains, Subfamily A, 6.82E-10 member 6A 206978 PM a CCR2 chemokine (C-C motif) receptor 2 7.07E-10 219666 PM a MS4A6A membrane-spanning 4-domains, Subfamily A, 7.8OE-10

member 6A 209671 PM X at TRAC T cell receptor alpha constant 226818 PM a MPEG1 Macrophage expressed 1 212671 PM S at HLA-DQA1 /// major histocompatibility complex, class II, DQ alpha 1 if HLA-DQA2 major histocompatibility com 228532 PM a C1orf162 chromosome 1 open reading frame 162 9.6OE-10 204912 PM a IL1ORA interleukin 10 receptor, alpha 1.01E-09 205821 PM a KLRK1 killer cell lectin-like receptor subfamily K, member 1 1.19E-09 204205 PM a APOBEC3G apolipoprotein B mRNA editing enzyme, catalytic 1.19E-09 polypeptide-like 3G 214181 PM x at LST1 leukocyte specific transcript 1 1.2OE-09 214470 PM a KLRB1 killer cell lectin-like receptor subfamily B, member 1 1.35E-09 201137 PM S at HLA-DPB1 major histocompatibility complex, class II, DP beta 1 1.35E-09 211902 PM X at TRD(a) T cell receptor delta locus 1. SOE-09 210982 PM S at HLA-DRA major histocompatibility complex, class II, DR alpha 1.74E-09 209835 PM X at CD44 CD44 molecule (indian blood group) 2.1OE-09 206.666 PM a GZMK granzyme K (granzyme 3; tryptase II) 2.13E-09 203760 PM S at SLA Src-like-adaptor 2.13E-09 202644 PM S at TNFAIP3 tumor necrosis factor, alpha-induced protein 3 2.24E-09 204446 PM S at ALOX5 arachidonate 5-lipoxygenase 2.34E-09 213416 PM a ITGA4 integrin, alpha 4 (antigen CD49D, alpha 4 subunit of 24OE-09 VLA-4 receptor) 209083 PM a CORO1A coronin, actin binding protein, 1A 2.41E-09 225701 PM a AKNA AT-hook transcription factor 2.49E-09 224927 PM a KIAA1949 KIAA1949 2.95E-09 211991 PM S at HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 3.OOE-09 235964 PM X at SAMHD1 SAM domain and HD domain 1 3.04E-09 202207 PM a ARL4C ADP-ribosylation factor-like 4C 3.09E-09 210895 PM S at CD86 CD86 molecule 3.43E-09 1555691 PM a at KLRK1 killer cell lectin-like receptor subfamily K, member 1 3.43E-09 226841 PM a MPEG1 macrophage expressed 1 3.66E-09 205269 PM a LCP2 lymphocyte cytosolic protein 2 (SH2 domain 3.68E-09 containing leukocyte protein of 76 kDa) 203416 PM a CD53 CD53 molecule 3.82E-09 US 2017/O 137885 A1 May 18, 2017 79

TABLE 7-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - first step (AR+ SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 204959 PM at MINDA myeloid cell nuclear differentiation antigen 3.96E-09 223322 PM at RASSFS Ras association (RalGDSAF-6) domain family 4.29E-09 member 5 209970 PM X at CASP1 caspase 1, apoptosis-related cysteine peptidase 4.61E-09 (interleukin 1, beta, convertase) 1552703 PM S at CARD16 caspase recruitment domain family, member 16 4.62E-09 CASP1 caspase 1, apoptosis-related cysteine 221 698 PM S a CLEC7A C-type lectin domain family 7, member A 4.92E-09 1559584 PM a at C16orf54 chromosome 16 open reading frame 54 S.09E-09 205270 PM S a LCP2 lymphocyte cytosolic protein 2 (SH2 domain 5.11E-09 containing leukocyte protein of 76 kDa) 209670 PM at TRAC T cell receptor alpha constant S.15E-09 209.606 PM at CYTIP cytohesin 1 interacting protein 5.42E-09 204891 PM S a LCK lymphocyte-specific protein tyrosine kinase S.S4E-09 1553906 PM s at FGD2 FYVE, RhoGEF and PH domain containing 2 5.99E-09 223344 PM S a MS4A7 membrane-spanning 4-domains, Subfamily A, 6.OOE-09 member 7 236295 PM a a NLRC3 NLR family, CARD domain containing 3 6.07E-09 217733 PM s a TMSB10 thymosin beta 10 6.O8E-09 205081 PM at CRIP1 cysteine-rich protein 1 (intestinal) 6.14E-09 208885 PM at LCP1 lymphocyte cytosolic protein 1 (L-plastin) 6.27E-09 21916.1 PM S a CKLF chemokine-like factor 6.34E-09 227346 PM at IKZF1 IKAROS family Zinc finger 1 (ikaros) 6.48E-09 223620 PM at GPR34 G protein-coupled receptor 34 6.6OE-09 213888 PM S a TRAF3IP3 TRAF3 interacting protein 3 6.77E-09 232024 PM at GIMAP2 GTPase, IMAP family member 2 6.89E-09 206682 PM at CLEC10A C-type lectin domain family 10, member A 7.07E-09 208894 PM at HLA-DRA major histocompatibility complex, class II, DR alpha 7.95E-09 204971 PM at CSTA cystatin A (Stefin A) 8.19E-09 202208 PM S at ARL4C ADP-ribosylation factor-like 4C 8.47E-09 226218 PM at IL7R interleukin 7 receptor 8.48E-09 211368 PM S at CASP1 caspase 1, apoptosis-related cysteine peptidase 8.75E-09 (interleukin 1, beta, convertase) 211366 PM x at CASP1 caspase 1, apoptosis-related cysteine peptidase 8.89E-09 (interleukin 1, beta, convertase) 205789 PM at CD1D CD1d molecule 9.29E-09 1554240 PM a at ITGAL integrin, alpha L (antigen CD11A (p180), lymphocyte 9.6OE-09 unction-associated antigen 1: alph 211367 PM S a CASP1 caspase 1, apoptosis-related cysteine peptidase O1E-08 (interleukin 1, beta, convertase) 226525 PM at STK17B serine/threonine kinase 17b O4E-08 218223 PM S a PLEKHO1 pleckstrin homology domain containing, family O O6E-08 member 1 2145.74 PM X a LST eukocyte specific transcript 1 1OE-08 209732 PM at CLEC2B C-type lectin domain family 2, member B 1OE-08 210538 PM s a BIRC3 baculoviral IAP repeat-containing 3 17E-08 202157 PM S a CELF2 CUGBP, Elav-like family member 2 17E-08 217456 PM X a HLA-E major histocompatibility complex, class I, E 23E-08 211582 PM X a LST eukocyte specific transcript 1 27E-08 223451 PM S a CKLF chemokine-like factor 3OE-08 226474 PM at NLRCS NLR family, CARD domain containing 5 31E-08 229390 PM at FAM26F amily with sequence similarity 26, member F 47E-08 201721 PM s a LAPTMS ysosomal protein transmembrane 5 56E-08 202206 PM at ARL4C ADP-ribosylation factor-like 4C 64E-08 201666 PM at TIMP1 TIMP metallopeptidase inhibitor 1 69E-08 205898 PM at CX3CR1 chemokine (C-X3-C motif) receptor 1 74E-08 204336 PM s a RGS19 regulator of G-protein signaling 19 82E-08 208306 PM X at HLA-DRB1 Major histocompatibility complex, class II, DR beta 1 84E-08 227353 PM at TMC8 transmembrane channel-like 8 85E-08 201288 PM at ARHGDIB Rho GDP dissociation inhibitor (GDI) beta 90E-08 224964 PM S a GNG2 guanine nucleotide binding protein (G protein), 93E-08 gamma 2 202643 PM S a TNFAIP3 tumor necrosis factor, alpha-induced protein 3 96E-08 209846 PM S a BTN3A2 butyrophilin, Subfamily 3, member A2 2.07E-08 222858 PM s a DAPP1 dual adaptor of phosphotyrosine and 3- 2O8E-08 phosphoinositides 201858 PM S a SRGN Serglycin 2.3OE-08 204924 PM at TLR2 toll-like receptor 2 2.35E-08 203741 PM s a ADCY7 adenylate cyclase 7 2.37E-08 213160 PM at DOCK2 dedicator of cytokinesis 2 2.38E-08 213975 PM S a LYZ lysozyme 2.39E-08 US 2017/O 137885 A1 May 18, 2017 80

