US 2016O23750 1A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0237501 A1 SHARP et al. (43) Pub. Date: Aug. 18, 2016

(54) BIOMARKERS FOR DIAGNOSIS OF Related U.S. Application Data TRANSIENT SCHEMICATTACKS (62) Division of application No. 13/182,630, filed on Jul. (71) Applicant: The Regents of the University of 14, 2011, now abandoned. California, Oakland, CA (US) (60) Provisional application No. 61/364.334, filed on Jul. 14, 2010. (72) Inventors: Frank SHARP, Davis, CA (US); Xinhua ZHAN. Vacaville, CA (US); Publication Classification Glen C. JICKLING, Sacramento, CA (US): S. Claiborne JOHNSTON, San (51) Int. Cl. Francisco, CA (US) CI2O I/68 (2006.01) (52) U.S. Cl. (73) Assignee: The Regents of the University of CPC ...... CI2O 1688 (2013.0); CI2O 2600/158 California, Oakland, CA (US) (2013.01); C12O 2600/1 18 (2013.01) (57) ABSTRACT (21) Appl. No.: 15/043,577 The present invention provides methods and compositions for diagnosing and predicting the risk and cause of transient (22) Filed: Feb. 14, 2016 ischemic attacks (TIA). Patent Application Publication Aug. 18, 2016 Sheet 1 of 4 US 2016/0237SO1 A1

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BOMARKERS FOR DIAGNOSIS OF present invention is based, in part, on gene expression profiles TRANSIENT SCHEMICATTACKS that provide insight into the immunological differences that exist in patients with TIAs. CROSS-REFERENCE TO RELATED APPLICATIONS BRIEF SUMMARY OF THE INVENTION 0001. This application is a divisional of U.S. application 0008. The present invention provides compositions and Ser. No. 13/182,630, filed on Jul. 14, 2011, which claims the methods for determining the occurrence, predicting the risk benefit of U.S. Provisional Application No. 61/364,334, filed of occurrence and predicting the cause of transient ischemic on Jul. 14, 2010, the entire disclosure of which is hereby attacks. incorporated herein by reference for all purposes. 0009. Accordingly, in one aspect, the invention provides methods for diagnosing a transientischemic attack (TIA) or a STATEMENT AS TO RIGHTS TO INVENTIONS predisposition for experiencing TIA, the method comprising: MADE UNDER FEDERALLY SPONSORED determining a level of expression of a plurality of TIA-asso RESEARCH AND DEVELOPMENT ciated biomarkers in a biological sample from a patient, wherein an increase or decrease of the level of expression 0002 This invention was made with Government support compared to a control indicates that the patient has suffered or under Grant No. NS056302, awarded by the National Insti is at risk of experiencing TIA, wherein the plurality of TIA tutes of Health. The government has certain rights in this associated biomarkers is selected from the biomarkers set invention. forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and 9. 0010. In some embodiments, the methods further com FIELD OF THE INVENTION prise obtaining a biological sample from the patient. In some 0003. The present invention provides methods and com embodiments, the biological sample is blood, serum or positions for diagnosing and predicting the risk and cause of plasma. transient ischemic attacks (TIA). 0011. In some embodiments, the determining step is per formed at 3 or fewer hours after a suspected ischemic event. BACKGROUND OF THE INVENTION In some embodiments, the determining step is performed at 3 or more hours after a suspected ischemic event, for example, 0004 Transient ischemic attacks (TIAS) are common, at about 6, 12, 24, 36, 48 or more hours after a suspected affecting over 300,000 persons per year in the United States ischemic event. In some embodiments, the determining step alone. Though TIA symptoms resolve by definition, TIAS are is performed at least 24 hours after a suspected ischemic far from benign. As many as 25% of TIA patients have recur event. rentischemic vascular events that occur within days to weeks 0012. In some embodiments, an increased expression following a TIA (1-3). Despite the high incidence and clinical level of one or more or all TIA-associated biomarkers importance, the development of therapies specifically tar selected from the group consisting of DKFZP434B061, geted toward TIA has been limited by the paucity of knowl FAM55D, FLJ30375, IGFBP5, LTER and SCN2A indicates edge regarding the underlying biology. Furthermore, the that the patient has suffered or is at risk of experiencing TIA. clinical diagnosis of TIA is imperfect and extensive evalua In some embodiments, an increased expression level of one or tion in those incorrectly diagnosed with TIA is costly (4). more or all TIA-associated biomarkers selected from the 0005 We have previously demonstrated that blood gene group consisting of GABRB2, ELAVL3, TWIST1, DPPA4, expression profiles in rats change following experimental DKFZP434P211, DLX6, ZNF479, ASTN2, SNX31, ischemic strokes and TIAS (5). Very brief focal ischemia in ALS2CR11, LOC440345 indicates that the patient has suf rats, simulating human TIA, elicits a dramatic change in brain fered or is at risk of experiencing TIA. tissue characterized by increased Heat Shock Protein 0013. In some embodiments, an increased expression (HSP70) expression, microglial activation and macrophage level of one or more or all TIA-associated biomarkers infiltration (6). This change in brain cellular function and selected from the group consisting of GABRB2, ELAVL3, inflammation alters blood immune cells, a process that can be COL1A1, SHOX2, GABRB2, TWIST1, DPPA4, detected using whole genome expression analysis (5). Fur DKFZP434P211, WIT1, SOX9, DLX6, ANXA3, EPHA3, thermore, the genes and associated functional pathways differ SOX11, SLC26A8, CCRL1, FREM2, STOX2, ZNF479, markedly between very brief focal ischemia and ischemic LOC338862, ASTN2, FOLH1, SNX31, KREMEN1, stroke (5). ZNF479, ALS2CR11, FIGN, RORB, LOC732096, GYPA, 0006 Human TIAS have also been associated with alter ALPL, LHX2, GALNT5, SRD5A2L2, GALNT14, OVOL2, ations in Systemic inflammation. TIA patients tend to have BMPR1B, UNC5B, ODZ2, ALPL, RASAL2, SHOX, elevated C-reactive protein (CRP) (7), IL-6, VCAM-1 and C19orf59, ZNF114, SRGAP1, ELAVL2, NCRNA00032, cytokine levels, as well as elevated leukocyte counts (8-10). LOC440345, FLJ30375, TFPI, PTGR1, ROBO1, NR2F2, Lp-PLA2, a marker of unstable atherosclerotic plaque, is also GRM5, LUM, FLJ39051, COL1A2, CASP5, OPCML, associated with TIA (11-12) as are fibrinogen (13-14) and TTC6, TFAP2B, CRISP2, SOX11, ANKRD30B, FLJ39051, D-Dimer (15). Whether such biological differences represent SCN2A, MYNN, FOXA2, DKFZP434B061, LOC645323, a cause or consequence of TIA remains unclear. However, SNIP, LOC645323, LOC374491, ADAM30, SIX3, better understanding of the pathophysiology represented by FLJ36144, CARD8, KREMEN1, RP1-127L4.6, FAM149A such differences will facilitate development of treatments B3GAT2, SPOCK3, G30, ITGBL1, IQGAP3, C7orfA5, targeted to TIA. ZNF608, LOC375010, LRP2, TGFB2, SHOX2, HOXC4/// 0007 Gene expression has been useful for identifying dif HOXC6, ELTD1, FAM182B///RP13-401N8.2, PROO478, ferences between patients with ischemic stroke and controls LIFR, FOLH1, EHF, NDST3, BRUNOL5, LOC728460, (16-18), but such studies have not been applied to TIA. The PDE1A, POU2AF1, FAT1, PCDH11X///PCDH11Y, US 2016/02375O1 A1 Aug. 18, 2016

FLJ37786, SLC22A4, DHRS13, EHF, MEG3, PIWIL1, MMP 19, MMP26, COL1A1, COL1A2, COL3A1, LOC203274, LOC100.133920///LOC286297, DMRT1, COL10A1, COL11A1, COL25A1, COL27A1, FGFs and ADM, VWA3B, GAFA3, HESX1, ADAMDEC1, CAV1, EGFR is increased in comparison to the control, and the LAMB4, TPTE, PPP1R1C, HPSE, AIM2, RUNDC3B, patient is determined to have atherosclerosis. CARD16, FAM124A, MGC39584, OSM, RFX2, MYBPC1, 0019. In some embodiments, the patient is exhibiting LTBR, C18orf2, SNRPN, FLJ36031, IL1B, TRPM1, symptoms of TIA. In some embodiments, the patient is OSTCL, MAPK14, KCNJ15///LOC100131955, FIGN, asymptomatic. HNT, S100A12, CHIT1, C7orf53, FAM13A1, GNAO1, 0020. In some embodiments, the methods further com MAPK14, FAM55D, PRKD2, LIMK2, C18orf54, IGFBP5, prise the step of providing an appropriate treatment or pre EVI1, PLSCR1, FOXC1, LOC646627, ZNF462, CNTLN, vention regime for TIA to the patient. ZNF438, DEFB105A///DEFB105B, LOC34.0017, C1orf67, 0021. In some embodiments, the level of expression of the ACSL1, ADH1B, SLC2A14///SLC2A3, IL1B, ST3GAL4, biomarker is determined at the transcriptional level. For UBE2J1, PNPLA3 and PAPPA indicates that the patient has example, RNA levels of the biomarker can be determined. suffered or is at risk of experiencing TIA. The RNA can be mRNA, rRNA, tRNA or microRNA 0014. In some embodiments, a decreased expression level (miRNA). In some embodiments, the level of RNA expres of one or more or all TIA-associated biomarkers selected sion is determined using a microarray. from the group consisting of ATG9B, DIP2C, EDAR, 0022. In some embodiments, the level of expression is GSTM1, GUSBL2, SMURF2, ZNF512B indicates that the determined by detecting hybridization of an TIA-associated patient has suffered or is at risk of experiencing TIA. gene probe to gene transcripts of the biomarkers in the bio 0015. In some embodiments, a decreased expression level logical sample. of one or more or all TIA-associated biomarkers selected 0023. In some embodiments, the hybridization step is per from the group consisting of NBPF10///RP11-94I2.2, formed on a nucleic acid microarray chip. In some embodi SFXN1, SPIN3, UNC84A, OLFM2, PPM1 K, P2RY10, ments, the hybridization step is performed in a microfluidics ZNF512B, MORF4L2, GIGYF2, ERAP2, SLFN13, assay plate. LOC4.01431, MED6, BAIAP2L1///LOC100128461, 0024. In some embodiments, the level of expression is LNPEP. MBNL1, NOS3, MCF2L, KIAA1659, SCAMP5, determined by amplification of gene transcripts of the biom LOC648921, ANAPC5, SPON1, FUS, GPR22, GAL3ST4, arkers. In some embodiments, the amplification reaction is a METTL3, LOC100131096, FAAH2, SMURF2, SNRPN, polymerase chain reaction (PCR). FBLN7, GLS, G3BP1, RCAN3, EPHX2, DIP2C, CCDC141, 0025. In some embodiments, the level of expression of the CLTC, FOSB, CACNA1I, UNQ6228, ATG9B, AK5, SPIN3, biomarker is determined at the protein level. RBM14, SNRPN, MAN1C1, HELLS, EDAR, SLC3A1, 0026. In some embodiments, the level of expression of at ZNF519, LOC10O1300707/FLOC10O130775/77 least 15 biomarkers is determined. In some embodiments, the LOC10O131787//FLOC10O131905//FLOC10O132291//7 level of expression of about 15-85, 20-70, 30-60 or 40-50 LOC100132488//RPS27, ZC3H12B, IQGAP2, SOX8, biomarkers are determined. In some embodiments, about 15, WHDC1L2, TNPO1, TNFRSF21, TSHZ2, DMRTC1/// 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, DMRTC1B, GSTM1, GSTM2, PNMA6A, CAND1, 100, or more, biomarkers are determined. The levels of CCND3, GSTM1, GUSBL2 indicates that the patient has expression of the plurality of biomarkers can be concurrently suffered or is at risk of experiencing TIA. or sequentially determined. 0016. In some embodiments, an increased expression 0027. In some embodiments, the control is the expression level of 2, 3, 4, 5, 6, 7, or more or all, TIA-associated biom level of a plurality of expressed endogenous reference biom arkers selected from the group consisting of FLJ30375, arkers. In some embodiments, the one or more or all endog SCN2A, DKFZP434B061, LTBR, FAM55D, and IGFBP5 enous reference biomarkers are listed in Table 3. In some and a decreased expression level of 2, 3, 4, 5, 6, 7, or more or embodiments, the TIA-associated biomarkers are overex all, TIA-associated biomarkers selected from the group con pressed or underexpressed at least about 1.2-fold, 1.3-fold, sisting of GUSBL2, GSTM1, EDAR, ATG9B, DIP2C, 14-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0- SMURF2, and ZNF512B indicates that the patient has suf fold, 2.1 fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, fered or is at risk of experiencing TIA. 2.7-fold, 2.8-fold, 2.9-fold, 3.0-fold, 3.1-fold, 3.2-fold, 3.3- 0017. In some embodiments, the methods further com fold, 3.4-fold or 3.5-fold, or more, in comparison to the prise determining the level of expression of one or biomarkers expression levels of a plurality of stably expressed endog selected from the group consisting of CNTN4, TLR5, enous reference biomarkers, e.g., those listed in Table 3. In GPR84, BCL6, NELL2, APBA2 and MLL. In some embodi some embodiments, the expression levels of 2, 3, 4, 5, 6, 7, 8, ments, detection of an increased level of expression of a 9, 10, 15, 20, 25, 30, 35, or all, the endogenous reference biomarker selected from CNTN4, TLR5, GPR84 and BCL6 biomarkers selected from the group consisting of USP7, indicates that the patient has suffered or is at risk of experi MAPRE2, CSNK1G2, SAFB2, PRKAR2A, PI4KB, CRTC1, encing TIA. In some embodiments, detection of a decreased HADHA, MAP1LC3B, KAT5, CDC2L1///CDC2L2, level of expression of a biomarker selected from NELL2, GTSE1, CDC2L1///CDC2L2, TCF25, CHP, LRRC40, hCG APBA2 and MLL indicates that the patient suffered or is at 2003956///LYPLA2///LYPLA2P1, DAXX, UBE2NL, EIF1, risk of experiencing TIA. KCMF1, PRKRIP1, CHMP4A, TMEM184C, TINF2, 0.018. In some embodiments, the methods further com PODNL1, FBXO42, LOC441258, RRP1, C10orf104, prises the step of determining the cause of stroke. In some ZDHHC5, C90rf23, LRRC45, NACC1, LOC100.133445/// embodiments, the patient overexpresses a plurality of genes LOC115110, PEX16 are determined as a control. listed in Table 7, indicative of a chronic inflammatory state. In 0028. In some embodiments, the control is the expression Some embodiments, the level of expression of one or more or level of the same biomarker in a healthy individual. In some all genes selected from the group consisting of MMP16, embodiments, the control is the expression level of the same US 2016/02375O1 A1 Aug. 18, 2016

biomarker in an individual who has not experienced a vascu hematological disorders, strokes caused by migraines, and lar event (e.g., TIA, ischemic stroke, myocardial infarction, strokes caused by medications such as hormone therapy), peripheral vascular disease, or venous thromboembolism). In hemorrhagic ischemic stroke, intracerebral hemorrhage, and some embodiments, the control is a threshold level of expres Subarachnoid hemorrhage. Sion, e.g., of the same TIA-associated biomarker, optionally 0033. The term “transient ischemic attack.” “TIA, or normalized to the expression level of a stably expressed “mini-stroke' interchangeably refer to a change in the blood endogenous reference biomarker, representative of a popula Supply to a particular area of the brain, resulting in brief tion of healthy individuals. neurologic dysfunction that persists, by definition, for less 0029. In a related aspect, the invention provides a solid than 24 hours. By definition, a TIA resolves within 24 hours, Support comprising a plurality of nucleic acids that hybridize but most TIA symptoms resolve within a few minutes. If to a plurality of the genes set forth in Tables 1, 2, 5A, 5B, 5C, symptoms persist longer, then it is categorized as a stroke. 5D, 7, 8 and/or 9, wherein the nucleic acids are attached to the Symptoms include temporary loss of vision (typically amau Solid Support. In some embodiments, the Solid Support com rosis fugax); difficulty speaking (aphasia); weakness on one prises a plurality of nucleic acids that hybridize to a plurality side of the body (hemiparesis); numbness or tingling (pares of the genes set forth in Tables 1 and 2. The solid support can thesia), usually on one side of the body, and dizziness, lack of further comprise a plurality of nucleic acids that hybridize to coordination or poor balance. The symptoms of a TIA usually a plurality of the genes set forth in Table 3. The solid support last a few seconds to a few minutes and most symptoms can be attached to at least about 15, 20, 25, 30, 35, 40, 45, 50, disappear within 60 minutes. 55, 60, 75, 80, 85,90, 95 or 100, or more, genes set forth in 0034 “TIA reference expression profile” refers to the pat Tables 1,2,5A, 5B, 5C,5D,7,8,9 and/or 3. The solid support tern of expression of a set of genes (e.g., a plurality of the can be a microarray. genes set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9 0030. In one embodiment, the solid support comprises 2, differentially expressed (i.e., overexpressed or underex 3,4,5,6,7,8,9, 10, 11, 12, 13, 14, or more orall, nucleic acids pressed) in an individual who has suffered or is at risk of that hybridize to a plurality of the genes selected from the experiencing TIA relative to the expression in a control (e.g., group consisting of GUSBL2, GSTM1, FLJ30375, SCN2A, the expression level in an individual free of an ischemic event DKFZP434B061, EDAR, ATG9B, DIP2C, LTBR, SMURF2, or the expression level of a stably expressed endogenous FAM55D, IGFBP5, and ZNF512B. reference biomarker). A gene from Tables 1, 5B, 5C, 5D, 7, 8 and/or 9 that is expressed at a level that is at least about 1.5- DEFINITIONS 1.6-, 1.7-, 1.8-, 1.9-, 2.0-2.1-, 2.2-, 2.3-, 2.4-, 2.5-, 2.6-, 2.7- 0031. Unless defined otherwise, all technical and scien 2.8-, 2.9-3.0-, 3.1-, 3.2-, 3.3-, 3.4- or 3.5-fold higher than the tific terms used herein generally have the same meaning as level in a control is a gene overexpressed in TIA and a gene commonly understood by one of ordinary skill in the art to from Tables 2, 5A, 5C, 5D, 7, 8 and/or 9 that is expressed at a which this invention belongs. Generally, the nomenclature level that is at least about 1.5-, 1.6-, 1.7-, 1.8-, 1.9-, 2.0-, 2.1-, used herein and the laboratory procedures in cell culture, 2.2-, 2.3-, 2.4-, 2.5-, 2.6-, 2.7-, 2.8-, 2.9-3.0-, 3.1-, 3.2-, 3.3-, molecular genetics, organic chemistry and nucleic acid chem 3.4- or 3.5-fold lower than the level in a control is a gene istry and hybridization described below are those well known underexpressed in TIA. Alternately, genes that are expressed and commonly employed in the art. Standard techniques are at a level that is at least about 10%, 20%, 30%, 40%, 50%, used for nucleic acid and peptide synthesis. Generally, enzy 60%, 70%, 80%, 90%, or 100% higher than the level in a matic reactions and purification steps are performed accord control is a gene overexpressed in TIA and a gene that is ing to the manufacturer's specifications. The techniques and expressed at a level that is at least about 10%, 20%, 30%, procedures are generally performed according to conven 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than the tional methods in the art and various general references (see level in a control is a gene underexpressed in TIA. generally, Sambrook et al. MOLECULAR CLONING: A 0035. A “plurality” refers to two or more, for example, 2. LABORATORY MANUAL, 3rded. (2001) Cold Spring Har 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, bor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel, 22, 23 or more (e.g., genes). In some embodiments, a plurality et al., CURRENT PROTOCOLS IN MOLECULAR BIOL refers to concurrent determination of expression levels about OGY, 1990-2008, Wiley Interscience), which are provided 15-85, 20-60 or 40-50 genes, for example, about 15, 20, 25, throughout this document. The nomenclature used herein and 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, or the laboratory procedures in analytical chemistry, and organic more, genes. In some embodiments, plurality” refers to all synthetic described below are those well known and com genes listed in one or more or all tables, e.g., all genes listed monly employed in the art. Standard techniques, or modifi in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. cations thereof, are used for chemical syntheses and chemical 0036. The terms “patient,” “subject” or “individual” inter analyses. changeably refers to a mammal, for example, a human or a 0032 “Ischemia' or “ischemic event as used herein non-human mammal, including primates (e.g., macaque, pan refers to diseases and disorders characterized by inadequate troglodyte, pongo), a domesticated mammal (e.g., felines, blood Supply (i.e., circulation) to a local area due to blockage canines), an agricultural mammal (e.g., bovine, ovine, por of the blood vessels to the area. Ischemia includes for cine, equine) and a laboratory mammal or rodent (e.g., rattus, example, strokes and transient ischemic attacks. Strokes murine, lagomorpha, hamster, guinea pig). include, e.g., ischemic stroke (including, but not limited to, 0037 “Sample' or “biological sample includes sections cardioembolic strokes, atheroembolic or atherothrombotic of tissues such as biopsy and autopsy samples, and frozen strokes, i.e., strokes caused by atherosclerosis in the carotid, sections taken for histologic purposes. Such samples include aorta, heart, and brain, Small vessel strokes (i.e., lacunar blood, sputum, tissue, lysed cells, brain biopsy, cultured cells, strokes), strokes caused by diseases of the vessel wall, i.e., e.g., primary cultures, explants, and transformed cells, stool, vasculitis, strokes caused by infection, strokes caused by urine, etc. A biological sample is typically obtained from a US 2016/02375O1 A1 Aug. 18, 2016 eukaryotic organism, most preferably a mammal such as a in Biochemistry and Molecular Biology—Hybridization with primate, e.g., chimpanzee or human; cow: dog: cat, a rodent, Nucleic Probes, “Overview of principles of hybridization and e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. the strategy of nucleic acid assays” (1993). Generally, strin 0038 Array' as used herein refers to a solid support gent hybridization conditions are selected to be about 5-10 comprising attached nucleic acid or peptide probes. Arrays C. lower than the thermal melting point for the specific typically comprise a plurality of different nucleic acid or sequence at a defined ionic strength Ph. The T is the tem peptide probes that are coupled to a Surface of a Substrate in perature (under defined ionic strength, Ph, and nucleic con different, known locations. These arrays, also described as centration) at which 50% of the probes complementary to the “microarrays' or colloquially “chips' have been generally target hybridize to the target sequence at equilibrium (as the described in the art, for example, U.S. Pat. Nos. 5,143,854, target sequences are present in excess, at T, 50% of the 5,445,934, 5,744,305, 5,677,195, 6,040,193, 5,424,186 and probes are occupied at equilibrium). Stringent hybridization Fodor et al., Science, 251:767-777 (1991). These arrays may conditions will be those in which the salt concentration is less generally be produced using mechanical synthesis methods than about 1.0 M sodium ion, typically about 0.01 to 1.0 M or light directed synthesis methods which incorporate a com sodium ion concentration (or other salts) at Ph 7.0 to 8.3 and bination of photolithographic methods and Solid phase Syn the temperature is at least about 30°C. for short probes (e.g., thesis methods. Techniques for the synthesis of these arrays 10 to 50 nucleotides) and at least about 60°C. for long probes using mechanical synthesis methods are described in, e.g., (e.g., greater than 50 nucleotides). Stringent hybridization U.S. Pat. No. 5,384.261. Arrays may comprise a planar sur conditions may also be achieved with the addition of desta face or may be nucleic acids or peptides on beads, gels, bilizing agents such as formamide. For selective or specific polymeric Surfaces, fibers such as fiber optics, glass or any hybridization, a positive signal is at least two times back other appropriate Substrate as described in, e.g., U.S. Pat. ground, optionally 10 times background hybridization. Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800, Exemplary stringent hybridization conditions can be as fol 992. Arrays may be packaged in Such a manner as to allow for lowing: 50% formamide, 5xSSC, and 1% SDS, incubating at diagnostics or other manipulation of an all inclusive device, 42°C., or, 5xSSC, 1% SDS, incubating at 65° C., with wash as described in, e.g., U.S. Pat. Nos. 5,856,174 and 5,922,591. in 0.2XSSC, and 0.1% SDS at 65° C. 0039. The term “gene” means the segment of DNA 0043. Nucleic acids that do not hybridize to each other involved in producing a polypeptide chain; it includes regions understringent hybridization conditions are still Substantially preceding and following the coding region (leader and trailer) identical if the polypeptides which they encode are substan as well as intervening sequences (introns) between individual tially identical. This occurs, for example, when a copy of a coding segments (exons). nucleic acid is created using the maximum codon degeneracy 0040. The terms “nucleic acid and “polynucleotide' are permitted by the genetic code. In Such cases, the nucleic acids used interchangeably herein to refer to deoxyribonucleotides typically hybridize under moderately stringent hybridization or ribonucleotides and polymers thereof in either single- or conditions. Exemplary "moderately stringent hybridization double-stranded form. The term encompasses nucleic acids conditions’ include a hybridization in a buffer of 40% forma containing known nucleotide analogs or modified backbone mide, 1 MNaCl, 1% SDS at 37°C., and a wash in 1xSSC at residues or linkages, which are synthetic, naturally occurring, 45° C. A positive hybridization is at least twice background. and non-naturally occurring, which have similar binding Those of ordinary skill will readily recognize that alternative properties as the reference nucleic acid, and which are hybridization and wash conditions can be utilized to provide metabolized in a manner similar to the reference nucleotides. conditions of similar stringency. Examples of such analogs include, without limitation, phos 0044) The terms “isolated,” “purified,” or “biologically phorothioates, phosphoramidates, methyl phosphonates, pure” refer to material that is substantially or essentially free chiral-methyl phosphonates, 2-O-methyl ribonucleotides, from components that normally accompany it as found in its peptide-nucleic acids (PNAs). native state. Purity and homogeneity are typically determined 0041 Unless otherwise indicated, aparticular nucleic acid using analytical chemistry techniques such as polyacryla sequence also encompasses conservatively modified variants mide gel electrophoresis or high performance liquid chroma thereof (e.g., degenerate codon Substitutions) and comple tography. A protein that is the predominant species present in mentary sequences, as well as the sequence explicitly indi a preparation is substantially purified. The term “purified’ cated. Specifically, degenerate codon Substitutions may be denotes that a nucleic acid or protein gives rise to essentially achieved by generating sequences in which the third position one band in an electrophoretic gel. Particularly, it means that of one or more selected (or all) codons is substituted with the nucleic acid or protein is at least 85% pure, more prefer mixed-base and/or deoxyinosine residues (Batzer et al., ably at least 95% pure, and most preferably at least 99% pure. Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. 0045. The term "heterologous' when used with reference Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. to portions of a nucleic acid indicates that the nucleic acid Probes 8:91-98 (1994)). The term nucleic acid is used inter comprises two or more Subsequences that are not found in the changeably with gene, cDNA, mRNA, oligonucleotide, and same relationship to each other in nature. For instance, the polynucleotide. nucleic acid is typically recombinantly produced, having two 0042. The phrase “stringent hybridization conditions' or more sequences from unrelated genes arranged to make a refers to conditions under which a probe will hybridize to its new functional nucleic acid, e.g., a promoter from one source target Subsequence, typically in a complex mixture of nucleic and a coding region from another source. Similarly, a heter acid, but to no other sequences. Stringent hybridization con ologous protein indicates that the protein comprises two or ditions are sequence-dependent and will be different in dif more Subsequences that are not found in the same relationship ferent circumstances. Longer sequences hybridize specifi to each other in nature (e.g., a fusion protein). cally at higher temperatures. An extensive guide to the 0046. An "expression vector is a nucleic acid construct, hybridization of nucleic acids is found in Tijssen, Techniques generated recombinantly or synthetically, with a series of US 2016/02375O1 A1 Aug. 18, 2016

specified nucleic acid elements that permit transcription of a age of amino acids in the encoded sequence is a “conserva particular nucleic acid in a host cell. The expression vector tively modified variant' where the alteration results in the can be part of a plasmid, virus, or nucleic acid fragment. Substitution of an amino acid with a chemically similar amino Typically, the expression vector includes a nucleic acid to be acid. Conservative substitution tables providing functionally transcribed operably linked to a promoter. similar amino acids are well known in the art. Such conser 0047. The terms “polypeptide,” “peptide' and “protein' vatively modified variants are in addition to and do not are used interchangeably hereinto refer to a polymer of amino exclude polymorphic variants, interspecies homologs, and acid residues. The terms apply to amino acid polymers in alleles of the invention. which one or more amino acid residue is an artificial chemical 0.052 The following eight groups each contain amino mimetic of a corresponding naturally occurring amino acid, acids that are conservative Substitutions for one another: as well as to naturally occurring amino acid polymers and 0053) 1) Alanine (A), Glycine (G); non-naturally occurring amino acid polymer. 0.054 2) Aspartic acid (D), Glutamic acid (E); 0048. The term "amino acid refers to naturally occurring 0.055 3) Asparagine (N), Glutamine (Q); and synthetic amino acids, as well as amino acid analogs and 0056 4) Arginine I, Lysine (K); amino acid mimetics that function in a manner similar to the 0057 5) Isoleucine (I), Leucine (L), Methionine (M), naturally occurring amino acids. Naturally occurring amino Valine (V); acids are those encoded by the genetic code, as well as those 0.058 6) Phenylalanine (F), Tyrosine (Y), Tryptophan amino acids that are later modified, e.g., hydroxyproline, (W); C-carboxyglutamate, and O-phosphoserine. “Amino acid 0059 7) Serine (S), Threonine (T); and analogs' refers to compounds that have the same basic chemi 0060) 8) Cysteine (C), Methionine (M) cal structure as a naturally occurring amino acid, i.e., an O. 0061 (see, e.g., Creighton, Proteins (1984)). carbon that is bound to a hydrogen, a carboxyl group, an 0062. The terms “identical” or percent “identity,” in the amino group, and an R group, e.g., homoserine, norleucine, context of two or more nucleic acids or polypeptide methionine sulfoxide, methionine methyl sulfonium. Such sequences, refer to two or more sequences or Subsequences analogs have modified R groups (e.g., norleucine) or modi that are the same or have a specified percentage of amino acid fied peptide backbones, but retain the same basic chemical residues or nucleotides that are the same (i.e., 60% identity, structure as a naturally occurring amino acid. “Amino acid preferably 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity mimetics' refers to chemical compounds that have a structure over a specified region of a TIA-associated gene (e.g., a gene that is different from the general chemical structure of an set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9), when amino acid, but that functions in a manner similar to a natu compared and aligned for maximum correspondence over a rally occurring amino acid. comparison window, or designated region as measured using 0049 Amino acids may be referred to herein by either one of the following sequence comparison algorithms or by their commonly known three letter symbols or by the one manual alignment and visual inspection. Such sequences are letter symbols recommended by the IUPAC-IUB Biochemi then said to be “substantially identical.” This definition also cal Nomenclature Commission. Nucleotides, likewise, may refers to the compliment of a test sequence. Preferably, the be referred to by their commonly accepted single-letter codes. identity exists over a region that is at least about 25 amino 0050 “Conservatively modified variants' applies to both acids or nucleotides in length, or more preferably over a amino acid and nucleic acid sequences. With respect to par region that is 50-100 amino acids or nucleotides in length. ticular nucleic acid sequences, conservatively modified Vari 0063 For sequence comparison, typically one sequence ants refers to those nucleic acids which encode identical or acts as a reference sequence, to which test sequences are essentially identical amino acid sequences, or where the compared. When using a sequence comparison algorithm, nucleic acid does not encode an amino acid sequence, to test and reference sequences are entered into a computer, essentially identical sequences. Because of the degeneracy of Subsequence coordinates are designated, if necessary, and the genetic code, a large number of functionally identical sequence algorithm program parameters are designated. nucleic acids encode any given protein. For instance, the Default program parameters can be used, or alternative codons GCA, GCC, GCG and GCU all encode the amino acid parameters can be designated. The sequence comparison alanine. Thus, at every position where an alanine is specified algorithm then calculates the percent sequence identities for by a codon, the codon can be altered to any of the correspond the test sequences relative to the reference sequence, based on ing codons described without altering the encoded polypep the program parameters. For sequence comparison of nucleic tide. Such nucleic acid variations are “silent variations.” acids and proteins to TIA-associated nucleic acids and pro which are one species of conservatively modified variations. teins, the BLAST and BLAST 2.0 algorithms and the default Every nucleic acid sequence herein which encodes a polypep parameters discussed below are used. tide also describes every possible silent variation of the 0064. A "comparison window', as used herein, includes nucleic acid. One of skill will recognize that each codon in a reference to a segment of any one of the number of contiguous nucleic acid (except AUG, which is ordinarily the only codon positions selected from the group consisting of from 20 to for methionine, and TGG, which is ordinarily the only codon 600, usually about 50 to about 200, more usually about 100 to for tryptophan) can be modified to yield a functionally iden about 150 in which a sequence may be compared to a refer tical molecule. Accordingly, each silent variation of a nucleic ence sequence of the same number of contiguous positions acid which encodes a polypeptide is implicit in each after the two sequences are optimally aligned. Methods of described sequence. alignment of sequences for comparison are well-known in the 0051. As to amino acid sequences, one of skill will recog art. Optimal alignment of sequences for comparison can be nize that individual substitutions, deletions or additions to a conducted, e.g., by the local homology algorithm of Smith & nucleic acid, peptide, polypeptide, or protein sequence which Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alters, adds or deletes a single amino acid or a small percent alignment algorithm of Needleman & Wunsch, J. Mol. Biol. US 2016/02375O1 A1 Aug. 18, 2016