TABLE 7-continued

Biopsy Microarray Signatures for SubAR using a 2-way 2-Step a roach - first ste AR + SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 1552316 PM a at MAP1 GTPase, IMAP family member 1 240 200905 PM X at LA-E major histocompatibility complex, class I, E 2.50 226219 PM at RHGAP30 Rho GTPase activating protein 30 2.52 209312 PM X at LA-DRB1 if major histocompatibility complex, class II, DR beta 1 if 2.53 E-E-E-E- LA-DRB4 major histocompatibility comp 202803 PM S a I TGB2 integrin, beta 2 (complement component 3 receptor 2.55E O 8 3 and 4 subunit) 33304 PM at ISG20 interferon stimulated exonuclease gene 20 kDa 2.56 228071 PM a GTPase, IMAP family member 7 2.57 201720 PM S a lysosomal protein transmembrane 5 2.59 219033 PM a poly (ADP-ribose) polymerase family, member B 2.70 200833 PM S a RAP1B, member of RAS oncogene family 2.72 227184 PM a platelet-activating factor receptor 2.73 222217 PM S a solute carrier family 27 (fatty acid transporter), 2.74 member 3 E-E-E-E-E-E-E- 224451 PM x at ARHGAP9 Rho GTPase activating protein 9 2.76 206118 PM a STAT4 signal transducer and activator of transcription 4 2.78 229391 PM S a FAM26F family with sequence similarity 26, member F 2.81 218870 PM a ARHGAP15 Rho GTPase activating protein 15 2.83 224916 PM a TMEM173 transmembrane protein 173 2.83 209795 PM a CD69 molecule 2.89 208965 PM S a interferon, gamma-inducible protein 16 2.91 209723 PM a SERPINB9 Serpin peptidase inhibitor, clade B (ovalbumin), 2.91 member 9 E-E-E-E-E-E-E-E- 1555852 PM at LOC10OSO7463 hypothetical LOC100507463 2.93 1552701 PM a at CARD16 caspase recruitment domain family, member 16 3.05 201859 PM a SRGN Serglycin 3.07 219574 PM a MAR1 membrane-associated ring finger (C3HC4) 1 3.2O 230391 PM a CD84 CD84 molecule 3.30 2355.29 PM X at SAMHD1 SAM domain and HD domain 1 3.35 228.055 PM a NAPSE3 napsin Baspartic peptidase pseudogene 3.36 212014 PM x at CD44 CD44 molecule (indian blood group) 3.46 211656 PM X at HLA-DQB1 /// major histocompatibility complex, class II, DQ beta 1 if 3.52 LOC10O133583 HLA class II histocompatibili E-E-E-E-E-E-E-E-E- 203761 PM a SLA Src-like-adaptor 3.53 209933 PM S at CD300a molecule 3.53 203233 PM a interleukin 4 receptor 3.54 204563 PM a SELL Selectin L. 3.58 215633 PM X at LST1 leukocyte specific transcript 1 3.61 234987 PM a SAMHD1 SAM domain and HD domain 1 3.61 242946 PM a EST 3.63 242946 PM at E-E-E-E-E-E-E- 235385 PM a MAR2 membrane-associated ring finger (C3HC4) 1 3.67 21.0113 PM S at NLRP1 NLR family, pyrin domain containing 1 3.67 228376 PM a GGTA1 glycoprotein, alpha-galactosyltransferase 1 3.68 E-E-E- o pseudogene 205039 PM S at IKAROS family Zinc finger 1 (ikaros) 3.69 2 7362 PM X a major histocompatibility complex, class II, DR beta 6 3.71 EE g (pseudogene) 209879 PM at SELPLG Selectin P ligand 3.77 204698 PM at ISG20 interferon stimulated exonuclease gene 20 kDa 3.87 215493 PM X a butyrophilin, Subfamily 2, member A1 3.95 211395 PM x a Fc fragment of IgG, low affinity Ilc, receptor for 4.15 E-E-E-E- (CD32) (gene pseudogene) 223773 PM S a SNEHG12 Small nucleolar RNA host gene 12 (non-protein 4.22E O 8 coding) 219279 PM at DOCK10 dedicator of cytokinesis 10 4.25 225353 PM S a C1QC complement component 1, q. Subcomponent C chain 4.33 216920 PM S a TARP TRGC2 TCRgamma alternate reading frame protein if T cell 4.35 E-E-E- receptor gamma constant 2 2O7651 PM at GPR171 G protein-coupled receptor 171 4.42 2271 78 PM at CELF2 CUGBP, Elav-like family member 2 4.42 2025.10 PM S a TNFAIP2 tumor necrosis factor, alpha-induced protein 2 4...SO 2098.23 PM X at HLA-DQB1 major histocompatibility complex, class II, DQ beta 1 4.63 1555756 PM a at CLEC7A C-type lectin domain family 7, member A 4.72 223.809 PM at RGS18 regulator of G-protein signaling 18 4.72 243366 PM S a EST 4.75 243366 PM S at E-E-E-E-E-E-E- 204222 PM S a GLIPR1 GLI pathogenesis-related 1 4.82 O 8 204220 PM at GMFG glia maturation factor, gamma 4.92 1557905 PM s at CD44 CD44 molecule (indian blood group) 5.25 US 2017/O 137885 A1 May 18, 2017 81

TABLE 7-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - first step (AR+ SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 229.625 PM at GBP5 guanylate binding protein 5 S.25E-08 213414 PM S at RPS19 ribosomal protein S19 5.3OE-08 230499 PM at EST 5.38E-08 230499 PM at 215193 PM X at HLA-DRB1 major histocompatibility complex, class II, DR beta 1 if 5.4OE-08 HLA-DRB3 major histocompatibility comp HLA-DRB4 HLA-DRBS LOC10O133661 LOC10O294036 LOC10OSO9582 LOC1005104.95 LOC100510519 232724 PM at MS4A6A membrane-spanning 4-domains, Subfamily A, 5.4OE-08 member 6A 210140 PM at CST7 cystatin F (leukocystatin) 5.42E-08 224252 PM S at FXYD5 FXYD domain containing ion transport regulator 5 S47E-08 219191 PM S at BIN2 bridging integrator 2 S.SOE-08 206991 PM S at CCR5 chemokine (C-C motif) receptor 5 S.S4E-08 208966 PM X at FI16 interferon, gamma-inducible protein 16 5.6OE-08 210785 PM S at C1orf58 chromosome 1 open reading frame 38 5.62E-08 242814 PM at SERPINB9 Serpin peptidase inhibitor, clade B (ovalbumin), S.71E-08 member 9 232543 PM X at ARHGAP9 Rho GTPase activating protein 9 S.73E-08 213418 PM at HSPA6 heat shock 70 kDa protein 6 (HSP7OB') 5.8OE-08 212829 PM at PIP4K2A phosphatidylinositol-5-phosphate 4-kinase, type II, 5.85E-08 alpha 223501 PM at TNFSF13B tumor necrosis factor (ligand) Superfamily, member 5.88E-08 3b 211581 PM x at LST1 eukocyte specific transcript 1 S.92E-08 202748 PM at GBP2 guanylate binding protein 2, interferon-inducible 6.11E-08 230925 PM at APBB1P amyloid beta (A4) precursor protein-binding, family 6.25E-08 B, member 1 interacting protein 2098.27 PM S at L16 interleukin 16 (lymphocyte chemoattractant factor) 649E-08 204882 PM at ARHGAP2S Rho GTPase activating protein 25 7.19E-08 204319 PM S at RGS10 regulator of G-protein signaling 10 7.27E-08 217985 PM S at BAZ1A bromodomain adjacent to Zinc finger domain, 1A 7.33E-08 212998 PM X at HLA-DQB1 /// major histocompatibility complex, class II, DQ beta 1 if 7.42E-08 LOC10O133583 HLA class II histocompatibili 205159 PM at CSF2RB colony stimulating factor 2 receptor, beta, low- 7.44E-08 affinity (granulocyte-macrophage) 204670 PM X at HLA-DRB1 major histocompatibility complex, class II, DR beta 1 if 7.56E-08 HLA-DRB4 major histocompatibility comp 221903 PM S at CYLD cylindromatosis (turban tumor syndrome) 7.6OE-08 223343 PM at MS4A7 membrane-spanning 4-domains, Subfamily A, 7.76E-08 member 7 205285 PM S at FYB FYN binding protein 7.83E-08 220005 PM at P2RY13 purinergic receptor P2Y, G-protein coupled, 13 8.O2E-08 218157 PM X at CDC42SE1 CDC42 Small effector 1 8.09E-08 204438 PM at MRC1 if mannose receptor, C type 1 mannose receptor, C 8.23E-08 MRC1L1 type 1-like 1 211654 PM X at HLA-DQB1 major histocompatibility complex, class II, DQ beta 1 8.44E-08 224882 PM at ACSS1 acyl-CoA synthetase short-chain family member 1 8.S2E-08 214567 PM S at XCL1 if XCL2 chemokine (C motif) ligand 1 if chemokine (C motif) 8.56E-08 igand 2 223502 PM S at TNFSF13B tumor necrosis factor (ligand) Superfamily, member 8.61E-08 13b 228581 PM at KCNJ10 potassium inwardly-rectifying channel, Subfamily J, 8.69E-08 member 10 229383 PM at MAR3 membrane-associated ring finger (C3HC4) 1 8.72E-08 202649 PM X at RPS19 ribosomal protein S19 8.78E-08 210889 PM S at FCGR2B Fc fragment of IgG, low affinity IIb, receptor (CD32) 8.93E-08 204174 PM at ALOXSAP arachidonate 5-lipoxygenase-activating protein 9.16E-08 204502 PM at SAMHD1 SAM domain and HD domain 1 9.17E-08 223640 PM at HCST hematopoietic cell signal transducer 9.31E-08 211597 PM S at HOPX HOP homeobox 9.39E-08 216834 PM at RGS1 regulator of G-protein signaling 1 9.57E-08 212063 PM at CD44 CD44 molecule (indian blood group) 9.76E-08 208805 PM at PSMA6 proteasome (prosome, macropain) subunit, alpha 9.9OE-08 type, 6 210279 PM at GPR18 G protein-coupled receptor 18 1.OOE-07 US 2017/O 137885 A1 May 18, 2017 82