48:443 (1970), by the search for similarity method of Pearson reactive with the antibodies raised against the polypeptide & Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by encoded by the second nucleic acid, as described below. Thus, computerized implementations of these algorithms (GAP, a polypeptide is typically Substantially identical to a second BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics polypeptide, for example, where the two peptides differ only Software Package, Genetics Computer Group, 575 Science by conservative substitutions. Another indication that two Dr. Madison, Wis.), or by manual alignment and visual nucleic acid sequences are Substantially identical is that the inspection (see, e.g., Current Protocols in Molecular Biology two molecules or their complements hybridize to each other (Ausubel et al., eds. 1995 supplement)). under stringent conditions, as described below. Yet another 0065. A preferred example of algorithm that is suitable for indication that two nucleic acid sequences are substantially determining percent sequence identity and sequence similar identical is that the same primers can be used to amplify the ity are the BLAST and BLAST 2.0 algorithms, which are Sequence. described in Altschul et al., Nuc. Acids Res. 25:3389-3402 0068. The phrase “selectively (or specifically) hybridizes (1977) and Altschulet al., J. Mol. Biol. 215:403-410 (1990), to refers to the binding, duplexing, or hybridizing of a mol respectively. BLAST and BLAST 2.0 are used, with the ecule only to a particular nucleotide sequence under stringent parameters described herein, to determine percent sequence hybridization conditions when that sequence is present in a identity for the nucleic acids and proteins of the invention. complex mixture (e.g., total cellular or library DNA or RNA). Software for performing BLAST analyses is publicly avail 0069. By “host cell' is meant a cell that contains an able through the National Center for Biotechnology Informa expression vector and Supports the replication or expression tion (http://www.ncbi.nlm.nih.gov/). This algorithm involves of the expression vector. Host cells may be, for example, first identifying high scoring sequence pairs (HSPs) by iden prokaryotic cells such as E. coli or eukaryotic cells such as tifying short words of length W in the query sequence, which yeast cells or mammalian cells such as CHO cells. either match or satisfy some positive-valued threshold score T 0070 “Inhibitors. “activators, and “modulators' of when aligned with a word of the same length in a database expression or of activity are used to refer to inhibitory, acti sequence. T is referred to as the neighborhood word score Vating, or modulating molecules, respectively, identified threshold (Altschulet al., supra). These initial neighborhood using in vitro and in vivo assays for expression or activity, word hits act as seeds for initiating searches to find longer e.g., ligands, agonists, antagonists, and their homologs and HSPs containing them. The word hits are extended in both mimetics. The term “modulator” includes inhibitors and acti directions along each sequence for as far as the cumulative vators. Inhibitors are agents that, e.g., inhibit expression of a alignment score can be increased. Cumulative scores are cal polypeptide or polynucleotide of the invention or bind to, culated using, for nucleotide sequences, the parameters M partially or totally block stimulation or enzymatic activity, (reward score for a pair of matching residues; always-0) and decrease, prevent, delay activation, inactivate, desensitize, or N (penalty score for mismatching residues; always.<0). For down regulate the activity of a polypeptide or polynucleotide amino acid sequences, a scoring matrix is used to calculate of the invention, e.g., antagonists. Activators are agents that, the cumulative score. Extension of the word hits in each e.g., induce or activate the expression of a polypeptide or direction are halted when: the cumulative alignment score polynucleotide of the invention orbind to, Stimulate, increase, falls off by the quantity X from its maximum achieved value: open, activate, facilitate, enhance activation or enzymatic the cumulative score goes to Zero or below, due to the accu activity, sensitize or up regulate the activity of a polypeptide mulation of one or more negative-scoring residue alignments; or polynucleotide of the invention, e.g., agonists. Modulators or the end of either sequence is reached. The BLAST algo include naturally occurring and synthetic ligands, antago rithm parameters W. T. and X determine the sensitivity and nists, agonists, Small chemical molecules and the like. Assays speed of the alignment. The BLASTN program (for nucle to identify inhibitors and activators include, e.g., applying otide sequences) uses as defaults a word length (W) of 11, an putative modulator compounds to cells, in the presence or expectation (E) of 10, M-5, N=-4 and a comparison of both absence of a polypeptide or polynucleotide of the invention Strands. For amino acid sequences, the BLASTP program and then determining the functional effects on a polypeptide uses as defaults a word length of 3, and expectation (E) of 10, or polynucleotide of the invention activity. Samples or assays and the BLOSUM62 scoring matrix (see Henikoff & Heni comprising a polypeptide or polynucleotide of the invention koff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)) align that are treated with a potential activator, inhibitor, or modu ments (B) of 50, expectation (E) of 10, M-5, N=-4, and a lator are compared to control samples without the inhibitor, comparison of both Strands. activator, or modulator to examine the extent of effect. Con 0066. The BLAST algorithm also performs a statistical trol samples (untreated with modulators) are assigned a rela analysis of the similarity between two sequences (see, e.g., tive activity value of 100%. Inhibition is achieved when the Karlin & Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5787 activity value of a polypeptide or polynucleotide of the inven (1993)). One measure of similarity provided by the BLAST tion relative to the control is about 80%, optionally 50% or algorithm is the smallest sum probability (P(N)), which pro 25-1%. Activation is achieved when the activity value of a vides an indication of the probability by which a match polypeptide or polynucleotide of the invention relative to the between two nucleotide oramino acid sequences would occur control is 110%, optionally 150%, optionally 200-500%, or by chance. For example, a nucleic acid is considered similar 1000-3000% higher. to a reference sequence if the Smallest Sum probability in a 0071. The term “test compound” or “drug candidate' or comparison of the test nucleic acid to the reference nucleic "modulator” or grammatical equivalents as used herein acid is less than about 0.2, more preferably less than about describes any molecule, either naturally occurring or Syn 0.01, and most preferably less than about 0.001. thetic, e.g., protein, oligopeptide (e.g., from about 5 to about 0067. An indication that two nucleic acid sequences or 25 amino acids in length, preferably from about 10 to 20 or 12 polypeptides are substantially identical is that the polypeptide to 18 amino acids in length, preferably 12, 15, or 18 amino encoded by the first nucleic acid is immunologically cross acids in length), Small organic molecule, polysaccharide, US 2016/02375O1 A1 Aug. 18, 2016

lipid, fatty acid, polynucleotide, RNAi, oligonucleotide, etc. sion of MMP26 in the TIA1 group compared to both control The test compound can be in the form of a library of test (p=6.67x10) and TIA2 groups (p=8.55x10) and no dif compounds, such as a combinatorial or randomized library ference in MMP26 expression between control subjects and that provides a sufficient range of diversity. Test compounds TIA2 patients (B2). The X axis shows categories of subjects. are optionally linked to a fusion partner, e.g., targeting com The Y axis shows the log 2-intensity/RNA expression. pounds, rescue compounds, dimerization compounds, stabi Pink controls. Dark blue-All TIA or TIA1. Light lizing compounds, addressable compounds, and other func blue=TIA2. tional moieties. Conventionally, new chemical entities with useful properties are generated by identifying a test com DETAILED DESCRIPTION pound (called a “lead compound') with some desirable prop erty or activity, e.g., inhibiting activity, creating variants of 1. Introduction the lead compound, and evaluating the property and activity 0077 Although transient ischemic attacks (TIAS) are of those variant compounds. Often, high throughput screen common, the underlying biology remains poorly understood. ing (HTS) methods are employed for Such an analysis. The present invention is based, in part, on the discovery that 0072 A “small organic molecule' refers to an organic TIAS differentially regulate gene expression in blood. The molecule, either naturally occurring or synthetic, that has a differentially regulated genes indicative of the occurrence or molecular weight of more than about 50 Daltons and less than risk of occurrence of TIAS find use in the diagnosis, treatment about 2500 Daltons, preferably less than about 2000 Daltons, and prevention of TIAS in patients. Patients with recent TIAS preferably between about 100 to about 1000 Daltons, more can be differentiated from controls without previous vascular preferably between about 200 to about 500 Daltons. events using gene expression profiles in blood. In addition, BRIEF DESCRIPTION OF THE DRAWINGS human patients appear to develop different immune response Subtypes following transient ischemic attacks. 0073 FIGS. 1A-B. Heat map of 460 genes/probes differ entially expressed in blood between Transient Ischemic 2. Individuals Who can Benefit from the Present Attack (TIA) patients and controls (FDRs 0.05, absolute fold Methods change 1.5). Each column on the X axis represents 1 patient, with 24 TIA patients (blue) and 27 controls (pink). Each row 0078 Individuals who will benefit from the present meth on the Y axis represents individual genes. TIAS cluster sepa ods may be exhibiting symptoms of TIA or stroke. Alterna rately from controls as indicated by the green arrow (top). tively, the subject may be suspected of having experienced Within TIA subjects, at least two clusters are apparent as TIA. In some embodiments, the Subject has not experienced indicated by the red arrow. These two TIA clusters are labeled and/or is not at risk of having an intracerebral hemorrhage. In TIA1 and TIA2. Two TIA patients (ID: 57 and 90) clustered Some embodiments, the Subject has not experienced and/or is with controls. Three controls (ID: 42, 68, and 74) clustered not at risk of having an intracerebral hemorrhage or hemor with TIAs. Red-up regulation. Green-down regulation. rhagic stroke. In some embodiments, the Subject has been ID=subjects ID. Diagnosis-blue (TIA) and pink (Controls). diagnosed as having not experienced and/or not at risk of 0074 FIG.2. Cross-validation results for the 34 out of 460 having an intracerebral hemorrhage or hemorrhagic stroke. TIA regulated genes that distinguish TIA patients from con 0079. In some embodiments, the levels of expression of trol subjects. The probability of predicted diagnosis is shown the panel of biomarkers is determined within 3 hours of a on the Y axis, and subjects are shown on the X axis. TIA Suspected ischemic event. In some embodiments, the levels of patients are shown on the right, and Control Subjects on the expression of the panel of biomarkers are determined at 3 or left. The predicted probability of TIA is shown in red, and the more hours after a Suspected ischemic event. In some embodi predicted probability of being control is shown in blue. TIA ments, the levels of expression of the panel of biomarkers are patients were distinguished from controls with 87.5% sensi determined within 6, 12, 18, 24, 36, 48 hours of a suspected tivity and 96.3% specificity using a 10-fold cross-validation. ischemic event. 0075 FIG. 3. Cross-validation results for the 26 up-regu 0080. In some cases, the subject is asymptomatic, but may lated genes identified by PAM to distinguish the TIA1 from have a risk or predisposition to experiencing TIA, e.g., based TIA2 groups. The probability of the predicted diagnosis is on genetics, a related disease condition, environment or lif shown on the Y axis, and Subjects are shown on the X axis. estyle. For example, in some embodiments, the patient Suffers TIA1 subjects are shown on the left, and TIA2 subjects on the from a chronic inflammatory condition, e.g., has an autoim right. The predicted probability of TIA2 is shown in red, and mune disease (e.g., rheumatoid arthritis, Crohn's disease the predicted probability of TIA1 is shown in blue. TIA1 inflammatory bowel disease), atherosclerosis, hypertension, could be distinguished from TIA2 patients with 100% sensi or diabetes. In some embodiments, the patient has high LDL tivity and 100% specificity. cholesterol levels or suffers from a cardiovascular disease 0.076 FIGS. 4A-B. MMP16 (A) and MMP26 (B) tran (e.g., atherosclerosis, coronary artery disease). In some Script expression in TIA patients (blue) and control Subjects embodiments, the patient has an endocrine system disorder, a (pink). A. MMP16. There was no difference in MMP16 neurodegenerative disorder, a connective tissue disorder, or a expression for all control subjects compared to all TIA skeletal and muscular disorder. Exemplary disorders associ patients (A1). There was a significant increase in expression ated with, related to, or causative of TIA are provided in Table of MMP16 in the TIA1 patients compared to both control 7 (p=1.35x107) and TIA2 groups (p=2.19x107) and no dif I0081. In some embodiments, the patient may have a neu ference in MMP16 expression between control subjects and rological disorder and have increased or decreased expression TIA2 patients (A2). B. MMP26. There was no difference in relative to a control level of expression of a plurality of MMP26 expression for all control subjects compared to all biomarkers selected from the group consisting of ACSL1, TIA patients (B1). There was a significant increase in expres ADH1B, AK5, ANXA3, APBA2, ASTN2 (includes US 2016/02375O1 A1 Aug. 18, 2016

EG:23245), BCL6, BMPR1B, CASP5, CAV1, CNTN4, S100A12, SLC22A4 (includes EG:6583), SNRPN, SPON1, DIP2C, ELAVL2, EPHX2, ERAP2, FAM124A, FAM13A, TLR5, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes FAM149A, FAT1, FOLH1, FOXC1, GABRB2, GIGYF2, EG: 115669), VWA3B and ZNF438. GNAO1, GRM5, GSTM1, HESX1, HOXC6, IGFBP5, IL1B, I0086. In some embodiments, the patient may have a meta IQGAP2, ITGBL1, LAMB4, LIFR, LTBR, MECOM, bolic disorder and have increased or decreased expression NBPF10, NDST3, NELL2, NOS3, NTM, ODZ2, OLFM2, relative to a control level of expression of a plurality of OPCML, PDE1A, RFX2, ROBO1, S100A12, SCN2A, biomarkers selected from the group consisting of ACSL1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, SOX9, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes SPOCK3, SPON1, TGFB2, TLR5, TNFRSF21, TRPM1, EG:23245), BCL6, CARD8, CASP5, CCRL1, CNTLN, TSHZ2, TTC6 (includes EG:115669), UNC5B, UNC84A CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, and ZNF608. EPHX2, FAT1, FOXA2, GABRB2, GUSBL2, IGFBP5, 0082 In some embodiments, the patient may have a skel IL1B, IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, etal or muscular disorder and have increased or decreased NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, expression relative to a control level of expression of a plu ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, rality of biomarkers selected from the group consisting of SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, ACSL1, ADM, AK5, ASTN2 (includes EG:23245), BCL6, UNC84A and VWA3B. BMPR1B, CARD8, CASP5, CCND3, CLTC, CNTN4, I0087. In some embodiments, the patient may have an COL1A1, COL1A2, DIP2C, DNAH14, EDAR, ELAVL2, endocrine system disorder and have increased or decreased EPHA3, EPHX2, FAM124A, FOSB, GABRB2, GIGYF2, expression relative to a control level of expression of a plu GNAO1, HOXC6, IL1B, KCNJ15, LAMB4, LIFR, LTBR, rality of biomarkers selected from the group consisting of LUM, MAPK14, MYBPC1, NOS3, ODZ2, OSM, PAPPA, ACSL1, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (in PDE1A, ROBO1, RUNDC3B, S100A12, SCN2A, SHOX, cludes EG:23245), BCL6, CARD8, CASP5, CCRL1, SLC22A4 (includes EG:6583), SOX9, SPOCK3, TLR5, CNTLN, CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), EPHA3, FAT1, FOXA2, GABRB2, GUSBL2, IL1B, TWIST1, UNC5B, VWA3B and ZNF438. IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, 0083. In some embodiments, the patient may have an NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, inflammatory disorder and have increased or decreased ROBO1, SHOX, SLC22A4 (includes EG:6583), SLC2A3, expression relative to a control level of expression of a plu SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, rality of biomarkers selected from the group consisting of UNC84A and VWA3B. ACSL1, ADM, AK5, ANXA3, APBA2, ASTN2 (includes I0088. In some embodiments, the patient may have an EG:23245), BCL6, CARD8, CASP5, CAV1, CCND3, autoimmune disease and have increased or decreased expres CCRL1, CLTC, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, sion relative to a control level of expression of a plurality of EPHX2, ERAP2, FAM124A, FBLN7, FOSB, FREM2, biomarkers selected from the group consisting of ACSL1, GABRB2, GRM5, IL1B, KCNJ15, LAMB4, LHX2, LNPEP. ADM, AK5, ASTN2 (includes EG:23245), BCL6, CARD8, LRP2, LTBR, LUM, MAPK14, MECOM, MYBPC1, NOS3, CASP5, CCND3, CLTC, CNTN4, COL1A2, DIP2C, ODZ2, OPCML, OSM, PAPPA, PDE1A, PPP1R1C, DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, ROBO1, RUNDC3B, S100A12, SCN2A, SFXN1, SLC22A4 GABRB2, GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, (includes EG:6583), SLC26A8, SMURF2, SNRPN, SPON1, LTBR, MAPK14, MYBPC1, NELL2, ODZ2, OPCML, TGFB2, TLR5, TNFRSF21, TNPO1, TTC6 (includes OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, EG:115669), TWIST1, UNC5B, VWA3B and ZNF438. SLC22A4 (includes EG:6583), SNRPN, SPON1, TLR5, 0084. In some embodiments, the patient may have a car TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), diovascular disorder and have increased or decreased expres VWA3B and ZNF438. sion relative to a control level of expression of a plurality of I0089. In some embodiments, the patient may have diabe biomarkers selected from the group consisting of ACSL1, tes and have increased or decreased expression relative to a ADM, AK5, ALPL, ASTN2 (includes EG:23245), BCL6, control level of expression of a plurality of biomarkers BMPR1B, C18ORF54, CACNA1 I, CARD16, CAV1, selected from the group consisting of ACSL1, ADAM30, CNTN4, DMRT1, DNAH14, EDAR, EPHX2, ERAP2, AK5, ALPL. ALS2CR11, ASTN2 (includes EG:23245), FAM13A, FOLH1, FOSB, FREM2, GABRB2, GRM5, BCL6, CARD8, CASP5, CCRL1, CNTLN, CNTN4, GSTM1, IL1B, IQGAP2, LIFR, LTBR, MAN1C1, COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, FAT1, MAPK14, MBNL1, MCF2L, MECOM, MYBPC1, NOS3, FOXA2, GABRB2, GUSBL2, IL1B, IQGAP2, ITGBL1, NTM, ODZ2, OLFM2, OPCML, PAPPA, PDE1A, ROBO1, LTBR, MAPK14, MBNL1, NELL2, NOS3, NTM, ODZ2, RORB, S100A12, SMURF2, SNRPN, SOX9, SPOCK3, OPCML, PAPPA, PLSCR1, ROBO1, SLC22A4 (includes SPON1, TFPI, TRPM1, UNC84A and VWA3B. EG:6583), SLC2A3, SMURF2, SNRPN, SPON1, SRGAP1, 0085. In some embodiments, the patient may have an TLR5, TSHZ2, UNC84A and VWA3B. immunological disorder and have increased or decreased 0090. In some embodiments, the patient may have a con expression relative to a control level of expression of a plu nective tissue disorder and have increased or decreased rality of biomarkers selected from the group consisting of expression relative to a control level of expression of a plu ACSL1, ADM, AK5, ANXA3, ASTN2 (includes EG:23245), rality of biomarkers selected from the group consisting of BCL6, CARD8, CASP5, CCND3, CCRL1, CLTC, CNTN4, ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, CARD8, CASP5, CCND3, CLTC, CNTN4, COL1A1, FAM124A, FAT1, FOSB, GABRB2, GOLGA6L2, GSTM1, COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, LTBR, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, MAPK14, MYBPC1, NELL2, NOS3, NTM, ODZ2, LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, OPCML, OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, ROBO1, RUNDC3B, S100A12, SHOX, SLC22A4 (includes US 2016/02375O1 A1 Aug. 18, 2016

EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (includes RUNDC3B, S100A12, SLC22A4 (includes EG:6583), EG: 115669), VWA3B and ZNF438. TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B 0091. In some embodiments, the patient may have rheu and ZNF438. matic disease and have increased or decreased expression 0097. In some embodiments, the patient may have coro relative to a control level of expression of a plurality of nary artery disease and have increased or decreased expres biomarkers selected from the group consisting of ACSL1, sion relative to a control level of expression of a plurality of ADM, ASTN2 (includes EG:23245), BCL6, CARD8, biomarkers selected from the group consisting of ACSL1, CASP5, CCND3, CLTC, CNTN4, DIP2C, DNAH14, EDAR, AK5, ASTN2 (includes EG:23245), BMPR1B, CARD16, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, CNTN4, DMRT1, DNAH14, ERAP2, FREM2, GRM5, KCNJ15, LAMB4, LTER, LUM, MAPK14, ODZ2, OSM, IL1B, IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 MECOM, NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, RORB, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and (includes EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (in VWA3B. cludes EG:115669), VWA3B and ZNF438. 0098. In some embodiments, the patient may have 0092. In some embodiments, the patient may have arthritis Crohn's disease and have increased or decreased expression and have increased or decreased expression relative to a con relative to a control level of expression of a plurality of trol level of expression of a plurality of biomarkers selected biomarkers selected from the group consisting of ACSL1, from the group consisting of ACSL1, ADM, ASTN2 (in AK5, APBA2, ASTN2 (includes EG:23245), CARD8, cludes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, DIP2C, DNAH14, ERAP2, FBLN7, FREM2, GRM5, LHX2, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, LNPEP, MECOM, ODZ2, OPCML, PAPPA, PDE1A, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, PPP1R1C, ROBO1, SFXN1, SLC22A4 (includes EG:6583), LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, SLC26A8, SNRPN, SPON1, TGFB2, TLR5, VWA3B and ROBO1, RUNDC3B, S100A12, SLC22A4 (includes ZNF438. EG:6583), TNFRSF21, TNPO1, TTC6 (includes 0099. In some embodiments, the patient may have a neu EG:115669), VWA3B, ZNF438. rodegenerative disorder and have increased or decreased 0093. In some embodiments, the patient may have athero expression relative to a control level of expression of a plu Sclerosis and have increased or decreased expression relative rality of biomarkers selected from the group consisting of to a control level of expression of a plurality of biomarkers ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, selected from the group consisting of ACSL1, AK5, ASTN2 FOLH1, GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, (includes EG:23245), BMPR1B, CARD16, CNTN4, OPCML, RFX2, SCN2A, SLC22A4 (includes EG:6583), DMRT1, DNAH14, ERAP2, FOSB, FREM2, GRM5, IL1B, SLC2A3, SLC3A1, SPON1, TSHZ2 and ZNF608. IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, 0100. In some embodiments, the patient may have Alzhe NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, RORB, imer's disease and have increased or decreased expression SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and relative to a control level of expression of a plurality of VWA3B. biomarkers selected from the group consisting of ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, 0094. In some embodiments, the patient may have inflam GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, matory bowel disease and have increased or decreased OPCML, RFX2, SLC22A4 (includes EG:6583), SLC2A3, expression relative to a control level of expression of a plu SLC3A1, SPON1, TSHZ2 and ZNF608. rality of biomarkers selected from the group consisting of ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), 3. Biomarkers Indicative of the Occurrence or Risk CARD8, DIP2C, DNAH14, ERAP2, FBLN7, FREM2, of TIA GRM5, IL1B, LHX2, LNPEP LTBR, MECOM, NOS3, ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, ROBO1, 0101 Overexpressed biomarkers indicative of the occur SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, rence of TIA or useful to predict the risk of experiencing TIA SPON1, TGFB2, TLR5, VWA3B and ZNF438. are listed in Table 1. In practicing the present methods, the expression levels of a plurality of biomarkers from Table 1 are 0095. In some embodiments, the patient may have non determined, optionally in combination with other TIA-asso insulin-dependent diabetes mellitus and have increased or ciated biomarkers described herein (e.g., in Tables 2, 5A, 5B, decreased expression relative to a control level of expression 5C, 5D, 7, 8 and/or 9) and known in the art. of a plurality of biomarkers selected from the group consist 0102 Preferably, the expression levels of a plurality in the ing of ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes range of about 15-85 total biomarkers are determined, for EG:23245), CARD8, CCRL1, CNTLN, CNTN4, COL1A2, example, about 20-70, 30-60 or 40-50 biomarkers. The DIP2C, DMRT1, EPHA3, FAT1, FOXA2, GABRB2, IL1B, expression levels of the biomarkers can be concurrently or IQGAP2, ITGBL1, MBNL1, NOS3, NTM, ODZ2, PLSCR1, sequentially determined. In some embodiments, the expres ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SPON1, sion levels of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, SRGAP1, TLR5, UNC84A and VWA3B. 45, 50, 60, 65,70, 75,80, 85,90, 95, 100, or more, biomarkers 0096. In some embodiments, the patient may have rheu listed in Table 1 are determined, optionally in combination matoid arthritis and have increased or decreased expression with other TIA-associated biomarkers described herein (e.g., relative to a control level of expression of a plurality of in Tables 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9) and known in the biomarkers selected from the group consisting of ACSL1, art. ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CLTC, 0103) In patients who have experienced TIA or who are at CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, risk of developing TIA, the biomarkers of Table 1 are over FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, expressed in comparison to a control level of expression. A MAPK14, ODZ2, OSM, PAPPA, PDE1A, ROBO1, control level of expression can refer to the level of expression US 2016/02375O1 A1 Aug. 18, 2016 10 of the same biomarker in an individual who has not had and is e.g., at least 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, not at risk for a vascular event or the level of expression of a 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7- stably expressed endogenous control gene. In patients who fold, 2.8-fold, 2.9-fold, 3.0-fold, 3.1-fold, 3.2-fold, 3.3-fold, have experienced TIA or who are at risk of developing TIA, 3.4-fold or 3.5-fold, or more, in comparison to a control level the biomarkers of Table 1 are overexpressed at least 1.5-fold, of expression. TABLE 1. TIA-associated biomarkers that are upregulated Fold Fold Change C hange (TLA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 1557122 s at GABRB2 gamma-aminobutyric acid NM 000813 349668 A up vs Contro (GABA) A receptor, beta 2 NM 021911 227612 at ELAVL3 ELAV (embryonic lethal, NM 001420 3.23.425 A up vs Contro abnormal vision, NM O32281 Drosophila)-like 3 (Hu antigen C) 1556499 s at COL1A1 collagen, type I, alpha 1 NM OOOO88 2.87107 A up vs Contro 21O135 s at SHOX2 short stature homeobox2 NM OO3O3O 2.86893 A up vs Contro NM OO6884 242344 at GABRB2 gamma-aminobutyric acid NM 000813 2.72.458 A up vs Contro (GABA) A receptor, beta 2 NM 021911 213943 at TWIST1 twist homolog 1 NM 000474 2.72279 A up vs Contro (Drosophila) 241199 X at DPPA4 developmental NM 0181.89 2.68174 A up vs Contro pluripotency associated 4 222253 s at POM121 membrane NR 003714 2.61011 A up vs Contro glycoprotein-like 1 pseudogene 206954 a WIT1 Wilms tumor upstream NM O15855 2.58643 A up vs Contro neighbor 1 NR 023920 202935 S. at SOX9 SRY (sex determining NM 000346 2.45928 A up vs Contro region Y)-box 9 239309 a DLX6 distal-less homeobox 6 NM OO5222 2.4523 A up vs Contro 209369 a ANXA3 annexin A3 NM 005139 2.41095 A up vs Contro 211164 a EPHA3 EPH receptor A3 NM O05233 2.393.14 A up vs Contro NM 182644 204913 s at SOX11 SRY (sex determining NM OO3108 2.34727 A up vs Contro region Y)-box 11 237340 a SLC26A8 solute carrier family 26, NM 052961 2.32491 A up vs Contro member 8 NM 138718 220351 a CCRL1 chemokine (C-C motif) NM O16557 2.32444 A up vs Contro receptor-like 1 NM 178445 230964 a FREM2 FRAS1 related NM 207361 2.30984 A up vs Contro extracellular matrix protein 2 231969 a STOX2 storkhead box2 NM 020225 2.2552 A up vs Contro 1555367 at ZNF479 Zinc finger protein 479 NM 033273 2.25193 A up vs Contro XM OO1714591 XM OO1719979 1557717 at LOC338862 hypothetical protein 2.22946 A up vs Contro LOC338862 1554816 at ASTN2 astrotactin 2 NM 014010 2.22748 A up vs Contro NM 1981 86 NM 1981.87 NM 198188 21748.7 x at FOLH1 folate hydrolase (prostate NM 001014986 2.1998.7 A up vs Contro specific membrane NM 004476 antigen) 1 241987 x at Sorting nexin 31 NM 152628 2. 9167 A up vs Contro 227250 at KREMEN1 kringle containing NM OO1039570 216406 A up vs Contro transmembrane protein 1 NM OO1039571 1555368 X at Zinc finger protein 479 NM 033273 2.162O3 A up vs Contro XM OO1714591 XM OO1719979 1563673 a at ALS2CR11 amyotrophic lateral NM 152525 2.15.177 A up vs Contro Sclerosis 2 (juvenile) chromosome region, candidate 11 239710 at FIGN fidgetin NM 018086 2. 4096 A up vs Contro 242385 at RORB RAR-related orphan NM OO6914 2.14023 A up vs Contro receptor B 1570009 at LOC732.096 similar to hCG2040240 XM OO1720784 2.13184 A up vs Contro XM OO1725.388 XR 016064 US 2016/02375O1 A1 Aug. 18, 2016 11

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 1559520 at GYPA Glycophorin A NM O02099 2.12904 TIA up vs Contro 215783 s at ALPL alkaline phosphatase, NM 000478 2.1006 TIA up vs Contro liver/bone/kidney NM OO11275O1 206140 a LHX2 LIM homeobox2 NM OO4789 2.0959 TIA up vs Contro 240390 a GALNTS UDP-N-acetyl-alpha-D- NM 014568 2.09257 TIA up vs Contro galactosamine:polypeptide N acetylgalactosaminyltransferase 24-1961 a SRDSA2L2 steroid 5 alpha-reductase NM 001010874 2.08494 TIA up vs Contro 2-like 2 219271 a GALNT14 UDP-N-acetyl-alpha-D- NM O24572 2.076OS TIA up vs Contro galactosamine:polypeptide N acetylgalactosaminyltransferase 206048 a OVOL2 ovo-like 2 (Drosophila) NM 021220 2.06333 TIA up vs Contro 242579 a BMPR1B bone morphogenetic NM 001203 2.05687 TIA up vs Contro protein receptor, type IB 226899 a UNCSB unc-5 homolog B (C. elegans) NM 170744 2.04351 TIA up vs Contro 231867 a ODZ2 odz, odd Ozften-m NM 00108.0428 2.03143 TIA up vs Contro homolog 2 (Drosophila) NM OO1122679 1557924 S at ALPL alkaline phosphatase, NM 000478 2.02022 TIA up vs Contro liver/bone/kidney NM OO11275O1 217194 a RASAL2 RAS protein activator like 2 NM 004841 2.OO632 TIA up vs Contro NM 170692 207570 a SHOX short stature homeobox NM 000451 2.OO103 TIA up vs Contro NM OO6883 235568 a C19Crf59 chromosome 19 open NM 174918 .99789 TIA up vs Contro reading frame 59 1552946 at ZNF114 Zinc finger protein 114 NM 153608 99445 TIA up vs Contro 1554473 at SRGAP1 SLIT-ROBORho GTPase NM O2O762 992O3 TIA up vs Contro activating protein 1 228260 at ELAVL2 ELAV (embryonic lethal, NM 004432 9905 TIA up vs Contro abnormal vision, Drosophila)-like 2 (Hu antigen B) 1559292 S at NCRNA00032 Clone IMAGE: 2275.835 XM 376821 TIA up vs Contro C9orf14 mRNA, partial XM 938.938 sequence; alternatively spliced 214984 at LOC440345 hypothetical protein XR O15786 98536 TIA up vs Contro LOC440345 1557155 a. at FLJ30375 CDNA clone XM OO1724993 TIA up vs Contro IMAGE: 5301781 XM OO1725199 XM OO1725628 215447 at TFPI Tissue factor pathway NM OO 1032281 // TIA up vs Contro inhibitor (lipoprotein NM OO6287 associated coagulation inhibitor), 228825 at prostaglandin reductase 1 NM 012212 .95262 TIA up vs Contro 213194 at roundabout, axon guidance NM OO2941 TIA up vs Contro receptor, homolog 1 NM 133631 (Drosophila) 209119 x at nuclear receptor Subfamily NM 021005 94377 TIA up vs Contro 2, group F, member 2 206819 at POM121 membrane NR 003714 93567 TIA up vs Contro glycoprotein-like 1 pseudogene 207235 S. at GRMS glutamate receptor, NM OOO842 TIA up vs Contro metabotropic 5 NM 001143831 201744 s at LUM lumican NM 002345 93131 TIA up vs Contro 230999 at FLJ39051 CDNA FLJ39051 fis, 926OS TIA up vs Contro clone NT2RP701 1452 229218 at COL1A2 collagen, type I, alpha 2 NM OOOO89 TIA up vs Contro 207500 at CASPS caspase 5, apoptosis NM 001136109 // TIA up vs Contro related cysteine peptidase NM 0011361.10 NM 0011361.11 NM 001136112 NM 004347 214111 at OPCML opioid binding protein cell NM 00101.2393 191158 TIA up vs Control adhesion molecule-like NM OO2545 US 2016/02375O1 A1 Aug. 18, 2016 12

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold- Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 1556666 a. at TTC6 tetratricopeptide repeat NM OO1007795 1.91015 TIA up vs Control domain 6 214451 at TFAP2B transcription factor AP-2 NM OO3221 1.89347 TIA up vs Control beta (activating enhancer binding protein 2 beta) 210262 at CRISP2 cysteine-rich Secretory NM 001142407 // 1.88349 TIA up vs Control protein 2 NM 001142408 NM OO1142417 NM OO1142435 NM O03296 204914 S at SOX11 SRY (sex determining NM OO3108 882O1 TIA up wS Contro region Y)-box 11 1562292 at ANKRD3OB ankyrin repeat domain 30B XM OO1716904 .86641 TIA up vs Contro XM OO1717561 // XM OO1717810 227925 at FLJ39051 CDNA FLJ39051 fis, 864.33 TIA up wS Contro clone NT2RP701 1452 229057 at SCN2A Sodium channel, voltage- NM OO104O142 85129 TIA up wS Contro gated, type II, alpha NM 00104.0143 Subunit NM 021007 237510 at MYNN Myoneurin, mRNA NM 018657 8504.1 TIA up wS Contro (cDNA clone IMAGE:4721583) 40284 at FOXA2 forkhead box A2 NM 021784 .8498 TIA up vs Contro NM 153675 233092 s at DKFZP434B061 DKFZP434B061 protein XR O15528 .84946 TIA up vs Contro XR 040812 230902 at LOC645323 CDNA clone NR 015436 84336 TIA up wS Contro IMAGE: S260726 NR 024383 / NR 024384 XR 041118 XR 041119 XR 041120 232547 at SNIP SNAP25-interacting NM O25248 1.83841 TIA up vs Control protein 238850 at LOC645323 hypothetical LOC645323 NR 015436 1.81503 TIA up vs Control NR 024383 / NR 024384 XR 041118 XR 041119 XR 041120 233879 at LOC374491 TPTE and PTEN NR 002815 81019 TIA up wS Contro homologous inositol lipid phosphatase pseudogene 243520 x at ADAM30 ADAM metallopeptidase NM 021794 8O193 TIA up wS Contro domain 30 206634 a SIX3 SIXhomeobox 3 NM 005413 78989 TIA up wS Contro 1560790 at FLJ36144 hypothetical protein XR 040632 78391 TIA up wS Contro FLJ36144 XR 040633 XR 040634 232969 a CARD8 caspase recruitment NM O14959 78.265 TIA up wS Contro domain family, member 8 235370 a KREMEN1 kringle containing NM OO1039570 77475 TIA up wS Contro transmembrane protein 1 NM OO1039571 1555990 at RP1-127L4.6 hypothetical protein NM 001010859 766O3 TIA up wS Contro LOC15O297 222291 a FAM149A amily with sequence NM OO1 OO6655 75785 TIA up wS Contro similarity 149, member A NM O15398 239144 a B3GAT2 beta-1,3- NM 080742 75721 TIA up wS Contro glucuronyltransferase 2 (glucuronosyltransferase S) 235342 a. SPOCK3 sparcosteonectin, cwcv NM OO1040159 75.314 TIA up wS Contro and kazal-like domains NM 016950 proteoglycan (testican) 3 1553024 at G30 protein LG30-like .75094 TIA up wS Contro 214927 a ITGBL1 integrin, beta-like 1 (with NM OO4791 73813 TIA up wS Contro EGF-like repeat domains) 229538 s at IQGAP3 IQ motif containing NM 178229 73797 TIA up wS Contro GTPase activating protein 3 US 2016/02375O1 A1 Aug. 18, 2016 13