TABLE 7-continued

Biopsy Microarray Signatures for SubAR using a 2-way 2-Step a roach - first ste AR + SubAR vs.TX p-value (su bAR + cAR Probeset Gene Symbol Gene Title vs. TX Bx) 204057 PM a IRF8 interferon regulatory factor 8 OO 226055 PM a ARRDC2 arrestin domain containing 2 OO 205758 PM a CD8A CD8a molecule O1 229723 PM a TAGAP T-cell activation RhoGTPase activating protein O1 218084 PM x at FXYD5 FXYD domain containing ion transport regulator 5 O1 218802 PM a CCDC109B coiled-coil domain containing 109B O2 205987 PM a CD1C CD1c molecule .04 205859 PM a LY86 lymphocyte antigen 86 OS 2O7794 PM a CCR2 chemokine (C-C motif) receptor 2 O9 204122 PM a TYROBP TYRO protein tyrosine kinase binding protein 1O 229560 PM a TLR8 toll-like receptor 8 .12 203923 PM S a CYBB cytochrome b-245, beta polypeptide .12 225479 PM a LRRC58 leucine rich repeat containing 58 17 222592 PM S a ACSLS acyl-CoA synthetase long-chain family member 5 23 230550 PM a MS4A6A membrane-spanning 4-domains, Subfamily A, 23 member 6A 222859 PM S a DAPP1 dual adaptor of phosphotyrosine and 3 24E O 7 phosphoinositides E-E-E-E-E-E-E-E-E-E-E-E-E-E-E- 226810 PM a OGFRL1 opioid growth factor receptor-like 1 28 221666 PM S a PYCARD PYD and CARD domain containing 29 203729 PM a EMP3 epithelial membrane protein 3 29 211990 PM a HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 29 226136 PM a GLIPR1 GLI pathogenesis-related 1 32 201426 PM S a VIM vimentin 32 205298 PM S a BTN2A2 butyrophilin, Subfamily 2, member A2 .33 206332 PM S a FI16 interferon, gamma-inducible protein 16 36 211339 PM S a TK IL2-inducible T-cell kinase 37 204490 PM S a CD44 CD44 molecule (indian blood group) 38 230669 PM a RASA2 RAS p21 protein activator 2 39 200003 PM S a RPL28 ribosomal protein L28 39 217478 PM S a HLA-DMA major histocompatibility complex, class II, DM alpha 40 236280 PM a EST 41 236280 PM at 222976 PM S a TPM3 tropomyosin 3 42 E-E-E-E-E-E-E-E-E-E-E-E-E-E- 232311 PM a Beta-2-microglobulin 42 220577 PM a GVINP1 GTPase, very large interferon inducible pseudogene 1 43 238668 PM a EST .44 E-E-E-E- 238668 PM at 232617 PM a CTSS cathepsin S 45 224833 PM a ETS1 v-ets erythroblastosis virus E26 Oncogene homolog 1 46 EE g (avian) 219014 PM a PLAC8 placenta-specific 8 49 219243 PM a GIMAP4 GTPase, IMAP family member 4 49 2098.29 PM a FAM6SB family with sequence similarity 65, member B SO 203471 PM S at PLEK pleckstrin 53 211144 PM x at TARP TRGC2 TCRgamma alternate reading frame protein if T cell 54 E-E-E-E-E- receptor gamma constant 2 211528 PM x at HLA-G major histocompatibility complex, class I, G 55 206584 PM at LY96 lymphocyte antigen 96 57 231747 PM at CYSLTR1 cysteinyl leukotriene receptor 1 59 230735 PM at EST 61 E-E-E-E- 230735 PM at 225604 PM S at GLIPR2 GLI pathogenesis-related 2 62 210072 PM at CCL19 chemokine (C-C motif) ligand 19 63 221058 PM S at CKLF chemokine-like factor 63 204923 PM at SASH3 SAM and SH3 domain containing 3 68 227677 PM at JAK3 Janus kinase 3 69 201012 PM at ANXA1 annexin A1 70 229155 PM at EST 72 229155 PM at E-E-E-E-E-E-E- 205101 PM at CITA class II, major histocompatibility complex, O 7 transactivator 216438 PM S at TMSB4X thymosin beta 4, X-linked if thymosin-like 3 TMSL3 1552318 PM at GIMAP1 GTPase, IMAP family member 1 213095 PM x at AIF1 allograft inflammatory factor 1 204316 PM at RGS10 regulator of G-protein signaling 10 203927 PM at NFKBIE nuclear factor of kappa light polypeptide gene E-E-E-E- enhancer in B-cells inhibitor, epsilon 217523 PM at CD44 CD44 molecule (indian blood group) 84 209901 PM x at AIF1 allograft inflammatory factor 1 84 US 2017/O 137885 A1 May 18, 2017 83

TABLE 7-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - first step (AR+ SubAR vs.TX p-value (SubAR + cAR Probeset ID Gene Symbol Gene Title Bx vs. TX Bx) 203508 PM a TNFRSF1B tumor necrosis factor receptor Superfamily, member 85E-07 1B 208944 PM a TGFBR2 transforming growth factor, beta receptor II 86E-07 (70/80 kDa) 210031 PM a CD247 CD247 molecule .87E-07 202953 PM a C1QB complement component 1, q. Subcomponent, B chain .87E-07 213733 PM a MYO1F myosin 1F .88E-07 201738 PM a EIF1B eukaryotic translation initiation factor 1B .88E-07 205884 PM a ITGA4 integrin, alpha 4 (antigen CD49D, alpha 4 subunit of .93E-07 VLA-4 receptor) 204.820 PM S at BTN3A2 if butyrophilin, Subfamily 3, member A2 i? .99E-07 BTN3A3 butyrophilin, Subfamily 3, member A3 218805 PM a GIMAPS GTPase, IMAP family member 5 .99E-07 212873 PM a HMHA1 histocompatibility (minor) HA-1 .99E-07 217979 PM a TSPAN13 tetraspanin 13 2.02E-07 228471 PM a ANKRD44 ankyrin repeat domain 44 2.03E-07 218322 PM S at ACSLS acyl-CoA synthetase long-chain family member 5 2.03E-07 215051 PM X at AIF1 allograft inflammatory factor 1 2.04E-O7 213398 PM S at SDR39U1 short chain dehydrogenase/reductase family 39U, 2.04E-O7 member 1 206637 PM at P2RY14 purinergic receptor P2Y, G-protein coupled, 14 2.OSE-O7

TABLE 8 Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - Second step (AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 227801 PM a TRIMS9 tripartite motif-containing 59 1.69E-08 212951 PM a GPR116 G protein-coupled receptor 116 6.33E-08 226668 PM a WDSUB1 WD repeat, sterile alpha motif and U-box domain 7.62E-08 containing 1 202357 PM S at CFB complement factor B 1.28E-07 211075 PM S at CD47 CD47 molecule 1.32E-07 204213 PM a PIGR polymeric immunoglobulin receptor 1.54E-07 226459 PM a PIK3AP1 phosphoinositide-3-kinase adaptor protein 1 1.54E-07 231779 PM a IRAK2 interleukin-1 receptor-associated kinase 2 1.7OE-07 235085 PM a SGK223 homolog of rat pragma of Rind2 1.84E-O7 226714 PM a SAMD4B sterile alpha motif domain containing 4B 1.98E-07 202242 PM a TSPANT tetraspanin 7 2.17E-07 213857 PM S at CD47 CD47 molecule 2.57E-07 205105 PM a MAN2A1 mannosidase, alpha, class 2A, member 1 2.62E-O7 204924 PM a TLR2 toll-like receptor 2 2.69E-07 204470 PM a CXCL1 chemokine (C-X-C motif) ligand 1 (melanoma growth 3.07E-07 stimulating activity, alpha) 204108 PM a NFYA nuclear transcription factor Y, alpha 3.2OE-07 236155 PM a ZCCHC6 Zinc finger, CCHC domain containing 6 4.22E-07 212950 PM a GPR116 G protein-coupled receptor 116 4.37E-07 209774 PM X at CXCL2 chemokine (C-X-C motif) ligand 2 5.78E-07 207966 PM S at GLG1 golgi glycoprotein 1 6.24E-07 211758 PM X at TXNDC9 thioredoxin domain containing 9 6.38E-07 238178 PM a EST 7.69E-07 238178 PM at 202334 PM S at UBE2B ubiquitin-conjugating enzyme E2B (RAD6 homolog) 7.75E-07 231334 PM a EST 8.26E-07 231334 PM at 223.809 PM a RGS18 regulator of G-protein signaling 18 8.34E-07 210405 PM X at TNFRSF10B tumor necrosis factor receptor Superfamily, member 9.02E-07 1Ob 230777 PM S at PRDM15 PR domain containing 15 9.91E-07 202907 PM S at NBN nibrin 1.02E-O6 202621 PM at IRF3 interferon regulatory factor 3 1.04E-O6 219938 PM S at PSTPIP2 proline-serine-threonine phosphatase interacting 1.07E-O6 protein 2 223047 PM at CMTM6 CKLF-like MARVEL transmembrane domain containing 6 1.O8E-O6 202018 PM S at LTF lactotransferrin 1.1OE-06 233878 PM S at XRN2 5'-3' exoribonuclease 2 1.19E-06 US 2017/O 137885 A1 May 18, 2017 84