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold- Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 1553329 at C7orfas chromosome 7 open NM 145268 72974 TIA up wS Contro reading frame 45 2323.03 at ZNF608 Zinc finger protein 608 NM 020747 72629 TIA up wS Contro 1558982 at LOC37SO10 hypothetical LOC375010 XR 041271 72485 TIA up wS Contro 2308.63 at LRP2 ow density lipoprotein- NM 004.525 .71146 TIA up vs Contro related protein 2 228121 at TGFB2 transforming growth NM OO1135599 70904 TIA up wS Contro actor, beta 2 NM O03238 208443 x at SHOX2 short stature homeobox2 NM OO3O3O 7O616 TIA up wS Contro NM OO6884 206858. S. at HOXC4 homeobox C4 NM OO4503 70414 TIA up vs Contro HOXC6 homeobox C6 NM 014620 NM 153633 NM 153693 219134 at ELTD1 EGF, latrophilin and seven NM 0221.59 .70282 TIA up wS Contro transmembrane domain containing 1 222205 x at FAM182B if amily with sequence XM 001132551 // 7OO42 TIA up wS Contro RP13-401N8.2 similarity 182, member B XM OO1133521 i? hypothetical gene XM OO1718365 Supported by XM 933752 220696 at PROO478 PROO478 protein 691.69 TIA up wS Contro 225571 at LIFR eukemia inhibitory factor NM OO1127671 69168 TIA up wS Contro receptor alpha NM 002310 217483 at FOLH1 olate hydrolase (prostate- NM 001014986 if 68955 TIA up wS Contro specific membrane NM 004476 antigen) 1 232360 at EHF ets homologous factor NM 012153 68951 TIA up wS Contro 220429 at NDST3 N-deacetylase/N- NM OO4784 68889 TIA up wS Contro Sulfotransferase (heparan glucosaminyl) 3 232416 at BRUNOLS bruno-like 5, RNA binding NM O21938 68747 TIA up wS Contro protein (Drosophila) 231434 at LOC728460 similar to FLJ32921 XM OO1128581 6873.3 TIA up wS Contro protein XM OO1129498 XM OO1723364 208396 s at PDE1A phosphodiesterase 1A, NM 001003683 // 68453 TIA up wS Contro calmodulin-dependent NM 005019 1569675 at POU2AF1 POU class 2 associating NM O06235 67876 TIA up wS Contro actor 1, mRNA (cDNA clone MGC: 45211 MAGE:5554.134) 201579 at FAT1 FAT tumor suppressor NM OO5245 67288 TIA up wS Contro homolog 1 (Drosophila) 210292 s at PCDH11X if protocadherin 11 X-linked NM 014522 6605 TIA up wS Contro PCDH11 Y fit protocadherin 11 Y- NM 032967 inked NM 032968 NM 032969 NM 032971 NM 032972 1558579 at FLJ37786 hypothetical LOC642691 XR 041472 66O29 TIA up wS Contro XR 041473 205896 at SLC22A4 solute carrier family 22 NM OO3059 65918 TLA up wS Contro (organic cation ergothioneine transporter), member 4 226121 at DHRS13 dehydrogenase/reductase NM 144683 .65414 TIA up vs Contro (SDR family) member 13 21985.0 s at EHF ets homologous factor NM 012153 .64412 TIA up vs Contro 235077 at MEG3 maternally expressed 3 NR 002766 .6384 TIA up vs Contro (non-protein coding) NR 003530 NR 003531 214868 at PIWIL1 piwi-like 1 (Drosophila) NM 004764 63171 TIA up wS Contro 232034 at LOC2O3274 CDNA FLJ31544 fis, 63147 TIA up wS Contro clone NT2RI200O865 1556704 s at LOC100133920 hypothetical protein NR 024443 .63034 TIA up vs Contro J. LOC286297 LOC10O13392O XM 001714612 hypothetical protein XM 372109 LOC286297 XM 933054 XM 933058 US 2016/02375O1 A1 Aug. 18, 2016 14

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold- Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 220493 at DMRT1 doublesex and mab-3 NM O21951 61917 TIA up wS Contro related transcription factor 1 202912 at ADM adrenomedullin NM OO1124 61874 TIA up wS Contro 1561200 at WWA3B von Willebrand factor A NM 144992 .61802 TIA up vs Contro domain containing 3B 1555726 at GAFA3 FGF-2 activity-associated XM OO1715321 // 61768 TIA up wS Contro protein 3 XM OO1722922 XM OO17236.36 211267 at HESX1 HESXhomeobox 1 NM OO3865 61355 TIA up wS Contro 206134 at ADAMDEC1 ADAM-like, decysin 1 NM O14479 .61274 TIA up vs Contro 203065 s at CAV1 caveolin 1, caveolae NM OO1753 6O773 TIA up wS Contro protein, 22 kDa 215516 at LAMB4 aminin, beta 4 NM OO7356 .60646 TIA up vs Contro 220205 at TPTE transmembrane NM 1992.59 60547 TIA up wS Contro phosphatase with tensin NM 19926O homology NM 199261 1555462 at PPP1R1C protein phosphatase 1, NM 001080545 .60542 TIA up vs Contro regulatory (inhibitor) subunit 1C 219403 s at HPSE heparanase NM 001098.540 60481 TIA up vs Contro NM OO6665 206513 at AIM2 absent in melanoma 2 NM 004.833 6O396 TIA up wS Contro 215321 at RUNDC3B RUN domain containing NM 001134405 .60322 TIA up vs Contro 3B NM 0011344.06 NM 138290 1552701 a. at CARD16 caspase recruitment NM 001017534 59587 TIA up wS Contro domain family, member 16 NM 052889 230519 at FAM124A family with sequence NM 145019 59.499 TIA up wS Contro similarity 124A 240814 at MGC39584 hypothetical gene XR O17735 59341 TIA up wS Contro supported by BCO29568 XR O17787 XR 041937 230170 at OSM oncostatin M NM O2O530 58899 TIA up wS Contro 226872 at RFX2 regulatory factor X, 2 NM OOO635 58786 TIA up wS Contro (influences HLA class II NM 134433 expression) 214087 s at MYBPC1 myosin binding protein C, NM OO2465 58609 TIA up wS Contro slow type NM 2068.19 NM 206820 NM 206821 203005 at LTBR lymphotoxin beta receptor NM 002342 58.399 TIA up wS Contro (TNFRSuperfamily, member 3) 223977 s at C18orf2 chromosome 18 open NM 031416 58384 TIA up wS Contro reading frame 2 NR 023925 NR 023926 NR 023927 NR 023928 240204 at SNRPN Small nuclear NM OO3097 1.58295 TIA up vs Control ribonucleoprotein NM 0228.05 polypeptide N NM 022806 NM O22807 NM 0228O8 NR 001289 229521 at FLJ36O31 hypothetical protein NM 175884 1.58141 TIA up vs Control FLJ36O31 205067 at IL1B interleukin 1, beta NM 000576 1.57884 TIA up vs Control 206479 at TRPM1 transient receptor potential NM OO2420 1.57541 TIA up vs Control cation channel, Subfamily M, member 1 1553931 at OSTCL oligosaccharyltransferase NM 145303 1.57501 TIA up vs Control complex subunit-like 210449 X at MAPK14 mitogen-activated protein NM 001315 1.57327 TIA up vs Control kinase 14 NM 139012 NM 139013 NM 139014 238428 at KCNJ15 potassium inwardly- NM OO2243 1.56965 TIA up vs Control LOC100131955 rectifying channel, NM 170736 Subfamily J, member 15 fif NM 170737 similar to pot XM OO1713900 US 2016/02375O1 A1 Aug. 18, 2016 15

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) XM OO1715532 XM O 238964 at FIGN idgetin NM 018086 bws Con O 227566 at HNT neurotrimin NM OO1048209 bws Con O NM O16522 205863 at S100A12 S100 calcium binding NM OO5621 S633 bws Con O protein A12 208168 s at CHIT1 chiltinase 1 NM OO3465 S6138 bws Con O (chitotriosidase) 2392.03 at C7orf53 chromosome 7 open NM 001134468 if .55912 bws Con O reading frame 53 NM 182597 1569025 S. at FAM13A1 amily with sequence NM 001015045 55876 bws Con O similarity 13, member A1 NM O14883 204763 s at guanine nucleotide binding NM O2O988 SS42 bws Con O protein (G protein), alpha NM 138736 activating activity polype 211561 x at MAPK14 mitogen-activated protein NM 001315 55337 TIAL bws Con O kinase 14 NM 139012 NM 139013 NM 139014 220645 at FAMSSD amily with sequence NM 001077639 SS166 bws Con O similarity 55, member D NM O17678 241669 x at PRKD2 protein kinase D2 NM 001079880 55139 bws Con O NM 001079881 NM 001079882 // NM 016457 210582 s at LIMK2 LIM domain kinase 2 NM OO1031801 S485 TIAL bws Con O NM 005569 NM O16733 1553652 a. at chromosome 18 open NM 173529 bws Con O reading frame 54 211959 at insulin-like growth factor NM 000599 bws Con O binding protein 5 243277 X at EVI1 ecotropic viral integration NM 001105077 S445 bws Con O site 1 NM 001105078 NM O05241 202446 s at PLSCR1 phospholipid scramblase 1 NM 021105 S4059 bws Con O 1553613 s at FOXC1 forkhead box C1 NM OO1453 S3964 bws Con O 1568933 at LOC646627 phospholipase inhibitor NM 00108.5474 S3874 bws Con O 244007 at ZNF462 Zinc finger protein 462 NM 021224 53545 bws Con O 239989 at CNTLN centlein, centrosomal NM 001114395 S3478 bws Con O protein NM O17738 229743 at ZNF438 Zinc finger protein 438 NM 001143766 bws Con O NM 001143767 NM 001143768 // NM 001143769 NM 001143770 1553.002 at DEFB1OSA defensin, beta 105A NM OO1040703 S2948 bws Con O DEFB1OSB defensin, beta 105B NM 152250 1560823 at LOC34.0017 hypothetical protein 51946 bws Con O LOC34.0017 1554540 at C1 Orf67 chromosome 1 open NM 144989 51941 bws Con O reading frame 67 207275 S. at ACSL1 acyl-CoA synthetase long NM OO1995 S1866 TIAL bws Con O chain family member 1 209.614 at ADH1B alcohol dehydrogenase 1B NM OOO668 51397 TIAL bws Con O (class I), beta polypeptide 216236 s at SLC2A14 solute carrier family 2 NM OO6931 S1356 TIAL bws Con O (facilitated glucose NM 153449 transporter), member 14 ft/ solute 394.02 at interleukin 1, beta NM 000576 S1316 bws Con O 203759 at ST3 beta-galactoside NM OO6278 S10O2 bws Con O alpha-2,3-Sialyltransferase 4 XM OO1714343 // XM OO1726541 XM OO1726562 222435 s at UBE21 ubiquitin-conjugating NM 016021 50758 TIAL bws Con O enzyme E2, J1 (UBC6 homolog, yeast) US 2016/02375O1 A1 Aug. 18, 2016

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold- Fold Change Change (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 233030 at PNPLA3 patatin-like phospholipase NM O25225 1.50269 TIA up vs Control domain containing 3 1559400 S. at PAPPA pregnancy-associated NM OO2581 1.50009 TIA up vs Control plasma protein A, pappalysin 1

0104 Underexpressed biomarkers indicative of the occur 0105. In patients who have experienced TIA or who are at rence of TIA or useful to predict the risk of experiencing TIA risk of developing TIA, the biomarkers of Table 2 are under are listed in Table 2. In practicing the present methods, the expressed in comparison to a control level of expression. A control level of expression can refer to the level of expression expression levels of a plurality of biomarkers from Table 2 are of the same biomarker in an individual who has not had and is determined, optionally in combination with other TIA-asso not at risk for a vascular event or the level of expression of a ciated biomarkers described herein (e.g., in Tables 1, 5A, 5B, stably expressed endogenous control gene. In patients who 5C, 5D, 7, 8 and/or 9) and known in the art. In some embodi have experienced TIA or who are at risk of developing TIA, ments, the expression levels of at least about 2, 3, 4, 5, 6, 7, 8, the biomarkers of Table 2 are underexpressed at least 1.5-fold, 9, 10, 15, 20, 30, 45, 50, 60, 65,70, 75,80, 85,90, 95, 100, or e.g., at least 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, more, biomarkers listed in Table 2 are determined, optionally 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7- in combination with other TIA-associated biomarkers fold, 2.8-fold, 2.9-fold, 3.0-fold, 3.1-fold, 3.2-fold, 3.3-fold, described herein (e.g., in Tables 1, 5A, 5B, 5C, 5D, 7, 8 and/or 3.4-fold or 3.5-fold, or more, in comparison to a control level 9) and known in the art. of expression. TABLE 2 TIA-associated biomarkers that are downregulated Fold- Fold Change Change(TLA vs. RefSeq, (TLA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 242191 a NBPF10 neuroblastoma breakpoint NM 0010397.03 -1.5.0043 TIA down vs RP11-94.2.2 family, member 10 fif NM 183372 Contro hypothetical protein XM OO1722184 LOC2OOO3O 232055 a. SFXN1 sideroflexin 1 NM O22754 -1.50117 TIA down vs Contro 1555883 s at SPIN3 spindlin family, member 3 NM 001010862 -1.50348 TIA down vs Contro 206487 a UNC84A unc-84 homolog A (C. elegans) NM 001130965 if -1.50376 TIA down vs NM O25154 Contro 2236O1 a OLFM2 olfactomed in 2 NM O581.64 -1.5119 TIA down vs Contro 244011 a PPM1K protein phosphatase 1K NM 152542 -1.51501 TIA down vs (PP2C domain containing) Contro 214615 a. P2RY1O purinergic receptor P2Y, NM O14499 fif -151779 TIA down ws G-protein coupled, 10 NM 198333 Contro 55872 at ZNFS12B Zinc finger protein 512B NM 020713 -1521.58 TIA down ws Contro 243857 a MORF4L2 Mrgx mRNA for MRGX NM 001142418 -1.52328 TIA down vs NM 001142419 Contro NM 001142420 NM 001142421 fff NM 001142422 15601.33 at GIGYF2 GRB10 interacting GYF NM 001103146 -1.52626 TIA down vs protein 2 NM 001103147 Control NM OO1103148 NM O15575 1554273 a at ERAP2 endoplasmic reticulum NM 001130140 -1.52883 TIA down vs aminopeptidase 2 NM 022350 Control 1553423 a at SLFN13 schlafen family member 13 NM 144682 -1.53028 TIA down vs Control 229094 at LOC4O1431 hypothetical gene XR 040272 -1.53069 TIA down vs LOC4O1431 XR 040273 Control XR 040274 XR 040275 US 2016/02375O1 A1 Aug. 18, 2016 17

TABLE 2-continued TIA-associated biomarkers that are downregulated Fold- Fold Change Change(TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 207078 at MED6 mediator complex subunit 6 NM OO5466 -1.53192 TIA down vs Control 227372 s at BAIAP2L1 BAI1-associated protein 2- NM 018842 -1.53271 TIA down wS LOC100128461 like 1 i? hypothetical XM OO1722656 Control protein LOC100128461 XM OO1724217 XM OO1724858 236728 at LNPEP leucyl cystinyl NM OO5575 -1.53387 TIA down wS aminopeptidase NM 175920 Control 215663 at MBNL1 muscleblind-like NM O21038 -1.53726 TIA down wS (Drosophila) NM 207292 Control NM 207293 NM 207294 NM 207295 NM 207296 229.093 at NOS3 nitric oxide synthase 3 NM OOO603 -153818 TLA down wS (endothelial cell) Contro 212935 at MCF2L MCF.2 cell line derived NM 001112732 f -1.53863 TIA down WS transforming sequence-like NM O24979 Contro 215750 at KIAA1659 KIAA1659 protein XM 001723799 f -1.54646 TIA down WS XM OO1725435 Contro XM OO1726785 212699 at SCAMPS Secretory carrier NM 138967 -1.54948 TIA down vs membrane protein 5 Contro 1565911 at LOC64892.1 MRNA full length insert XM 001715629 f -1.54981 TIA down WS cDNA clone XM OO1720571 // Contro EUROIMAGE 209544 XR 018520 239651 a ANAPCS anaphase promoting NM 001137559 f -1.55844. TIA down WS complex subunit 5 NM O16237 Contro 213993 a SPON1 spondin 1, extracellular NM OO6108 -155928 TIA down wS matrix protein Contro 231108 a FUS fusion (involved in NM 004960 -156277 TIA down wS t(12; 16) in malignant Contro liposarcoma) 221288 a GPR22 G protein-coupled receptor NM O05295 -1563O3 TIA down wS 22 Contro 219815 a. GAL3ST4 galactose-3-O- NM O24637 -1.5674 TIA down vs Sulfotransferase 4 Contro 242111 a METTL3 methyltransferase like 3 NM O19852 -1.56742 TIA down vs Contro 239062 a LOC100131096 hypothetical XM 001720907 f -1.57675 TIA down WS LOC100131096 XM OO1726205 // Contro XM OO1726705 230792 a FAAH2 fatty acid amide hydrolase 2 NM 174912 -157807 TIA down wS Contro 232020 a SMURF2 SMAD specific E3 NM O22739 -157992 TIA down wS ubiquitin protein ligase 2 Contro 226587 a SNRPN Small nuclear NM OO3097 -158OO6 TIA down wS ribonucleoprotein NM O22805 Contro polypeptide N NM O22806 NM O22807 NM O22808 NR OO1289 2292.47 at FBLN7 ibulin 7 NM OO1128165 f -1.58734 TIA down WS NM 153214 Contro 223O80 at GLS Glutaminase, mRNA NM O14905 -1.594.04 TIA down vs (cDNA clone MGC: 33744 Contro MAGE:5263220) 1557350 at G3BP1 GTPase activating protein NM OO5754 -1.6.194 TIA down vs (SH3 domain) binding NM 198395 Contro protein 1 2198.64 s at RCAN3 RCAN family member 3 NM O13441 -161977 TIA down wS Contro 209368 at EPHX2 epoxide hydrolase 2, NM OO1979 -1.62474 TIA down vs cytoplasmic Contro 212504 at DIP2C DIP2 disco-interacting NM O14974 -1.62614 TIA down vs protein 2 homolog C Contro (Drosophila) 1553645 at CCDC141 coiled-coil domain NM 173648 -1.62867 TIA down vs containing 141 Contro US 2016/02375O1 A1 Aug. 18, 2016 18

TABLE 2-continued TIA-associated biomarkers that are downregulated Fold- Fold Change Change(TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 239871 at CLTC Clathrin, heavy chain (He), NM OO4859 -1.63031 TIA down vs mRNA (cDNA clone Contro IMAGE: 4812912) 202768 at FOSB FBJ murine osteosarcoma NM 001114171 f -1.63049 TIA down WS viral oncogene homolog B NM OO6732 Contro 221631 at CACNA1I calcium channel, Voltage- NM OO10O3406 -163297 TIA down wS dependent, T type, alpha 1I NM O21096 Contro Subunit 1558569 at UNQ6228 MRNA, cDNA XM 001725293 f -1.63796 TIA down WS DKFZp667K1619 (from XM OO1725359 // Contro clone DKFZp667K1619) XM 001726164 229252 at ATG9B ATG9 autophagy related 9 NM 173681 -1.64694 TIA down vs homolog B (S. cerevisiae) Contro 2228.62 s at AK5 adenylate kinase 5 NM O12093 -1.64741 TIA down vs NM 174858 Contro 1555882 at SPIN3 spindlin family, member 3 NM OO1 010862 -1.65127 TIA down vs Contro 239635 at RBM14 RNA binding motif protein NM OO6328 -1.65349 TIA down vs 14 Contro 1560741 at SNRPN Small nuclear NM OO3097 -165945 TIA down wS ribonucleoprotein NM O22805 Contro polypeptide N NM O22806 NM O22807 NM O22808 NR OO1289 214180 at MAN1C1 mannosidase, alpha, class NM O2O379 -1.66631 TIA down vs 1C, member 1 Control 220085 at HELLS helicase, lymphoid- NM O18063 -1.67692 TIA down vs specific Control 220048 at EDAR ectodysplasin A receptor NM O22336 -1.69385 TIA down wS Control 239667 at SLC3A1 solute carrier family 3 NM 000341 -1.69708 TIA down wS (cystine, dibasic and Control neutral amino acid transporters, a 1568873 at ZNF519 Zinc finger protein 519 NM 145287 -1.70283 TIA down wS Control 236621 at LOC100130070 similar to NM OO1030 -1.70558 TIA down wS LOC100130775 / metallopanstimulin / XM OO1721002 Control LOC100131787 similar to rCG63653 XM OO1722161 LOC100131905 i? similar to metallopans XM OO1722.965/// LOC10O132291 XM OO1723889 LOC10O1324.88 RPS27 229234 at ZC3H12B Zinc finger CCCH-type NM OO1O10888 -1.72127 TIA down vs containing 12B Contro 241723 at IQGAP2 IQ motif containing NM OO6633 -1.73571 TIA down wS GTPase activating protein 2 Contro 226913 s at SOX8 SRY (sex determining NM O14587 -1.73755 TIA down wS region Y)-box 8 Contro 1557450 s at WHDC1L2 WAS protein homology XM 926785 -1.75555 TIA down wS region 2 domain Contro containing 1-like 2 1556116 s at TNPO1 Transportin 1, mRNA NM OO2270 -1.7577 TIA down wS (cDNA clone MGC: 17116 NM 153188 Contro IMAGE:4178989) 218856 at TNFRSF21 tumor necrosis factor NM O14452 -1.77712 TIA down wS receptor Superfamily, Contro member 21 244521 at TSHZ2 Cell growth-inhibiting NM 173485 -1.86.192 TIA down vs protein 7 Contro 1553998 at DMRTC1 if DMRT-like family C1 /// NM 001080851 f -1.867.04 TIA down WS DMRTC1B DMRT-like family C1 B NM O33053 Contro 204550 x at GSTM1 glutathione S-transferase NM OOO561 -1.95.136 TIA down vs mu 1 NM 146421 Contro 2193O8 is at AKS adenylate kinase 5 NM O12093 -1.95614 TIA down vs NM 174858 Contro 204418 x at GSTM2 glutathione S-transferase NM OOO848 -195729 TIA down wS mu 2 (muscle) NM 001142368 Contro 235758 at PNMA6A paraneoplastic antigen like NM O32882 -195731 TIA down wS 6A Contro US 2016/02375O1 A1 Aug. 18, 2016

TABLE 2-continued TIA-associated biomarkers that are downregulated Fold- Fold Change Change(TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description) 239771 at CAND1 cullin-associated and NM 018448 -1.97531 TIA down wS neddylation-dissociated 1 Control 1562028 at CCND3 Cyclin D3 (CCND3), NM 001136017 if -2.00377 TIA down WS transcript variant 3, mRNA NM OO11361.25 Control NM OO1136126 NM OO1760 215333 x at GSTM1 glutathione S-transferase NM OOO561 -2.03103 TIA down vs mu 1 NM 146421 Control 232207 at GUSBL2 glucuronidase, beta-like 2 NR OO3660 -2.10621 TIA down vs XR 042150 if Control XR 042151

4. Comparison to a Control Level of Expression to the reference biomarker are normalized by dividing the expression level of the target biomarker to the expression 0106 The expression of the TIA-associated biomarkers levels of a plurality of endogenous reference biomarkers. The are compared to a control level of expression. As appropriate, normalized expression level of a target biomarker can be used the control level of expression can be the expression level of to predict the occurrence or lack thereof of stroke or TIA, the same TIA-associated biomarker in an otherwise healthy and/or the cause of stroke or TIA. individual (e.g., in an individual who has not experienced 0109. In some embodiments, the expression level of the and/or is not at risk of experiencing TIA). In some embodi TIA-associated biomarker from a patient Suspected of having ments, the control level of expression is the expression level or experiencing TIA and from a control patient are normal of a plurality of stably expressed endogenous reference biom ized with respect to the expression levels of a plurality of arkers, as described herein or known in the art. In some stably expressed endogenous. The expression levels of the embodiments, the control level of expression is a predeter normalized expression of the TIA-associated biomarker is mined threshold level of expression of the same TIA-associ compared to the expression levels of the normalized expres ated biomarker, e.g., based on the expression level of the sion of the same TIA-associated biomarker in a control biomarker in a population of otherwise healthy individuals. In patient. The determined fold change in some embodiments, the expression level of the TIA-associ expression normalized expression of target biomarker in ated biomarker and the TIA-associated biomarker in an oth TIA patient/normalized expression of target biomarker in erwise healthy individual are normalized to (i.e., divided by), control patient. Overexpression or underexpression of the e.g., the expression levels of a plurality of stably expressed normalized TIA-associated biomarker in the TIA patient by at endogenous reference biomarkers. least about 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7- 0107. In some embodiments, the overexpression or under fold, 1.8-fold, 1.9-fold, 2.0-fold, 2.1 fold, 2.2-fold, 2.3-fold, expression of a TIA-associated biomarker is determined with 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3.0- reference to the expression of the same TIA-associated biom fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold or 3.5-fold, or more, arker in an otherwise healthy individual. For example, a in comparison to the expression levels of the normalized healthy or normal control individual has not experienced TIA-associated biomarker in a healthy control patient indi and/or is not at risk of experiencing TIA. The healthy or cates that the TIA patient has experienced or is at risk of normal control individual generally has not experienced a experiencing TIA. vascular event (e.g., TIA, ischemic stroke, myocardial infarc 0110. In some embodiments, the control level of expres tion, peripheral vascular disease, or venous thromboembo sion is a predetermined threshold level. The threshold level lism). The healthy or normal control individual generally can correspond to the level of expression of the same TIA does not have one or more vascular risk factors (e.g., hyper associated biomarker in an otherwise healthy individual or a tension, diabetes mellitus, hyperlipidemia, or tobacco Smok population of otherwise healthy individuals, optionally nor ing). As appropriate, the expression levels of the target TIA malized to the expression levels of a plurality of endogenous associated biomarker in the healthy or normal control reference biomarkers. After expression levels and normalized individual can be normalized (i.e., divided by) the expression expression levels of the TIA-associated biomarkers are deter levels of a plurality of stably expressed endogenous reference mined in a representative number of otherwise healthy indi biomarkers. viduals and individuals predisposed to experiencing TIA, 0108. In some embodiments, the overexpression or under normal and TIA expression levels of the TIA-associated expression of a TIA-associated biomarker is determined with biomarkers can be maintained in a database, allowing for reference to one or more stably expressed endogenous refer determination of threshold expression levels indicative of the ence biomarkers. Internal control biomarkers or endogenous presence or absence of risk to experience TIA or the occur reference biomarkers are expressed at the same or nearly the rence of TIA. If the predetermined threshold level of expres same expression levels in the blood of patients with stroke or sion is with respect to a population of normal control patients, TIAS as compared to control patients. Target biomarkers are then overexpression or underexpression of the TIA-associ expressed at higher or lower levels in the blood of the stroke ated biomarker (usually normalized) in the TIA patient by at or TIA patients. The expression levels of the target biomarker least about 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7- US 2016/02375O1 A1 Aug. 18, 2016 20 fold, 1.8-fold, 1.9-fold, 2.0-fold, 2.1 fold, 2.2-fold, 2.3-fold, levels of a plurality of endogenous reference biomarkers are 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3.0- determined as a control. In some embodiments, the expres fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold or 3.5-fold, or more, sion levels of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, in comparison to the threshold level indicates that the TIA 30, 35, or more, endogenous reference biomarkers, e.g., as patient has experienced or is at risk of experiencing TIA. If listed in Table 3 or known in the art, are determined as a the predetermined threshold level of expression is with control. respect to a population of patients known to have experienced 0112. In some embodiments, the expression levels of the TIA or known to be at risk for experiencing TIA, then an endogenous reference biomarkers GAPDH, ACTB, B2M, expression level in the patient Suspected of experiencing TIA HMBS and PPIB are determined as a control. In some that is approximately equal to the threshold level (or overex embodiments, the expression levels of 2,3,4,5,6,7,8,9, 10. pressed or underexpressed greater than the threshold level of 15, 20, 25, or more, endogenous reference biomarkers expression), indicates that the TIA patient has experienced or selected from the group consisting of USP7, MAPRE2. is at risk of experiencing TIA. CSNK1G2, SAFB2, PRKAR2A, PI4KB, CRTC1, HADHA, 0111. With respect to the endogenous reference biomark MAP1LC3B, KAT5, CDC2L1///CDC2L2, GTSE1, ers used for comparison, preferably, the endogenous refer CDC2L1///CDC2L2, TCF25, CHP, LRRC40, hCG ence biomarkers are stably expressed in blood. Exemplary 2003956///LYPLA2///LYPLA2P1, DAXX, UBE2NL, EIF1, endogenous reference biomarkers that find use are listed in KCMF1, PRKRIP1, CHMP4A, TMEM184C, TINF2, Table 3, below. Further suitable endogenous reference biom PODNL1, FBXO42, LOC441258, RRP1, C10orf104, arkers are published, e.g., in Stamova, et al., BMC Medical ZDHHC5, C90rf23, LRRC45, NACC1, LOC100.133445/// Genomics (2009) 2:49. In some embodiments, the expression LOC115110, PEX16 are determined as a control. TABLE 3 The 38 endogenous reference biomarkers stably expressed in blood for use in normalization and as control levels. Table 3 - Stably Expressed Endogenous Reference Biomarkers RefSeq, RefSeq Protein Probe Set ID Gene Symbol Gene Title GenBank ID UniGene ID Transcript ID ID 201499 s at USP7 ubiquitin specific peptidase NM OO3470.1 Hs.7O6830 NM OO3470 NP OO3461 7 (herpesvirus associated) 202501 at MAPRE2 microtubule-associated NM O14268.1 HS.532824 NM 001143826 NP OO1137298 protein, RP/EB family, NM 001143827 NP OO1137299 member 2 NM O14268 NP O55083 NR 026570 202573 at CSNK1 G2 casein kinase 1, gamma 2 ALS30441 Hs.651905 NM 001319 NP 001310 203280 at SAFEB2 scaffold attachment factor NM 014649.1 Hs.655392 NM 014649 NP O55464 B2 204842 X at PRKAR2A protein kinase, cAMP BCOO2763.1 Hs.631923 NM 004157 NP 004148 dependent, regulatory, type II, alpha 206138 s at PI4KB phosphatidylinositol 4 NM 002651.1 HS.632465 NM 002651 NP 002642 kinase, catalytic, beta 207159 X at CRTC1 CREB regulated NM O25021.1 HS.371.096 NM 001098482 NP 001091952 transcription coactivator 1 NM O15321 NP 056136 208.630 at HADHA hydroxyacyl-Coenzyme A AI972144 Hs.516.032 NM 000182 NP 000173 dehydrogenase 3 ketoacyl-Coenzyme A hiolase enoyl-Coenzyme A hydratase (trifunctional protein), alpha Subunit 208786 s at MAP1LC3B microtubule-associated AF1834.17.1 Hs.356061 NM O22818 NP 073729 protein 1 light chain 3 beta 209192 X at KATS K(lysine) acetyltransferase BCOOO166.2 HS.397.010 NM OO6388 NP OO6379 5 NM 182709 NP 874368 NM 182710 NP 874369 210474 S at CDC2L1 if cell division cycle 2-like 1 UO4819.1 HS.651228 NM 024011 NP 076916 CDC2L2 (PITSLRE proteins) // cell NM 033486 NP 277021 division cycle 2-like 2 NM 033487 NP 277022 (PITSLRE proteins) NM 033488 NP 277023 || NM 033489 NP 277024 NM 03.3492 NP 277027 NM 033493 NP 277028 NM 033529 NP 277071 211040 x at GTSE1 G-2 and S-phase BCOO6325.1 HS.386.189 NM 016426 NP 057510 expressed 1 211289 x at CDC2L1 cell division cycle 2-like 1 AFO67524.1 Hs.651228 NM 024011 ff NP 076916 CDC2L2 (PITSLRE proteins) // cell NM 033486 NP 277021 division cycle 2-like 2 NM 033487 NP 277022 (PITSLRE proteins) NM 033488 NP 277023 || NM 033489 NP 277024 NM 03.3492 NP 277027 US 2016/02375O1 A1 Aug. 18, 2016 21

TABLE 3-continued The 38 endogenous reference biomarkers stably expressed in blood for use in normalization and as control levels. Table 3 - Stably Expressed Endogenous Reference Biomarkers RefSeq, RefSeq Protein Probe Set ID Gene Symbol Gene Title GenBank ID UniGene ID Transcript ID ID NM 033493 NP 277028 NM 033529 NP 277071 213311 S. at TCF25 transcription factor 25 BFOOO2S1 HS.415342 NM O14972 NP 055787 (basic helix-loop-helix) 214665 S at CHP calcium binding protein AKOOOO95.1 HS.406234 NM 007 236 NP OO9167 P22 215063 x at LRRC40 leucine rich repeat AL390149.1 HS.147836 NM. O17768 NP 060238 containing 40 215200 x at — AKO22362.1 HS.663419 - 215568 x at hCG 2003956 hCG20O3956 ALO31295 Hs.533479 NM OO7260 ?/ NP O09191 J. LY PLA2 lysophospholipase II NR OO1444 LYPLA2P1 lysophospholipase II pseudogene 1 216038 x at DAXX death-domain associated BE965715 Hs.336916 NM 001141969 NP OO1135441 protein NM OO1141970 NP OO11354.42 NM 001350 NP 001341 NR 024517 217393 x at UBE2NL ubiquitin-conjugating AL109622 Hs.585177 NM 001012989 NP 001013.007 enzyme E2N-like 217549 at AWS74933 HS.527860 - 217672 X at EIF1 eukaryotic translation BF114906 Hs.150580 NM OO58O1 NP OO5792 initiation factor 1 217938. S. at KCMF1 potassium channel NM 020122.1 HS.654968 NM 020122 NP 064507 modulatory factor 1 218378 s at PRKRIP1 PRKR interacting protein 1 NM O24653.1 HS.406395 NM O24653 NP 078929 (IL11 inducible) 218571 S. at CHMP4A chromatin modifying NM 014169.1 HS.279761 NM 014169 NP 054888 protein 4A 219074 at TMEM184C transmembrane protein NM 018241.1 Hs.203896 NM 018241 NP O60711 184C 22005.2 s at TINF2 TERF1 (TRF1)-interacting NM 012461.1 HS.496.191 NM 001099274 / NP 001092744/// nuclear factor 2 NM 012461 NP 036593 220411 x at PODNL1 podocan-like 1 NM O24825.1 HS.448497 NM OO1146254 NP OO1139726 NM OO1146255 NP OO1139727 NM O24825 NP O79101 221813 at FBXO42 F-box protein 42 AI129395 HS.522384 NM 018994 NP 061867 222207 x at LOC441258 Williams Beuren syndrome AKO24602.1 HS.711232 chromosome region 19 pseudogene 222733 X at RRP1 ribosomal RNA processing BC000380.1 HS.110757 NM OO3683 NP OO3674 1 homolog (S. cerevisiae) 224667 X at C10orf104 chromosome 10 open AKO23981.1 HS.426296 NM 173473 NP 775744 reading frame 104 224858 at ZDHHCS Zinc finger, DHHC-type AKO23130.1 HS.27239 NM O15457 NP 056272 containing 5 225,403 at C9Crf23 chromosome 9 open ALS28391 HS.15961 NM 148178 NP 680544 reading frame 23 NM 148179 NP 680545 2262.53 at LRRC45 leucine rich repeat BE965418 HS.143774 NM 144999 NP 659436 containing 45 227651 at NACC1 nucleus accumbens AI498.126 Hs.531614 NM 052876 NP 443108 associated 1, BEN and BTB (POZ) domain containing 232190 x at LOC100133445 hypothetical AI393958 Hs.132272 NR 026927 J. LOC115110 LOC10O133445 F. XR 036887 hypothetical protein XR O38144 LOC115110 49878 at PEX16 peroxisomal biogenesis AAS23441 Hs.100915 NM OO4813 NP 004804 factor 16 NM 057174 NP 476515