TABLE 8-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - second step (AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 244353 PM S at SLC2A12 Solute carrier family 2 (facilitated glucose transporter), 2OE-06 member 12 204785 PM X at IFNAR2 interferon (alpha, beta and omega) receptor 2 21E-06 226000 PM at CTTNBP2NL CTTNBP2 N-terminal like 24E-06 241891 PM at EST 3OE-06 241891 PM at 208791 PM at CLU clusterin 38E-06 233047 PM at FRMD7 FERM domain containing 7 39E-06 226538 PM at MAN2A1 mannosidase, alpha, class 2A, member 1 44E-06 208792 PM S at CLU clusterin 48E-06 218313 PM S at GALNT7 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- 6OE-06 acetylgalactosaminyltransferase 7 (Gal 203568 PM S at TRIM38 tripartite motif-containing 38 62E-06 223218 PM S at NFKBIZ. nuclear factor of kappa light polypeptide gene 69E-06 enhancer in B-cells inhibitor, Zeta 224358 PM S at MS4A7 membrane-spanning 4-domains, subfamily A, member 7 76E-06 227125 PM a IFNAR2 interferon (alpha, beta and omega) receptor 2 78E-06 1552615 PM at ACACB acetyl-CoA carboxylase beta 84E-06 218865 PM a MOSC1 MOCO Sulphurase C-terminal domain containing 1 87E-06 210031 PM a CD247 CD247 molecule 91E-06 212226 PM S at PPAP2B phosphatidic acid phosphatase type 2B 95E-06 230912 PM a ASPDH aspartate dehydrogenase domain containing 2O8E-O6 201042 PM a TGM2 transglutaminase 2 (C polypeptide, protein-glutamine- 2.14E-O6 gamma-glutamyltransferase) 203513 PM a SPG11 spastic paraplegia 11 (autosomal recessive) 2.39E-06 243O88 PM a EST 2.58E-O6 243O88 PM at 204324 PM S at GOLIM4 golgi integral membrane protein 4 2.58E-O6 235905 PM a ZNF704 Zinc finger protein 704 2.65E-06 1564679 PM at ASB15 ankyrin repeat and SOCS box-containing 15 2.71E-O6 203868 PM S at WCAM1 vascular cell adhesion molecule 1 2.72E-O6 212695 PM a CRY2 cryptochrome 2 (photolyase-like) 2.77E-06 223217 PM S at NFKBIZ. nuclear factor of kappa light polypeptide gene 2.78E-06 enhancer in B-cells inhibitor, Zeta 227213 PM a ADAT2 , tRNA-specific 2, TAD2 homolog 2.91E-O6 (S. cerevisiae) 206513 PM a AIM2 absent in melanoma 2 2.96E-O6 1552749 PM a at KLC3 kinesin light chain 3 2.96E-O6 240413 PM a PYHIN1 pyrin and HIN domain family, member 1 3.OSE-O6 238960 PM S at LARP4 La ribonucleoprotein domain family, member 4 3.06E-O6 1562966 PM at KIAA1217 KIAA1217 3.1OE-06 202898 PM a SDC3 Syndecan 3 3.16E-O6 22.9872 PM S at LOC10O132999 hypothetical LOC100132999 3.22E-O6 218404 PM a SNX10 Sorting nexin 10 3.44E-O6 219998 PM a HSPC159 galectin-related protein 3.SOE-06 211003 PM X at TGM2 transglutaminase 2 (C polypeptide, protein-glutamine- 3.S2E-06 gamma-glutamyltransferase) 203008 PM X at TXNDC9 thioredoxin domain containing 9 3.59E-06 213513 PM X at ARPC2 actin related protein 2/3 complex, subunit 2, 34 kDa 3.77E-06 203765 PM at GCA grancalcin, EF-hand calcium binding protein 3.83E-O6 221510 PM S at GLS glutaminase 3.91E-O6 214791 PM at SP14OL SP140 nuclear body protein-like 4.01E-06 217947 PM at CMTM6 CKLF-like MARVEL transmembrane domain containing 6 4.12E-06 206503 PM X at PML promyelocytic leukemia 4.26E-06 222033 PM S at FLT1 fms-related tyrosine kinase 1 (vascular endothelial 4.32E-06 growth factor? vascular permeability 202651 PM at LPGAT1 lysophosphatidylglycerol acyltransferase 1 4.48E-06 237587 PM at EST 4.SSE-06 237587 PM at 209970 PM X at CASP1 caspase 1, apoptosis-related cysteine peptidase 4.57E-06 (interleukin 1, beta, convertase) 222976 PM S at TPM3 tropomyosin 3 4.61E-06 227678 PM at XRCC6BP1 XRCC6 binding protein 1 4.64E-06 209035 PM at MDK midkine (neurite growth-promoting factor 2) 4.78E-06 205624 PM at CPA3 carboxypeptidase A3 (mast cell) 4.78E-06 203332 PM S at INPP5D inositol polyphosphate-5-phosphatase, 145 kDa 4.82E-06 211917 PM S at PRLR prolactin receptor 4.86E-06 219283 PM at C1GALT1C1 C1GALT1-specific chaperone 1 4.94E-06 239005 PM at FLJ39739 Hypothetical FLJ39739 4.99E-06 228114 PM X at C16orf13 chromosome 16 open reading frame 13 S.OOE-06 205295 PM at CKMT2 creatine kinase, mitochondrial 2 (sarcomeric) 5.19E-06 242131 PM at ATP6 ATP synthase FO subunit 6 S.23E-06 US 2017/O 137885 A1 May 18, 2017 85

TABLE 8-continued

Biopsy Microarray Si atures for SubAR using a 2-way 2-Step a roach - Second ste AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 202688 PM at TNFSF10 tumor necrosis factor (ligand) Superfamily, member 10 5.33 235536 PM at SNORD89 Small nucleolar RNA, CD box 89 5.35 214212 PM x at FERMT2 fermitin family member 2 5.35 212148 PM at PBX1 pre-B-cell leukemia homeobox 1 5.38 212504 PM at DIP2C DIP2 disco-interacting protein 2 homolog C 5.51 E-E-E-E-E- (Drosophila) 201697 PM S a D NMT1 DNA (cytosine-5-)-methyltransferase 1 5.53 212501 PM at EBPB CCAAT?enhancer binding protein (C/EBP), beta S.S4 204446 PM S a LOXS arachidonate 5-lipoxygenase 5.57 206011 PM at ASP1 caspase 1, apoptosis-related cysteine peptidase S.63 E-E-E-E- (interleukin 1, beta, convertase) 224663 PM s a FL2 cofilin 2 (muscle) 5.75 201949 PM x at APZB capping protein (actin filament) muscle Z-line, beta S.91 219436 PM S a MCN endomucin S.96 22O146 PM a toll-like receptor 7 6.03 209310 PM s 8. ASP4 caspase 4, apoptosis-related cysteine peptidase 6.11 2O7702 PM s 8. M AGI2 membrane associated guanylate kinase, WW and PDZ 6.12 domain containing 2 E-E-E-E-E-E- 204794 PM a USP2 dual specificity phosphatase 2 6.14 219202 PM a HBDF2 rhomboid 5 homolog 2 (Drosophila) 6.28 233496 PM S FL2 cofilin 2 (muscle) 6.38 224.578 PM a CC2 regulator of chromosome condensation 2 6.46 223104 PM a JAGN1 jagunal homolog 1 (Drosophila) 6.54 219161 PM S CKLF chemokine-like factor 6.57 226612 PM a UBE2OL1 ubiquitin-conjugating enzyme E2O family-like 1 6.62 204974 PM a RAB3A RAB3A, member RAS oncogene family 6.66 223.002 PM s 8. XRN2 5'-3' exoribonuclease 2 6.67 242601 PM a HEPACAM2 HEPACAM family member 2 6.71 205102 PM a TMPRSS2 transmembrane protease, serine 2 6.93 1569926 PM S. at SLC34A3 solute carrier family 34 (sodium phosphate), member 3 7.01 213596 PM a CASP4 caspase 4, apoptosis-related cysteine peptidase 7.18 200713 PM s at MAPRE1 microtubule-associated protein, RP/EB family, 7.54 member 1 203132 PM a RB1 retinoblastoma 1 7.60 209752 PM a REG1A regenerating islet-derived 1 alpha 7.65 211573 PM X at TGM2 transglutaminase 2 (C polypeptide, protein-glutamine 7.82 E-E-E- o gamma-glutamyltransferase) 207213 PM s at USP2 ubiquitin specific peptidase 2 7.87 217984 PM a RNASET2 ribonuclease T2 7.97 1553304 PM at LSM14B LSM14B, SCD6 homolog B (S. cerevisiae) 7.97 22993.7 PM x at LILRB1 Leukocyte immunoglobulin-like receptor, Subfamily B 7.98 E-E-E-E- (with TM and ITIM domains), member 200609 PM S at WDR1 WD repeat domain 1 8.01 205467 PM a CASP10 caspase 10, apoptosis-related cysteine peptidase 8.03 225331 PM a CCDC50 coiled-coil domain containing 50 8.OS 1S60017 PM at TMTC3 transmembrane and tetratricopeptide repeat 8.07 E-E-E-E- containing 3 200797 PM s at MCL1 myeloid cell leukemia sequence 1 (BCL2-related) 8.10 231337 PM a LOC10OSOS498 hypothetical LOC100505498 8.35 221666 PM S at PYCARD PYD and CARD domain containing 8.67 217733 PM s at TMSB10 hymosin beta 10 8.89 220933 PM S at ZCCHC6 Zinc finger, CCHC domain containing 6 892 235050 PM a SLC2A12 Solute carrier family 2 (facilitated glucose transporter), 8.98 E-E-E-E-E-E- 200634 PM a PFN1 9.1O 227727 PM a MRGPRF MAS-related GPR, member F 9.13 2I6638 PM S at PRLR prolactin receptor 9.14 2071.68 PM s at H2AFY H2A histone family, member Y 9.63 226184 PM a FMNL2 ormin-like 2 9.70 204846 PM a CP ceruloplasmin (ferroxidase) 9.71 210527 PM x at TUBA3C tubulin, alpha 3c 9.81 211368 PM s at CASP1 caspase 1, apoptosis-related cysteine peptidase 9.84 (interleukin 1, beta, convertase) E-E-E-E-E-E-E-E- 1556656 PM at EST 9.89E O 6 1556656 PM at 223323 PM x at TRPM7 transient receptor potential cation channel, Subfamily 9.92E O 6 M, member 7 210513 PM S at VEGFA vascular endothelial growth factor A 9.95 1553155 PM x at ATP6VOD2 ATPase, H+ transporting, lysosomal 38 kDa, VO subunit d2 1.01 212010 PM S at CDV3 CDV3 homolog (mouse) 1.02 o 209311 PM at BCL2-like 2 1.02 O 5 201917 PM S at solute carrier family 25, member 36 1.02 O 5 US 2017/O 137885 A1 May 18, 2017 86