5. Methods of Determining the Cause of TIA COL1A1, COL1A2, COL3A1, COL10A1, COL11A1, 0113 Subsets of the TIA-associated biomarkers described COL25A1, COL27A1, FGFs and EGFR may have athero herein further find use in predicting or determining the cause Sclerosis. of TIA. 0115 Individuals can have a risk or predisposition to 0114 For example, patients that overexpress genes experiencing TIA, e.g., based on genetics, a related disease involved in extracellular matrix remodeling including one or condition, environment or lifestyle. For example, in some more or all genes selected from MMP16, MMP19, MMP26, embodiments, the patient Suffers from a chronic inflamma US 2016/02375O1 A1 Aug. 18, 2016 22 tory condition, e.g., has an autoimmune disease (e.g., rheu MAPK14, MBNL1, MCF2L, MECOM, MYBPC1, NOS3, matoid arthritis, Crohn's disease inflammatory bowel dis NTM, ODZ2, OLFM2, OPCML, PAPPA, PDE1A, ROBO1, ease), atherosclerosis, hypertension, or diabetes. In some RORB, S100A12, SMURF2, SNRPN, SOX9, SPOCK3, embodiments, the patient has high LDL-cholesterol levels or SPON1, TFPI, TRPM1, UNC84A and VWA3B. Suffers from a cardiovascular disease (e.g., atherosclerosis, I0120 In some embodiments, the patient may have an coronary artery disease). In some embodiments, the patient immunological disorder and have increased or decreased has an endocrine system disorder, a neurodegenerative disor expression relative to a control level of expression of a plu der, a connective tissue disorder, or a skeletal and muscular rality of biomarkers selected from the group consisting of disorder. Exemplary disorders associated with, related to, or ACSL1, ADM, AK5, ANXA3, ASTN2 (includes EG:23245), causative of TIA are provided in Table 7. BCL6, CARD8, CASP5, CCND3, CCRL1, CLTC, CNTN4, 0116. In some embodiments, the patient may have a neu COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, rological disorder and have increased or decreased expression FAM124A, FAT1, FOSB, GABRB2, GOLGA6L2, GSTM1, relative to a control level of expression of a plurality of GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, LTBR, biomarkers selected from the group consisting of ACSL1, MAPK14, MYBPC1, NELL2, NOS3, NTM, ODZ2, ADH1B, AK5, ANXA3, APBA2, ASTN2 (includes OPCML, OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, EG:23245), BCL6, BMPR1B, CASP5, CAV1, CNTN4, S100A12, SLC22A4 (includes EG:6583), SNRPN, SPON1, DIP2C, ELAVL2, EPHX2, ERAP2, FAM124A, FAM13A, TLR5, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes FAM149A, FAT1, FOLH1, FOXC1, GABRB2, GIGYF2, EG: 115669), VWA3B and ZNF438. GNAO1, GRM5, GSTM1, HESX1, HOXC6, IGFBP5, IL1B, I0121. In some embodiments, the patient may have a meta IQGAP2, ITGBL1, LAMB4, LIFR, LTBR, MECOM, bolic disorder and have increased or decreased expression NBPF10, NDST3, NELL2, NOS3, NTM, ODZ2, OLFM2, relative to a control level of expression of a plurality of OPCML, PDE1A, RFX2, ROBO1, S100A12, SCN2A, biomarkers selected from the group consisting of ACSL1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, SOX9, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes SPOCK3, SPON1, TGFB2, TLR5, TNFRSF21, TRPM1, EG:23245), BCL6, CARD8, CASP5, CCRL1, CNTLN, TSHZ2, TTC6 (includes EG:115669), UNC5B, UNC84A CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, and ZNF608. EPHX2, FAT1, FOXA2, GABRB2, GUSBL2, IGFBP5, 0117. In some embodiments, the patient may have a skel IL1B, IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, etal or muscular disorder and have increased or decreased NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, expression relative to a control level of expression of a plu ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, rality of biomarkers selected from the group consisting of SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, ACSL1, ADM, AK5, ASTN2 (includes EG:23245), BCL6, UNC84A and VWA3B. BMPR1B, CARD8, CASP5, CCND3, CLTC, CNTN4, I0122. In some embodiments, the patient may have an COL1A1, COL1A2, DIP2C, DNAH14, EDAR, ELAVL2, endocrine system disorder and have increased or decreased EPHA3, EPHX2, FAM124A, FOSB, GABRB2, GIGYF2, expression relative to a control level of expression of a plu GNAO1, HOXC6, IL1B, KCNJ15, LAMB4, LIFR, LTBR, rality of biomarkers selected from the group consisting of LUM, MAPK14, MYBPC1, NOS3, ODZ2, OSM, PAPPA, ACSL1, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (in PDE1A, ROBO1, RUNDC3B, S100A12, SCN2A, SHOX, cludes EG:23245), BCL6, CARD8, CASP5, CCRL1, SLC22A4 (includes EG:6583), SOX9, SPOCK3, TLR5, CNTLN, CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), EPHA3, FAT1, FOXA2, GABRB2, GUSBL2, IL1B, TWIST1, UNC5B, VWA3B and ZNF438. IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, 0118. In some embodiments, the patient may have an NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, inflammatory disorder and have increased or decreased ROBO1, SHOX, SLC22A4 (includes EG:6583), SLC2A3, expression relative to a control level of expression of a plu SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, rality of biomarkers selected from the group consisting of UNC84A and VWA3B. ACSL1, ADM, AK5, ANXA3, APBA2, ASTN2 (includes I0123. In some embodiments, the patient may have an EG:23245), BCL6, CARD8, CASP5, CAV1, CCND3, autoimmune disease and have increased or decreased expres CCRL1, CLTC, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, sion relative to a control level of expression of a plurality of EPHX2, ERAP2, FAM124A, FBLN7, FOSB, FREM2, biomarkers selected from the group consisting of ACSL1, GABRB2, GRM5, IL1B, KCNJ15, LAMB4, LHX2, LNPEP. ADM, AK5, ASTN2 (includes EG:23245), BCL6, CARD8, LRP2, LTBR, LUM, MAPK14, MECOM, MYBPC1, NOS3, CASP5, CCND3, CLTC, CNTN4, COL1A2, DIP2C, ODZ2, OPCML, OSM, PAPPA, PDE1A, PPP1R1C, DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, ROBO1, RUNDC3B, S100A12, SCN2A, SFXN1, SLC22A4 GABRB2, GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, (includes EG:6583), SLC26A8, SMURF2, SNRPN, SPON1, LTBR, MAPK14, MYBPC1, NELL2, ODZ2, OPCML, TGFB2, TLR5, TNFRSF21, TNPO1, TTC6 (includes OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, EG:115669), TWIST1, UNC5B, VWA3B and ZNF438. SLC22A4 (includes EG:6583), SNRPN, SPON1, TLR5, 0119. In some embodiments, the patient may have a car TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), diovascular disorder and have increased or decreased expres VWA3B and ZNF438. sion relative to a control level of expression of a plurality of 0.124. In some embodiments, the patient may have diabe biomarkers selected from the group consisting of ACSL1, tes and have increased or decreased expression relative to a ADM, AK5, ALPL, ASTN2 (includes EG:23245), BCL6, control level of expression of a plurality of biomarkers BMPR1B, C18ORF54, CACNA1 I, CARD16, CAV1, selected from the group consisting of ACSL1, ADAM30, CNTN4, DMRT1, DNAH14, EDAR, EPHX2, ERAP2, AK5, ALPL. ALS2CR11, ASTN2 (includes EG:23245), FAM13A, FOLH1, FOSB, FREM2, GABRB2, GRM5, BCL6, CARD8, CASP5, CCRL1, CNTLN, CNTN4, GSTM1, IL1B, IQGAP2, LIFR, LTBR, MAN1C1, COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, FAT1, US 2016/02375O1 A1 Aug. 18, 2016

FOXA2, GABRB2, GUSBL2, IL1B, IQGAP2, ITGBL1, EG:23245), CARD8, CCRL1, CNTLN, CNTN4, COL1A2, LTBR, MAPK14, MBNL1, NELL2, NOS3, NTM, ODZ2, DIP2C, DMRT1, EPHA3, FAT1, FOXA2, GABRB2, IL1B, OPCML, PAPPA, PLSCR1, ROBO1, SLC22A4 (includes IQGAP2, ITGBL1, MBNL1, NOS3, NTM, ODZ2, PLSCR1, EG:6583), SLC2A3, SMURF2, SNRPN, SPON1, SRGAP1, ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SPON1, TLR5, TSHZ2, UNC84A and VWA3B. SRGAP1, TLR5, UNC84A and VWA3B. 0.125. In some embodiments, the patient may have a con I0131. In some embodiments, the patient may have rheu nective tissue disorder and have increased or decreased matoid arthritis and have increased or decreased expression expression relative to a control level of expression of a plu relative to a control level of expression of a plurality of rality of biomarkers selected from the group consisting of biomarkers selected from the group consisting of ACSL1, ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CLTC, CARD8, CASP5, CCND3, CLTC, CNTN4, COL1A1, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, MAPK14, ODZ2, OSM, PAPPA, PDE1A, ROBO1, LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, RUNDC3B, S100A12, SLC22A4 (includes EG:6583), ROBO1, RUNDC3B, S100A12, SHOX, SLC22A4 (includes TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (includes and ZNF438. EG: 115669), VWA3B and ZNF438. 0.132. In some embodiments, the patient may have coro 0126. In some embodiments, the patient may have rheu nary artery disease and have increased or decreased expres matic disease and have increased or decreased expression sion relative to a control level of expression of a plurality of relative to a control level of expression of a plurality of biomarkers selected from the group consisting of ACSL1, biomarkers selected from the group consisting of ACSL1, AK5, ASTN2 (includes EG:23245), BMPR1B, CARD16, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CNTN4, DMRT1, DNAH14, ERAP2, FREM2, GRM5, CASP5, CCND3, CLTC, CNTN4, DIP2C, DNAH14, EDAR, IL1B, IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, MECOM, NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, KCNJ15, LAMB4, LTER, LUM, MAPK14, ODZ2, OSM, RORB, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 VWA3B. (includes EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (in I0133. In some embodiments, the patient may have cludes EG:115669), VWA3B and ZNF438. Crohn's disease and have increased or decreased expression 0127. In some embodiments, the patient may have arthritis relative to a control level of expression of a plurality of and have increased or decreased expression relative to a con biomarkers selected from the group consisting of ACSL1, trol level of expression of a plurality of biomarkers selected AK5, APBA2, ASTN2 (includes EG:23245), CARD8, from the group consisting of ACSL1, ADM, ASTN2 (in DIP2C, DNAH14, ERAP2, FBLN7, FREM2, GRM5, LHX2, cludes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, LNPEP, MECOM, ODZ2, OPCML, PAPPA, PDE1A, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, PPP1R1C, ROBO1, SFXN1, SLC22A4 (includes EG:6583), FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, SLC26A8, SNRPN, SPON1, TGFB2, TLR5, VWA3B and LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, ZNF438. ROBO1, RUNDC3B, S100A12, SLC22A4 (includes I0134. In some embodiments, the patient may have a neu EG:6583), TNFRSF21, TNPO1, TTC6 (includes rodegenerative disorder and have increased or decreased EG:115669), VWA3B, ZNF438. expression relative to a control level of expression of a plu 0128. In some embodiments, the patient may have athero rality of biomarkers selected from the group consisting of Sclerosis and have increased or decreased expression relative ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, to a control level of expression of a plurality of biomarkers FOLH1, GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, selected from the group consisting of ACSL1, AK5, ASTN2 OPCML, RFX2, SCN2A, SLC22A4 (includes EG:6583), (includes EG:23245), BMPR1B, CARD16, CNTN4, SLC2A3, SLC3A1, SPON1, TSHZ2 and ZNF608. DMRT1, DNAH14, ERAP2, FOSB, FREM2, GRM5, IL1B, I0135) In some embodiments, the patient may have Alzhe IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, imer's disease and have increased or decreased expression NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, RORB, relative to a control level of expression of a plurality of SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and biomarkers selected from the group consisting of ASTN2 VWA3B. (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, 0129. In some embodiments, the patient may have inflam GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, matory bowel disease and have increased or decreased OPCML, RFX2, SLC22A4 (includes EG:6583), SLC2A3, expression relative to a control level of expression of a plu SLC3A1, SPON1, TSHZ2 and ZNF608. rality of biomarkers selected from the group consisting of ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), 6. Methods of Detecting Biomarkers Associated with CARD8, DIP2C, DNAH14, ERAP2, FBLN7, FREM2, TIA GRM5, IL1B, LHX2, LNPEP LTBR, MECOM, NOS3, 0.136 Gene expression may be measured using any ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, ROBO1, method known in the art. One of skill in the art will appreciate SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, that the means of measuring gene expression is not a critical SPON1, TGFB2, TLR5, VWA3B and ZNF438. aspect of the invention. The expression levels of the biomar 0130. In some embodiments, the patient may have non kers can be detected at the transcriptional or translational (i.e., insulin-dependent diabetes mellitus and have increased or protein) level. decreased expression relative to a control level of expression 0.137 In some embodiments, the expression levels of the of a plurality of biomarkers selected from the group consist biomarkers are detected at the transcriptional level. A variety ing of ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes of methods of specific DNA and RNA measurement using US 2016/02375O1 A1 Aug. 18, 2016 24 nucleic acid hybridization techniques are known to those of of Fluorescent Probes and Research Chemicals, a combined skill in the art (see, Sambrook, Supra and Ausubel, Supra) and handbook and catalogue Published by Molecular Probes, Inc. may be used to detect the expression of the genes set forth in (1996). Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. Some methods 0143. In general, a detector which monitors a particular involve an electrophoretic separation (e.g., Southern blot for probe or probe combination is used to detect the detection detecting DNA, Northern blot for detecting RNA, RNAse reagent label. Typical detectors include spectrophotometers, protection assays), but measurement of DNA and RNA can phototubes and photodiodes, microscopes, Scintillation also be carried out in the absence of electrophoretic separa counters, cameras, film and the like, as well as combinations tion (e.g., by dot blot). Southern blot of genomic DNA (e.g., thereof. Examples of suitable detectors are widely available from a human) can be used for Screening for restriction frag from a variety of commercial sources known to persons of ment length polymorphism (RFLP) to detect the presence of skill in the art. Commonly, an optical image of a Substrate a genetic disorder affecting a polypeptide of the invention. All comprising bound labeling moieties is digitized for Subse forms of RNA can be detected, including, e.g., message RNA quent computer analysis. (mRNA), microRNA (miRNA), ribosomal RNA (rRNA) and 0144. Most typically, the amount of RNA is measured by transfer RNA (tRNA). quantifying the amount of label fixed to the Solid Support by 0.138. The selection of a nucleic acid hybridization format binding of the detection reagent. Typically, the presence of a is not critical. A variety of nucleic acid hybridization formats modulator during incubation will increase or decrease the are known to those skilled in the art. For example, common amount of label fixed to the solid support relative to a control formats include Sandwich assays and competition or dis incubation which does not comprise the modulator, or as placement assays. Hybridization techniques are generally compared to a baseline established for a particular reaction described in Hames and Higgins Nucleic Acid Hybridization, type. Means of detecting and quantifying labels are well A Practical Approach, IRL Press (1985); Gall and Pardue, known to those of skill in the art. Proc. Natl. Acad. Sci. U.S.A., 63:378-383 (1969); and Johnet 0145. In preferred embodiments, the target nucleic acid or al. Nature, 223:582-587 (1969). the probe is immobilized on a solid support. Solid supports 0139 Detection of a hybridization complex may require Suitable for use in the assays of the invention are known to the binding of a signal-generating complex to a duplex of those of skill in the art. As used herein, a Solid Support is a target and probe polynucleotides or nucleic acids. Typically, matrix of material in a Substantially fixed arrangement. Such binding occurs through ligand and anti-ligand interac 0146 For example, in one embodiment of the invention, tions as between a ligand-conjugated probe and an anti-ligand microarrays are used to detect the pattern of gene expression. conjugated with a signal. The binding of the signal generation Microarrays provide one method for the simultaneous mea complex is also readily amenable to accelerations by expo Surement of the expression levels of large numbers of genes. Sure to ultrasonic energy. Each array consists of a reproducible pattern of a plurality of 0140. The label may also allow indirect detection of the nucleic acids (e.g., a plurality of nucleic acids that hybridize hybridization complex. For example, where the label is a to a plurality of the genes set forth in Tables 1, 2, 5A, 5B, 5C, hapten or antigen, the sample can be detected by using anti 5D, 7, 8 and/or 9) attached to a solid support. Labeled RNA or bodies. In these systems, a signal is generated by attaching DNA is hybridized to complementary probes on the array and fluorescent or enzyme molecules to the antibodies or in some then detected by laser scanning. Hybridization intensities for cases, by attachment to a radioactive label (see, e.g., Tijssen, each probe on the array are determined and converted to a “Practice and Theory of Enzyme Immunoassays,' Labora quantitative read-out of relative gene expression levels in tory Techniques in Biochemistry and Molecular Biology, Bur transient ischemic attacks. don and van Knippenberg Eds. Elsevier (1985), pp. 9-20). 0.147. In some embodiments, a sample is obtained from a 0141. The probes are typically labeled either directly, as subject, total mRNA is isolated from the sample and is con with isotopes, chromophores, lumiphores, chromogens, or verted to labeled cRNA and then hybridized to an array. indirectly, such as with biotin, to which a streptavidin com Relative transcript levels are calculated by reference to appro plex may later bind. Thus, the detectable labels used in the priate controls present on the array and in the sample. See, assays of the present invention can be primary labels (where Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134 the label comprises an element that is detected directly or that 1136 (1999). produces a directly detectable element) or secondary labels 0.148. A variety of automated solid-phase assay tech (where the detected label binds to a primary label, e.g., as is niques are also appropriate. For instance, very large scale common in immunological labeling). Typically, labeled sig immobilized polymer arrays (VLSIPSTM), available from nal nucleic acids are used to detect hybridization. Comple Affymetrix, Inc. (Santa Clara, Calif.) can be used to detect mentary nucleic acids or signal nucleic acids may be labeled changes in expression levels of a plurality of genes involved by any one of several methods typically used to detect the in the same regulatory pathways simultaneously. See, Tijssen, presence of hybridized polynucleotides. The most common supra. Fodor et al. (1991) Science, 251: 767-777; Sheldon et method of detection is the use of autoradiography with H, al. (1993) Clinical Chemistry39(4): 718–719, and Kozaletal. I, S, 'C, or P-labeled probes or the like. (1996) Nature Medicine 207): 753-759. Integrated microflu 0142. Other labels include, e.g., ligands that bind to idic systems and other point-of-care diagnostic devices avail labeled antibodies, fluorophores, chemiluminescent agents, able in the art also find use. See, e.g., Liu and Mathies, Trends enzymes, and antibodies which can serve as specific binding Biotechnol. (2009). 27(10):572-81 and Tothill, Semin Cell pair members for a labeled ligand. An introduction to labels, Dev Biol (2009).20(1):55-62. Microfluidics systems forusein labeling procedures and detection of labels is found in Polak detecting levels of expression of a plurality of nucleic acids and Van Noorden Introduction to Immunocytochemistry, 2nd are available, e.g., from NanoString Technologies, on the ed., Springer Verlag, NY (1997); and in Haugland Handbook internet at nanostring.com. US 2016/02375O1 A1 Aug. 18, 2016