TABLE 8-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - second step (AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 227396 PM at PTPRT protein tyrosine phosphatase, receptor type, J O4E-05 209278 PM S at TFPI2 tissue factor pathway inhibitor 2 O4E-05 209903 PM S at ATR ataxia telangiectasia and Rad3 related O6E-05 202763 PM at CASP3 caspase 3, apoptosis-related cysteine peptidase O8E-OS 218238 PM at GTPBP4. GTP binding protein 4 .09E-OS 206226 PM at HRG histidine-rich glycoprotein 1OE-05 224,462 PM S at CHCHD6 coiled-coil-helix-coiled-coil-helix domain containing 6 11E-OS 220603 PM S at MCTP2 multiple C2 domains, transmembrane 2 11E-OS 235.161 PM at LOC1005064S1 if hypothetical LOC100506451 ff, hypothetical 1E-OS LOC10OSO9094 LOC10OSO9094 211366 PM X at CASP1 caspase 1, apoptosis-related cysteine peptidase 12E-05 (interleukin 1, beta, convertase) 239636 PM at MCF2L MCF.2 cell line derived transforming sequence-like 12E-05 228740 PM at EST 12E-05 228740 PM at 216323 PM X at TUBA3C tubulin, alpha 3c fit tubulin, alpha 3d if tubulin, 13E-OS TUBA3D alpha 3e TUBA3E 205068 PM S at ARHGAP26 Rho GTPase activating protein 26 13E-OS 217983 PM S at RNASET2 ribonuclease T2 14E-05 206059 PM at ZNF91 Zinc finger protein 91 1SE-OS 206944 PM at HTR6 5-hydroxytryptamine (serotonin) receptor 6 17E-OS 215264 PM at EMX1 empty spiracles homeobox 1 18E-05 213551 PM X at PCGF2 polycomb group ring finger 2 18E-05 218194 PM at REXO2 REX2, RNA exonuclease 2 homolog (S. cerevisiae) 18E-05 227438 PM at ALPK1 alpha-kinase 1 19E-05 1053 PM at RFC2 replication factor C (activator 1) 2, 40 kDa 2OE-OS 227874 PM at EMCN endomucin 2OE-OS 201918 PM at SLC25A36 solute carrier family 25, member 36 2OE-OS 213355 PM at ST3GAL6 ST3 beta-galactoside alpha-2,3-sialyltransferase 6 21E-05 213923 PM at RAP2B RAP2B, member of RA5 oncogene family 23E-OS 220990 PM S at MIR21 if microRNA 21 / transmembrane protein 49 24E-05 TMEM49 213535 PM S at UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, 2SE-OS yeast) 205910 PM S at CEL F. carboxyl ester lipase (bile salt-stimulated lipase) f/ 2SE-OS LOC10OSO82O6 bile salt-activated lipase-like 204702 PM S at NFE2L3 nuclear factor (erythroid-derived 2)-like 3 27E-OS 230550 PM at MS4A6A membrane-spanning 4-domains, subfamily A, member 6A 29E-OS 205027 PM S at MAP3K8 mitogen-activated protein kinase kinase kinase 8 3OE-OS 209476 PM at TMX1 thioredoxin-related transmembrane protein 1 3OE-OS 209422 PM at PHF.20 PHD finger protein 20 32E-OS 207 754 PM at RASSF8 Ras association (RalGDSAF-6) domain family (N- .33E-OS terminal) member 8 35150 PM at CD40 CD40 molecule, TNF receptor Superfamily member 5 34E-05 41220 PM at SEPT9 septin 9 3SE-OS 227730 PM at EST 4OE-05 227730 PM at 206613 PM S a TAF1A TATA box binding protein (TBP)-associated factor, RNA 4OE-05 polymerase I, A, 48 kDa 201179 PM S a GNAI3 guanine nucleotide binding protein (G protein), alpha 41E-05 inhibiting activity polypeptide 3 208.850 PM S a THY1 Thy-1 cell Surface antigen 43E-05 217985 PM s a BAZ1A bromodomain adjacent to Zinc finger domain, 1A 44E-05 200798 PM X a MCL1 myeloid cell leukemia sequence 1 (BCL2-related) 4SE-OS 1555486 PM a at PRRSL proline rich 5 like 4SE-OS 221932 PM S a GLRXS glutaredoxin 5 4SE-OS 205079 PM s a MPDZ multiple PDZ domain protein 46E-05 241154 PM X a EST 47E-OS 241154 PM X at 219089 PM S a ZNF576 Zinc finger protein 576 SOE-OS 206219 PM s a WAV1 vav 1 guanine nucleotide exchange factor S2E-OS 1553153 PM at ATP6VOD2 ATPase, H+ transporting, lysosomal 38 kDa, VO subunit d2 S4E-OS 208.540 PM X at S100A11 S100 calcium binding protein A11 S6E-OS 223318 PM S a ALKBH7 alkB, alkylation repair homolog 7 (E. Coii) S6E-OS 226618 PM at UBE2OL1 ubiquitin-conjugating enzyme E2O family-like 1 57E-05 218092 PM S a AGFG1 Arf6AP with FG repeats 1 6SE-OS 229041 PM S a EST 66E-05 229041 PM S at 214366 PM S a ALOX5 arachidonate 5-lipoxygenase 66E-05 226820 PM at ZNF362 Zinc finger protein 362 68E-05 210426 PM x at RORA RAR-related orphan receptor A 68E-05 US 2017/O 137885 A1 May 18, 2017 87

TABLE 8-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - second step (AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 209545 PM S at RIPK2 receptor-interacting serine-threonine kinase 2 68E-05 214329 PM X at TNFSF10 tumor necrosis factor (ligand) Superfamily, member 10 69E-05 210176 PM a TLR1 toll-like receptor 1 .72E-OS 242167 PM a EST .73E-OS 242167 PM at 224352 PM S at CFL2 cofilin 2 (muscle) .73E-OS 223451 PM S at CKLF chemokine-like factor .76E-OS 202625 PM a LYN v-yes-1 Yamaguchi sarcoma viral related oncogene .79E-05 homolog 202748 PM a GBP2 guanylate binding protein 2, interferon-inducible 81E-05 209906 PM a C3AR1 complement component 3a receptor 1 81E-05 213869 PM X at THY1 Thy-1 cell Surface antigen 84E-05 225994 PM a CPSF2 cleavage and polyadenylation specific factor 2, 100 kDa 84E-05 226048 PM a MAPK8 mitogen-activated protein kinase 8 .8SE-OS 203828 PM S at L32 interleukin 32 .88E-OS 203947 PM a CSTF3 cleavage stimulation factor, 3' pre-RNA, subunit 3, .88E-OS 77 kDa 244811 PM a PHIP pleckstrin homology domain interacting protein .88E-OS 236293 PM a RHOH ras homolog gene family, member H .9OE-OS 214467 PM a GPR65 G protein-coupled receptor 65 91E-05 235309 PM a RPS1SA ribosomal protein S15a 91E-05 212024 PM x at FLII flightless 1 homolog (Drosophila) .93E-OS 205841 PM a AK2 Janus kinase 2 94E-05 205887 PM X at MSH3 mutS homolog 3 (E. coli) .9SE-OS 208743 PM S at YWHAB tyrosine 3-monooxygenase tryptophan 5- .98E-OS monooxygenase activation protein, beta polypeptid 238668 PM a EST .98E-OS 238668 PM at 205809 PM S at WASL Wiskott-Aldrich syndrome-like .99E-OS 218008 PM a C7orfa2 chromosome 7 open reading frame 42 .99E-OS 204198 PM S at RUNX3 runt-related transcription factor 3 2.OOE-OS 201040 PM a GNAI2 guanine nucleotide binding protein (G protein), alpha 2.01E-OS inhibiting activity polypeptide 2 223010 PM S at OCLAD1 OCIA domain containing 1 2.03E-OS 225511 PM a GPRCSB G protein-coupled receptor, family C, group 5, 2.04E-OS member B 226748 PM a LYSMD2 LysM, putative peptidoglycan-binding, domain 2.OSE-OS containing 2 206150 PM a CD27 CD27 molecule 2.06E-OS 213136 PM a PTPN2 protein tyrosine phosphatase, non-receptor type 2 2.07E-OS 202238 PM S at NNMT nicotinamide N-methyltransferase 2.07E-OS 203079 PM S at CUL2 cullin 2 2.07E-OS 201724 PM S at GALNT1 UDP-N-acetyl-alpha-D-galactosamine:potypeptide N- 2.O8E-OS acetylgalactosaminyltransferase 1 (Gal 226147 PM S at PIGR polymeric immunoglobulin receptor 2.O8E-OS 203091 PM a FUBP1 ar upstream element (FUSE) binding protein 1 2.11E-OS 219033 PM a PARP8 poly (ADP-ribose) polymerase family, member 8 2.12E-OS 225924 PM a FNIP2 olliculin interacting protein 2 2.14E-OS 230565 PM a ATP6V1G3 ATPase, H+ transporting, lysosomal 13 kDa, V1 subunit G3 2.14E-OS 1553906 PM S at FGD2 FYVE, RhoGEF and PH domain containing 2 2.16E-OS 208296 PM X at TNFAIP8 tumor necrosis factor, alpha-induced protein 8 2.18E-OS 209787 PM S at HMGN4 high mobility group nucleosomal binding domain 4 2.18E-OS 202957 PM a HCLS1 hematopoietic cell-specific Lyn Substrate 1 2.19E-OS 210785 PM S at C1orf58 chromosome 1 open reading frame 38 2.2OE-OS 228770 PM a GPR146 G protein-coupled receptor 146 2.23E-OS 200829 PM X at ZNF2O7 Zinc finger protein 207 2.26E-OS 223344 PM S at MS4A7 membrane-spanning 4-domains, subfamily A, member 7 2.28E-OS 222885 PM a EMCN endomucin 2.3OE-OS 202211 PM a ARFGAP3 ADP-ribosylation factor GTPase activating protein 3 2.32E-OS 238,581 PM a GBP5 guanylate binding protein 5 2.36E-OS 208821 PM a SNRPB Small nuclear ribonucleoprotein polypeptides B and B1 2.38E-OS 203137 PM a WTAP Wilms tumor 1 associated protein 2.38E-OS 213102 PM a ACTR3 ARP3 actin-related protein 3 homolog (yeast) 24OE-05 227384 PM S at EST 2.41E-OS 227384 PM S at 233632 PM S at XRN1 5'-3' exoribonuclease 1 2.42E-OS 220742 PM S at NGLY1 N-glycanase 1 2.44E-OS 208.642 PM S at XRCCS X-ray repair complementing defective repair in 2.46E-OS Chinese hamster cells 5 (double-strand-b 225814 PM at XRN1 5'-3' exoribonuclease 1 2.46E-OS 209295 PM at TNFRSF10B tumor necrosis factor receptor Superfamily, member 10b 2.47E-OS 218665 PM at FZD4 frizzled homolog 4 (Drosophila) 2.48E-OS US 2017/O 137885 A1 May 18, 2017 88

TABLE 8-continued Biopsy Microarray Signatures for SubAR using a 2-way 2-Step approach - second step (AR vs. SubAR p-value(cAR Bx Probeset ID Gene Symbol Gene Title vs. SubAR Bx) 219023 PM at AP1AR adaptor-related protein complex 1 associated 2. SOE-OS regulatory protein 2025.10 PM S at TNFAIP2 tumor necrosis factor, alpha-induced protein 2 2.53E-OS 221477 PM S at SOD2 Superoxide dismutase 2, mitochondrial 2.57E-05 203182 PM S at SRPK2 SRSF protein kinase 2 2.59E-OS 209189 PM at FOS FBJ murine osteosarcoma viral oncogene homolog 2.61E-OS 219574 PM at MARCH1 membrane-associated ring finger (C3HC4) 1 2.62E-OS 217549 PM at EST217549 PM at 2.62E-OS 2101.06 PM at RDHS retinol dehydrogenase 5 (11-cis-9-cis) 2.64E-OS 33760 PM at PEX14 peroxisomal biogenesis factor 14 26SE-OS 238423 PM at SYTL3 synaptotagmin-like 3 26SE-OS 230176 PM at EST 2.66E-OS 230176 PM at 218546 PM at C1orf115 chromosome 1 open reading frame 115 2.7OE-OS 1558702 PM at TEX10 testis expressed 10 2.75E-05 212733 PM at KIAAO226 KIAAO226 2.75E-05 229659 PM S at EST 2.76E-OS 229.659 PM S at 207809 PM S at ATP6AP1 ATPase, H+ transporting, lysosomal accessory protein 1 2.77E-05 202431 PM S at MYC v-myc myelocytomatosis viral oncogene homolog 2.79E-05 (avian) 212433 PM X at RPS2 ribosomal protein S2 2.8OE-OS 223.086 PM X at MRPLS1 mitochondrial ribosomal protein L51 2.81E-OS 228162 PM at ESD esterase D 2.84E-OS 214770 PM at MSR1 macrophage scavenger receptor 1 2.84E-OS 201830 PM S at NET1 neuroepithelial cell transforming 1 2.85E-OS 212314 PM at SEL1L3 sel-1 suppressor of lin-12-like 3 (C. elegans) 2.86E-OS 209360 PM S at RUNX1 runt-related transcription factor 1 2.89E-05 221 698 PM S at CLEC7A C-type lectin domain family 7, member A 2.90E-OS 201359 PM at COPB1 coatomer protein complex, Subunit beta 1 2.91E-OS 217157 PM X at IGKG) // IGKC immunoglobulin kappa locus immunoglobulin 2.92E-OS kappa constant

TABLE 9 2-Way 2-Step Microarray Analysis (AR v. SubAR: AR v. TX; and SubAR v. TX) using biopsy samples - Results Predicted

Real TX SCAR AR

TX 22 2 1 SCAR O 18 AR O 2 18 Positive Negative % Predictive Sensitivity Specificity Predictive Predicitve Method Classifies Accuracy (%) (%) Value (%) Value (%) AUC

Nearest Centroid TX w.S. AR 97% 100% 94% 95% 100% O.96S (2 Step Prediction) TX vs. SCAR 95% 100% 90% 91% 100% O.947 AR ws. SCAR 86% 90% 81% 81% 90% O.862

TABLE 10 3-Way 1-Step NGS Analysis (AR v. SubAR v. TX) using biopsy samples - Results Predicted

Real TX SUBAR AR

TX 22 2 1 SCAR 8 11 3 AR O 8 11 US 2017/O 137885 A1 May 18, 2017 89

TABLE 10-continued 3-Way 1-Step NGS Analysis (AR v. SubAR v. TX) using biopsy samples - Results Predictive Negative % Predictive Sensitivity Specificity Positive Predicitve Method Classifies Accuracy (%) (%) Value (%) Value (%) AUC

Nearest Centroid TX w.S. AR 97% 100% 92% 95% 100% O.967 (1 Step Prediction) TX vs. SCAR 80% 729% 83% 729, 91% 0.795 AR ws. SCAR 69% S8% 79% 79% 59% 0.689

TABLE 11 Biopsy NGS Signatures for SubAR using a 2-Step approach (AR + SubAR VS. TX and SubAR VSTX) - first Step: AR + SubAR VS. TX p-value(AR+ Column ID To Gene Name SCAR vs. TX) 1 CCR2 chemokine (C-C motif) receptor 2 4.89E-13 2 Tbc1 d10c TBC1 domain family, member 10C 5.04E-11 3 Ly9 lymphocyte antigen 9 188E-10 4 Co48 CD48 molecule 3.78E-10 5 Bin2 bridging integrator 2 5.43E-10 6 Co2 CD2 molecule 5.64E-10 7 ALOX5 arachidonate 5-lipoxygenase 7.26E-10 8 KZF3 IKAROS family Zinc finger 3 (Aiolos) 7.8OE-10 9 C247 CD247 molecule 8.24E-10 10 CD1D CD1d molecule 1.OSE-09 11 C96 CD96 molecule 1.27E-09 12 Ptpre protein tyrosine phosphatase, receptor 1.61E-09 13 kZf1 IKAROS family Zinc finger 1 (Ikaros) 2.45E-09 14 PTPN22 protein tyrosine phosphatase, non-recep 2.S1E-09 15 EMB embigin homolog (mouse) 2.94E-09 16 runt-related transcription factor 3 3.OOE-09 17 MINDA myeloid cell nuclear differentiation an 3.08E-09 18 Arl4c ADP-fibosylation factor-like 4C 3.41E-09 19 L16 interleukin 16 (lymphocyte chemoattract 4.57E-09 2O DOCK2 dedicator of cytokinesis 2 S.47E-09 21 TGAL integrin, alpha L (antigen CD11A (p180) 6.07E-09 22 Fgd2 FYVE, RhoGEF and PH domain containing 2 6.43E-09 23 PARVG parvin, gamma 6.49E-09 24 CD3D CD3d molecule, delta (CD3-TCR complex) 6. SOE-09 25 Mpeg1 macrophage expressed 1 6.53E-09 26 LCP1 ymphocyte cytosolic protein 1 (L-plast 6.58E-09 27 ARHGAP15 Rho GTPase activating protein 15 7.55E-09 28 NLRCS NLR family, CARD domain containing 5 7.7OE-09 29 GZMK granzyme K (granzyme 3; tryptase II) 7.96E-09 30 BIRC3 baculoviral IAP repeat-containing 3 8.08E-09 31 TMC8 transmembrane channel-like 8 8.56E-09 32 RGS18 regulator of G-protein signaling 18 1.OOE-08 33 Cd3g CD3g molecule, gamma (CD3-TCR complex) 1.OOE-08 34 Amical adhesion molecule, interacts with CXADR 1.04E-08 35 12rg interleukin 2 receptor, gamma (severe c 1.19E-08 36 npp5d inositol polyphosphate-5-phosphatase, 1 1.25E-08 37 cStA cystatin A (Stefin A) 1.26E-08 38 LIMD2 LIM domain containing 2 144E-08 39 dapp1 ual adaptor of phosphotyrosine and 3-p 1.65E-08 40 NCKAP1L, NCK-associated protein 1-like 168E-08 41 MS4af membrane-spanning 4-domains, Subfamily 18OE-08 42 TNFAIP3 tumor necrosis factor, alpha-induced pr 1.87E-08 43 IL7R interleukin 7 receptor 188E-08 44 EVI2B ecotropic viral integration site 2B 188E-08 45 C1orf162 chromosome 1 open reading frame 162 198E-08 46 SLAMF7 SLAM family member 7 2.09E-08 47 RNASE6 ribonuclease, RNase A family, kó 2.2OE-08 48 CXorf21 chromosome X open reading frame 21 2.38E-08 49 SCML4 sex comb on midleg-like 4 (Drosophila) 2.42E-08 50 CCL5 chemokine (C-C motif) ligand 5 2.44E-08 51 EST EST2 2.S2E-08 52 Pyhin1 pyrin and HIN domain family, member 1 2.64E-08 53 Co.8a. CD8a molecule 2.79E-08 S4 CdS2 CD52 molecule 2.99E-08 55 SAMD3 sterile alpha motif domain containing 3 3.16E-08 5 6 btk Bruton agammaglobulinemia tyrosine kina 3.18 E-08 US 2017/O 137885 A1 May 18, 2017 90

TABLE 11-continued Biopsy NGS Signatures for SubAR using a 2-Step approach (AR + SubAR VS. TX and SubAR VSTX) - first Step: AR + SubAR VS. TX p-value(AR+ Column ID To Gene Name SCAR vs. TX) 57 IRF4 interferon regulatory factor 4 3.24E-08 58 GAB3 GRB2-associated binding protein 3 3.2SE-08 59 CSF2RA colony stimulating factor 2 receptor, a 3.36E-08 60 P2RY13 purinergic receptor P2Y, G-protein coup 3.46E-08 61 FYB FYN binding protein (FYB-120/130) 3.58E-08 62 TRAF3IP3 TRAF3 interacting protein 3 3.86E-08 63 PTAFR platelet-activating factor receptor 3.94E-08 64 Arhgap25 Rho GTPase activating protein 25 3.99E-08 65 myolf myosin IF 4.09E-08 66 CELF2 CUG triplet repeat, RNA binding protein 4.18E-08 67 MS4A6A membrane-spanning 4-domains, Subfamily 4.18E-08 68 kcna3 potassium voltage-gated channel, shaker 4.3OE-08 69 CLIC2 chloride intracellular channel 2 4.33E-08 70 IL1ORA interleukin 10 receptor, alpha 4.73E-08 71 NHEDC2 Na+ H+ exchanger domain containing 2 4.76E-08 72 HEMIS hymocyte selection pathway associated 4.88E-08 73 RHGAP30 Rho GTPase activating protein 30 4.97E-08 74 RKCB protein kinase C, beta S.O.3E-08 75 sCLS1 hematopoietic cell-specific Lyn Substra S.O8E-08 76 gS10 regulator of G-protein signaling 10 5.66E-08 77 vi2a ecotropic viral integration site 2A 5.83E-08 78 l sialophorin 5.84E-08 79 IL1B interleukin 1, beta 5.88E-08 8O LOC10O133678 similar to hCG2042724; similar to HLA c 6.41E-08 81 ITGA4 integrin, alpha 4 (antigen CD49D, alpha 6.94E-08 82 CCDC109B coiled-coil domain containing 109B 7.03E-08 83 Gapt GRB2-binding adaptor protein, transmemb 7.43E-08 84 APBB1P amyloid beta (A4) precursor protein-bin 7.S1E-08 85 arhgdib Rho GDP dissociation inhibitor (GDI) be 7.69E-08 86 CD18O CD180 molecule 7.79E-08 87 PIK3CG phosphoinositide-3-kinase, catalytic, g 7.94E-08 88 CCR5 chemokine (C-C motif) receptor 5 8. OSE-08 89 dgkA diacylglycerol kinase, alpha 80 kDa 8.25E-08 90 RASSF2 Ras association (RalGDSAF-6) domain fa 8.S2E-08 91 TAGAP T-cell activation RhoGTPase activating 8.59E-08 92 CASP1 caspase 1, apoptosis-related cysteine p 8.74E-08 93 LOC606724 coronin, actin binding protein, 1A pseu 9.01E-08 94 REEP4 receptor accessory protein 4 9.04E-08 95 GIMAP7 GTPase, IMAP family member 7 9.16E-08 96 KLRB1 killer cell lectin-like receptor subfam 9.85E-08 97 lcp2 lymphocyte cytosolic protein 2 (SH2 dom 9.99E-08 98 Lair1 leukocyte-associated immunoglobulin-lik O1E-07 99 CD44 CD44 molecule (Indian blood group) O2E-07 OO GZMA granzyme A (granzyme 1, cytotoxic T-lym O3E-07 O1 rac2 ras-related C3 botulinum toxin substrat 13E-07 O2 STAMBPL1 STAM binding protein-like 1 17E-07 O3 FAM78A family with sequence similarity 78, mem .33E-07 O4 FAIM3 Fas apoptotic inhibitory molecule 3 35E-07 05 Co6 CD6 molecule 39E-07 O6 EST EST9 42E-07 O7 MAP4K1 mitogen-activated protein kinase kinase 47E-07 O8 CLEC10A C-type lectin domain family 10, member S2E-07 09 SP140 SP140 nuclear body protein S2E-07 10 SELL Selectin L. S9E-07 11 CRTAM cytotoxic and regulatory T cell molecul 6OE-07 12 FCER1G Fc fragment of IgE, high affinity I, re 64E-07 13 CP ceruloplasmin (ferroxidase) .73E-07 14 GPR171 G protein-coupled receptor 171 .82E-07 15 Cx3cr1 chemokine (C-X3-C motif) receptor 1 .87E-07 16 TBXAS1 hromboxane A synthase 1 (platelet) .87E-07 17 SLAMF1 signaling lymphocytic activation molecu .88E-07 18 P2RX7 purinergic receptor P2X, ligand-gated I .93E-07 19 SAMHD1 SAM domain and HD domain 1 94E-07 2O EST EST16 2.OOE-07 21 Miat myocardial infarction associated transc 2.01E-07 22 gmfg glia maturation factor, gamma 2.07E-07 23 LCK ymphocyte-specific protein tyrosine ki 2.11E-07 24 SLA Src-like-adaptor 2.14E-07 25 CARD16 caspase recruitment domain family, memb 2.15E-07 26 ETS1 v-ets erythroblastosis virus E26 oncoge 2.17E-07 27 BAZ1A bromodomain adjacent to Zinc finger dom 2.2OE-07 US 2017/O 137885 A1 May 18, 2017 91

TABLE 11-continued Biopsy NGS Signatures for SubAR using a 2-Step approach (AR + SubAR VS. TX and SubAR VSTX) - first Step: AR + SubAR VS. TX p-value(AR+ Column ID To Gene Name SCAR vs. TX) 28 Selplg Selectin P ligand 2.28E-07 29 IFI16 interferon, gamma-inducible protein 16 2.29E-07 30 rassfS Ras association (RalGDSAF-6) domain fa 2.S1E-07 31 ADCY7 adenylate cyclase 7 2.58E-07 32 PLCB2 phospholipase c, beta 2 2.59E-07 33 kcnJ10 potassium inwardly-rectifying channel, 2.6OE-07 34 STAT4 signal transducer and activator of train 2.62E-07 35 GPR65 G protein-coupled receptor 65 2.66E-07 36 AIM2 absent in melanoma 2 2.69E-07 37 SERPINB9 serpin peptidase inhibitor, clade B (ov 2.69E-07 38 Ccdc88b coiled-coil domain containing 88B 2.71E-07 39 FECH ferrochelatase (protoporphyria) 2.91E-07 40 Akna AT-hook transcription factor 2.99E-07 41 APOBEC3D apolipoprotein B mRNA editing enzyme, c 3.OOE-07 42 BTN3A2 butyrophilin, subfamily 3, member A2 3.01E-07 43 ARHGAP9 Rho GTPase activating protein 9 3.2OE-07 44 pAG1 phosphoprotein associated with glycosph 3.23E-07 45 SIGLEC10 sialic acid binding Ig-like lectin 10 3.26E-07 46 FGL2 -like 2 3.3OE-07 47 Polf2 POU class 2 homeobox2 3.43E-07 48 CYTIP cytohesin 1 interacting protein 3.44E-07 49 Gad1 glutamate decarboxylase 1 (brain, 67 kDa 3.56E-07 50 toll-like receptor 10 3.56E-07 51 WAS Wiskott-Aldrich syndrome (eczema-thromb 3.59E-07 52 prex1 phosphatidylinositol-3,4,5-trisphosphat 3.64E-07 53 CD69 CD69 molecule 3.68E-07 S4 SLAMF6 SLAM family member 6 3.74E-07 55 CD37 CD37 molecule 3.8OE-07 56 ST8SIA4 ST8 alpha-N-acetyl-neuraminide alpha-2, 3.83E-07 57 ANKRD44 ankyrin repeat domain 44 3.9 OE-07 58 RASAL3 RAS protein activator like 3 3.92E-07 59 KLRD1 killer cell lectin-like receptor subfam 3.93E-07 60 SMAP2 Small ArfCAP2 4.13E-O7 61 pstpip2 proline-Serine-threonine phosphatase in 4.24E-O7 62 FAM6SB amily with sequence similarity 65, mem 4.25E-07 63 GIMAP4 GTPase, IMAP family member 4 4.36E-O7 64 LY86 ymphocyte antigen 86 4.42E-O7 65 FMNL1 ormin-like 1 4.63E-O7 66 ermit ermitin family homolog 3 (Drosophila) 4.7OE-07 67 complement component 1, S Subcomponent 4.78E-07 68 butyrophilin, subfamily 2, member A2 4.78E-07 69 EST17 4.92E-O7 70 ol-like receptor 6 4.94E-O7 71 interferon regulatory factor 8 4.98E-O7 72 CD163 CD163 molecule S.O2E-07 73 LILRB1 eukocyte immunoglobulin-like receptor, S.O.3E-07 74 APOBEC3F apolipoprotein B mRNA editing enzyme, c S.14E-07 75 tgaX integrin, alpha X (complement component 5.19E-07 76 CTSS cathepsin S S.S4E-07 77 HCST hematopoietic cell signal transducer S.6SE-07 78 ccdc.69 coiled-coil domain containing 69 S.66E-07 79 C1r complement component 1, r Subcomponent S.67E-07 8O Nkg7 natural killer cell group 7 sequence 5.7OE-07 81 csf1 colony stimulating factor 1 (macrophage S.82E-07 82 pycar PYD and CARD domain containing 5.87E-07 83 SP14OL SP140 nuclear body protein-like 5.93E-07 84 Cd53 CD53 molecule 6.01E-O7 85 Srgn Serglycin 6.09E-07 86 SERPINB8 serpin peptidase inhibitor, clade B (ov 6.15E-07 87 L4R interleukin 4 receptor 6.3OE-07 88 GBP2 guanylate binding protein 2, interferon 6.39E-07 89 Fcgr2b Fc fragment of IgG, low affinity IIb, r 6.49E-07 90 TIMP1 TIMP metallopeptidase inhibitor 1 6.SSE-07 91 C17orf37 chromosome 17 open reading frame 87 6.64E-O7 92 GLIPR2 GLI pathogenesis-related 2 6.65E-07 93 lysozyme (renal amyloidosis) 7.18E-07 94 KIAAO748 7.3OE-07 95 v- myeloblastosis viral oncogene hom 7.48E-07 96 C-type lectin domain family 7, member A 7.62E-07 97 kelch-like 6 (Drosophila) 7.67E-07 98 interleukin 4 induced 1 7.87E-07 US 2017/O 137885 A1 May 18, 2017 92

TABLE 11-continued Biopsy NGS Signatures for SubAR using a 2-Step approach (AR + SubAR vs. TX and SubAR vs TX) - first step: AR + SubAR vs. TX p-value(AR+ Column ID To Gene Name SCAR vs. TX) 199 APOBEC3G apolipoprotein B mRNA editing enzyme, c 8.OOE-07 2OO TRANK1 lupus brain antigen 1 8.2OE-07

TABLE 12 Biopsy NGS Signatures for SubAR using a 2-Step approach (AR+ SubAR vs. TX and AR v. SubAR) - second step: AR vs. SubAR p-value (cAR vs. Column ID To Gene Name SubAR) 4057 LTF lactotransferrin 3.02E-07 400746 C1orf130 chromosome 1 open reading frame 130 1.17E-O6 4.192 Mk midkine (neurite growth-promoting facto 1.6OE-06 51705 EMCN endomlucin 3.01E-O6 4316 mmp7 matrix metallopeptidase 7 (matrilysin, 4.37E-06 1056 Cel carboxyl ester lipase (bile salt-stimul S.O1E-O6 1408O3 TRPM6 transient receptor potential cation cha S.75E-06 245973 ATP6V1C2 ATPase, H+ transporting, lysosomal 42 kD S.97E-06 S5917 CTTNBP2NL CTTNBP2 N-terminal like 7.89E-06 221395 Gpr116 G protein-coupled receptor 116 9.47E-O6 S284 PIGR polymeric immunoglobulin receptor 1.OSE-OS 6289 SAA2 serum amyloid A2 1.32E-OS 15728S SGK223 homolog of rat pragma of Rind2 1.38E-OS 9021 socs3 suppressor of cytokine signaling 3 1.39E-OS S6938 ARNTL2 aryl hydrocarbon receptor nuclear trans 14SE-OS 64332 NFKBIZ. nuclear factor of kappa light potypepti 147E-OS S1279 C1RL complement component 1, r Subcomponent- 1.6SE-OS 834 CASP1 caspase 1, apoptosis-related cysteine p 1.69E-05 1191 clu clusterin 1.91E-OS 10S60 SLC19A2 solute carrier family 19 (thiamine tran 194E-OS 2321 FLT1 fms-related tyrosine kinase 1 (vascular 2.OOE-OS S452 Polf2 POU class 2 homeobox2 2.09E-OS 11228 rassf8 Ras association (RalGDSAF-6) domain fa 2.21E-OS 2919 CXCL1 chemokine (C-X-C motif) ligand 1 (melan 2.34E-OS 7102 TSPANT tetraspanin 7 2.34E-OS 64092 SAMSN1 SAM domain, SH3 domain and nuclear loca 2. SOE-OS 9447 AIM2 absent in melanoma 2 2.54E-OS 1334.18 EMB embigin homolog (mouse) 2.58E-OS 3455 FNAR2 interferon (alpha, beta and omega) rece 2.63E-OS S847S Ms4af membrane-spanning 4-domains, Subfamily 2.83E-OS 54997 TESC escalcin 2.84E-OS 6372 Cxc6 chemokine (C-X-C motif) ligand 6 (granu 2.87E-OS 201633 TIGIT T cell immunoreceptor with Ig and ITIM 2.99E-OS 2S3012 HEPACAM2 HEPACAM family member 2 3.26E-OS 118788 Pik3ap1 phosphoinositide-3-kinase adaptor prote 3.32E-OS 245,972 Atp6vOd2 ATPase, H+ transporting, lysosomal 38 kD 3.34E-OS 7852 CXCR4 chemokine (C-X-C motif) receptor 4 3.36E-OS 79668 PARP8 poly (ADP-ribose) polymerase family, me 3.42E-OS 942 CD86 CD86 molecule 3.S1E-OS 112597 LOCS41471 hypothetical LOC541471; non-protein cod 3.57E-05 S8191 CXCL16 chemokine (C-X-C motif) ligand 16 3.58E-OS 22982 dip2c DIP2 disco-interacting protein 2 homolo 3.66E-OS 11177 BAZ1A bromodomain adjacent to Zinc finger dom 3.79E-0S 863S RNASET2 ribonuclease T2 3.82E-OS 3273 HRG histidine-rich glycoprotein 3.8SE-OS 10346 TRIM22 ripartite motif-containing 22 4.OOE-05 83988 NCALD neurocalcin delta 4.07E-OS 639 PRDM1 PR domain containing 1, with ZNF domain 4.1OE-05 83660 TLN2 alin 2 4.11E-05 284996 Rnfl49 ring finger protein 149 4.12E-OS 4773 NFATC2 nuclear factor of activated T-cells, cy 4.2OE-05 S967 REG1A regenerating islet-derived 1 alpha; reg 4.2SE-OS 9235 L32 interleukin 32 4.45E-05 27071 dapp dual adaptor of phosphotyrosine and 3-p 4S2E-OS 7127 TNFAIP2 tumor necrosis factor, alpha-induced pr 4.64E-OS 4064 CD18O CD180 molecule 4.81E-OS 10859 LILRB1 leukocyte immunoglobulin-like receptor, 4.87 E-OS