0149 Detection can be accomplished, for example, by extended or ligated only when a selected sequence is present. using a labeled detection moiety that binds specifically to Alternatively, the selected sequences can be generally ampli duplex nucleic acids (e.g., an antibody that is specific for fied using, for example, nonspecific PCR primers and the RNA-DNA duplexes). One preferred example uses an anti amplified target region later probed for a specific sequence body that recognizes DNA-RNA heteroduplexes in which the indicative of a mutation. High throughput multiplex nucleic antibody is linked to an enzyme (typically by recombinant or acid sequencing or "deep sequencing to detect captured covalent chemical bonding). The antibody is detected when expressed biomarker genes also finds use. High throughput the enzyme reacts with its substrate, producing a detectable sequencing techniques are known in the art (e.g., 454 product. Coutlee et al. (1989) Analytical Biochemistry 181: Sequencing on the internet at 454.com). 153-162; Bogulayski (1986) et al. J. Immunol. Methods 0153. An alternative means for determining the level of 89:123-130; Prooijen-Knegt (1982) Exp. Cell Res. 141:397 expression of the nucleic acids of the present invention is in 407; Rudkin (1976) Nature 265:472-473, Stollar (1970) situ hybridization. In situ hybridization assays are well Proc. Nat I Acad. Sci. USA 65:993-1000; Ballard (1982) Mol. known and are generally described in Angereret al., Methods Immunol. 19:793-799; Pisetsky and Caster (1982) Mol. Enzymol. 152:649-660 (1987). In an in situ hybridization Immunol. 19:645-650; Viscidietal. (1988).J. Clin. Microbial. assay, cells, preferentially human cells, e.g., blood cells, are 41:199-209; and Kiney et al. (1989).J. Clin. Microbiol. 27:6- fixed to a solid support, typically a glass slide. If DNA is to be 12 describe antibodies to RNA duplexes, including homo and probed, the cells are denatured with heat or alkali. The cells heteroduplexes. Kits comprising antibodies specific for are then contacted with a hybridization solutionata moderate DNA:RNA hybrids are available, e.g., from Digene Diagnos temperature to permit annealing of specific probes that are tics, Inc. (Beltsville, Md.). labeled. The probes are preferably labeled with radioisotopes 0150. In addition to available antibodies, one of skill in the or fluorescent reporters. art can easily make antibodies specific for nucleic acid 0154) In other embodiments, quantitative RT-PCR is used duplexes using existing techniques, or modify those antibod to detect the expression of a plurality of the genes set forth in ies that are commercially or publicly available. In addition to Tables 1, 2, 5A, 5B, 5C, 5D,7,8 and/or 9. A general overview the art referenced above, general methods for producing poly of the applicable technology can be found, for example, in clonal and monoclonal antibodies are known to those of skill A-Z of Ouantitative PCR, Bustin, ed., 2004, International in the art (see, e.g., Paul (3rd ed.) Fundamental Immunology University Line; Ouantitative PCR Protocols, Kochanowski Raven Press, Ltd., NY (1993); Coligan, et al., Current Pro and Reischl, eds., 1999, Humana Press; Clinical Applications tocols in Immunology, Wiley Interscience (1991-2008); Har of PCR, Lo, ed., 2006, Humana Press: PCR Protocols: A low and Lane, Antibodies. A Laboratory Manual Cold Spring Guide to Methods and Applications (Innis et al. eds. (1990)) Harbor Press, NY (1988); Harlow and Lane. Using Antibod and PCR Technology. Principles and Applications for DNA ies, Cold Spring Harbor Press, NY (1999); Stites et al. (eds.) Amplification (Erlich, ed. (1992)). In addition, amplification Basic and Clinical Immunology (4th ed.) LangeMedical Pub technology is described in U.S. Pat. Nos. 4,683,195 and lications, Los Altos, Calif., and references cited therein; God 4,683.202. Methods for multiplex PCR, known in the art, are ing Monoclonal Antibodies. Principles and Practice (2d ed.) applicable to the present invention. Academic Press, New York, N.Y., (1986); and Kohler and Milstein Nature 256: 495-497 (1975)). Other suitable tech 0155 Accordingly, in one embodiment of the invention niques for antibody preparation include selection of libraries provides a reaction mixture comprising a plurality of poly of recombinant antibodies in phage or similar vectors (see, nucleotides which specifically hybridize (e.g., primers) to a Huse et al. Science 246:1275-1281 (1989); and Ward et al. plurality of nucleic acid sequences of the genes set forth in Nature 341:544-546 (1989)). Specific monoclonal and poly Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. In some embodi clonal antibodies and antisera will usually bind with a K, of ments, the reaction mixture is a PCR mixture, for example, a at least about 0.1 uM, preferably at least about 0.01 uM or multiplex PCR mixture. better, and most typically and preferably, 0.001 uM or better. 0156 This invention relies on routine techniques in the 0151. The nucleic acids used in this invention can be either field of recombinant genetics. Generally, the nomenclature positive or negative probes. Positive probes bind to their and the laboratory procedures in recombinant DNA technol targets and the presence of duplex formation is evidence of ogy described below are those well known and commonly the presence of the target. Negative probes fail to bind to the employed in the art. Standard techniques are used for cloning, Suspect target and the absence of duplex formation is evi DNA and RNA isolation, amplification and purification. Gen dence of the presence of the target. For example, the use of a erally enzymatic reactions involving DNA ligase, DNA poly wild type specific nucleic acid probe or PCR primers may merase, restriction endonucleases and the like are performed serve as a negative probe in an assay sample where only the according to the manufacturers specifications. Basic texts nucleotide sequence of interest is present. disclosing the general methods of use in this invention 0152 The sensitivity of the hybridization assays may be include Sambrook et al., Molecular Cloning, A Laboratory enhanced through use of a nucleic acid amplification system Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expres that multiplies the target nucleic acid being detected. sion: A Laboratory Manual (1990); and Current Protocols in Examples of such systems include the polymerase chain reac Molecular Biology (Ausubel et al., eds., 1994-2008, Wiley tion (PCR) system, in particular RT-PCR, multiplex PCR, InterScience)). quantitative PCR or real time PCR, and the ligase chain 0157 For nucleic acids, sizes are given in either kilobases reaction (LCR) system. Other methods recently described in (kb) or base pairs (bp). These are estimates derived from the art are the nucleic acid sequence based amplification agarose or acrylamide gel electrophoresis, from sequenced (NASBA, Cangene, Mississauga, Ontario) and Q Beta Rep nucleic acids, or from published DNA sequences. For pro licase systems. These systems can be used to directly identify teins, sizes are given in kilodaltons (kDa) or amino acid mutants where the PCR or LCR primers are designed to be residue numbers. Proteins sizes are estimated from gel elec US 2016/02375O1 A1 Aug. 18, 2016 26 trophoresis, from sequenced proteins, from derived amino primarily by physiological status, one where the samples are acid sequences, or from published protein sequences. grouped primarily by disease status and one where the 0158 Oligonucleotides that are not commercially avail samples are grouped primarily by pharmacological status. able can be chemically synthesized according to the Solid Within each table the samples can be further grouped accord phase phosphoramidite triester method first described by ing to the two remaining categories. For example the physi Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 ological status table could be further categorized according to (1981), using an automated synthesizer, as described in Van disease and pharmacological status. Devanter et. al., Nucleic Acids Res. 12:6159-6168 (1984). 0163 As will be appreciated by one of skill in the art, the Purification of oligonucleotides is by either native acrylamide present invention may be embodied as a method, data pro gel electrophoresis or by anion-exchange HPLC as described cessing system or program products. Accordingly, the present in Pearson & Reanier, J. Chrom. 255:137-149 (1983). invention may take the form of data analysis systems, meth 0159. In some embodiments, the expression level of the ods, analysis Software, etc. Software written according to the biomarkers described herein are detected at the translational present invention is to be stored in some form of computer or protein level. Detection of proteins is well known in the art, readable medium, such as memory, hard-drive, DVD ROM or and methods for protein detection known in the art find use. CD ROM, or transmitted over a network, and executed by a Exemplary assays for determining the expression levels of a processor. The present invention also provides a computer plurality of proteins include, e.g., ELISA, flow cytometry, system for analyzing physiological states, levels of disease mass spectrometry (e.g., MALDI or SELDI), surface plas states and/or therapeutic efficacy. The computer system com mon resonance (e.g., BiaCore), microfluidics and other bio prises a processor, and memory coupled to said processor sensor technologies. See, e.g., Tothill, Semin Cell Dev Biol which encodes one or more programs. The programs encoded (2009) 20(1):55-62. in memory cause the processor to perform the steps of the above methods wherein the expression profiles and informa 7. TIA Reference Profiles tion about physiological, pharmacological and disease states 0160 The invention also provides ischemia reference pro are received by the computer system as input. Computer files. The TIA reference profiles comprise information corre systems may be used to execute the software of an embodi lating the expression levels of a plurality of TIA-associated ment of the invention (see, e.g., U.S. Pat. No. 5,733,729). genes (i.e., a plurality of the genes set forth in Tables 1, 2, 5A, 8. Providing Appropriate Treatment and Prevention 5B, 5C, 5D, 7, 8 and/or 9) to the occurrence or risk of TIA. The profiles can conveniently be used to diagnose, monitor Regimes to Patient and prognose ischemia. (0164. In some embodiments, the methods further com 0161 The reference profiles can be entered into a data prise the step of prescribing and providing appropriate treat base, e.g., a relational database comprising data fitted into ment and/or prevention regimes to a patient diagnosed as predefined categories. Each table, or relation, contains one or having TIA or at risk of the occurrence of TIA or stroke. For more data categories in columns. Each row contains a unique example, medications and life-style adjustments (e.g., diet, instance of data for the categories defined by the columns. For exercise, stress) to minimize risk factors can be recom example, a typical database for the invention would include a mended, including reducing blood pressure and cholesterol table that describes a sample with columns for age, gender, levels, and controlling diabetes. reproductive status, expression profile and so forth. Another 0.165. In additions, several medications to decrease the table would describe a disease: Symptoms, level, Sample iden likelihood of a stroke after a transient ischemic attack. The tification, expression profile and so forth. In one embodiment, medication selected will depend on the location, cause, sever the invention matches the experimental sample to a database ity and type of TIA, if TIA has occurred. of reference samples. The database is assembled with a plu 0166 In some embodiments, the patient may be pre rality of different samples to be used as reference samples. An scribed a regime of an anti-platelet drug. The most frequently individual reference sample in one embodiment will be used anti-platelet medication is aspirin. An alternative to aspi obtained from a patient during a visit to a medical profes rin is the anti-platelet drug clopidogrel (Plavix). Some studies sional. Information about the physiological, disease and/or indicate that aspirin is most effective in combination with pharmacological status of the sample will also be obtained another anti-platelet drug. In some embodiments, the patient through any method available. This may include, but is not is prescribed a combination of low-dose aspirin and the anti limited to, expression profile analysis, clinical analysis, medi platelet drug dipyridamole (Aggrenox), to reduce blood clot cal history and/or patient interview. For example, the patient ting. Ticlopidine (Ticlid) is another anti-platelet medication could be interviewed to determine age, sex, ethnic origin, that finds use to prevent or reduce the risk of stroke in patients symptoms or past diagnosis of disease, and the identity of any who have experienced TIA. therapies the patient is currently undergoing. A plurality of 0167. In some embodiments, the patient may be pre these reference samples will be taken. A single individual scribed a regime of an anticoagulant. Exemplary anticoagul may contribute a single reference sample or more than one lants include aspirin, heparin, warfarin, and dabigatran. sample over time. One skilled in the art will recognize that 0168 Patients having a moderately or severely narrowed confidence levels in predictions based on comparison to a neck (carotid) artery, may require or benefit from carotid database increase as the number of reference samples in the endarterectomy. This preventive Surgery clears carotid arter database increases. ies of fatty deposits (atherosclerotic plaques) before another 0162 The database is organized into groups of reference TIA or stroke can occur. In some embodiments, the patient samples. Each reference sample contains information about may require or benefit from carotid angioplasty, or stenting. physiological, pharmacological and/or disease status. In one Carotid angioplasty involves using a balloon-like device to aspect the database is a relational database with data orga open a clogged artery and placing a small wire tube (stent) nized in three data tables, one where the samples are grouped into the artery to keep it open. US 2016/02375O1 A1 Aug. 18, 2016 27

9. Solid Supports and Kits 5A, 5B, 5C, 5D, 7, 8 and/or 9. The probes may be immobi lized on a microarray as described herein. 0169. The invention further provides a solid supports com 0172. In addition, the kit can comprise appropriate buffers, prising a plurality of nucleic acid probes that hybridize to a salts and other reagents to facilitate amplification and/or plurality (e.g., two or more, or all) of the genes set forth in detection reactions (e.g., primers, labels) for determining the Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9, and optionally expression levels of a plurality of the biomarkers set forth in Table 3. For example, the solid support can be a microarray Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. The kits can also attached to a plurality of nucleic acid probes that hybridize to include written instructions for the use of the kit. a plurality (e.g., two or more, or all) of the genes set forth in Table 1, and optionally Table 3. In various embodiments, the 0173. In one embodiment, the kits comprise a plurality of Solid Support can be a microarray attached to a plurality of antibodies that bind to a plurality of the biomarkers set forth nucleic acid probes that hybridize to a plurality (e.g., two or in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. The antibodies more, or all) of the genes set forth in Tables 5A, 5B, 5C, and may or may not be immobilized on a solid Support, e.g., an 5D, and optionally Table 3. In various embodiments, the solid ELISA plate. Support can be a microarray attached to a plurality of nucleic acid probes that hybridize to a plurality (e.g., two or more, or EXAMPLES all) of the genes set forth in Table 7, and optionally Table 3. In various, the Solid Support can be a microarray attached to a 0.174. The following examples are offered to illustrate, but plurality of nucleic acid probes that hybridize to a plurality not to limit the claimed invention. (e.g., two or more, or all) of the genes set forth in Table 8, and optionally Table 3. In various, the solid support can be a Example 1 microarray attached to a plurality of nucleic acid probes that hybridize to a plurality (e.g., two or more, or all) of the genes Materials and Methods set forth in Table 9, and optionally Table 3. 0170 In various embodiments, the solid supports are con Subjects figured to exclude genes not associated with or useful to the 0.175 TIA and control patients were recruited from the diagnosis, prediction or confirmation of a stroke or the causes University of California Davis Medical Center, University of of stroke. For example, genes which are overexpressed or California San Francisco Medical Center and Wake Forest underexpressed less than 1.5-fold in subjects having or sus University Health Sciences. Institutional Review Boards at pected of having TIA, in comparison to a control level of each institution approved the study, and written informed expression can be excluded from the present solid Supports. consent was obtained from all patients. In some embodiments, genes that are overexpressed or under expressed less than 1.2-fold in Subjects with ischemic stroke, 0176 A total of 27 control patients were compared to 24 including cardioembolic stroke, atherothrombotic stroke, and TIA patients studied within 3 to 69 hours (average=29.2 stroke Subsequent to atrial fibrillation, in comparison to a hours) of symptoms onset. The diagnosis of TIA was made by control level of expression can be excluded from the present two independent board certified neurologists with access to Solid Supports. The Solid Support can comprise a plurality of all clinical data. TIA was defined as an acute loss of focal nucleic acid probes that hybridize to a plurality (e.g., two or cerebral or ocular function lasting <12 hours with a presumed more, orall) of the genes useful for the diagnosis of ischemic ischemic etiology. To be recruited into the study TIA patients stroke, cardioembolic stroke, carotid Stenosis, and/or atrial were required to have an ABCD scores4 to further support fibrillation, as described herein. As appropriate, nucleic acid the diagnosis of TIA. This ensured that TIA patients at higher probes that hybridize to a plurality (e.g., two or more, or all) risk for recurrent vascular events were studied (4, 19). The of the genes useful for the diagnosis of ischemic stroke, controls were recruited from the spouses or family members cardioembolic stroke, carotid stenosis, and/or atrial fibrilla of TIA patients or people from the community. They were tion can be arranged in a predetermined array on the Solid Subjects free of vascular events such as TIA, ischemic stroke, Support. In various embodiments, nucleic acids not specifi myocardial infarction, peripheral vascular disease, or venous cally identified and/or not relating to the diagnosis of and/or thromboembolism. Control subjects with hypertension and/ not associated with the diagnosis of TIA are not attached to or diabetes were also excluded in order to reduce the possi the Solid Support. In various embodiments, nucleic acids not bility of controls having silent TIA or other vascular events. specifically identified and/or not relating to the diagnosis of Hypertension and diabetes both increase the probability of and/or not associated with the diagnosis of ischemic stroke, TIA, as shown by the ABCD score (4, 20). cardioembolic stroke, carotid stenosis, and/or atrial fibrilla tion are not attached to the solid Support. The solid Support RNA Isolation may be a component in a kit. 0177. A venous blood sample was collected into PAXgene 0171 The invention also provides kits for diagnosing TIA vacutainers (PreAnalytiX, Hilden, Germany). Total RNA was or a predisposition for developing TIA. For example, the isolated according to the manufacturer's protocol. invention provides kits that include one or more reaction vessels that have aliquots of some or all of the reaction com Microarray Hybridization ponents of the invention in them. Aliquots can be in liquid or dried form. Reaction vessels can include sample processing (0178 Biotin-labeled cDNA was synthesized from 50ng of cartridges or other vessels that allow for the containment, total RNA using the Ovation Whole Blood Solution (Nugen) processing and/or amplification of samples in the same ves kit according to protocol. Each RNA sample was processed sel. The kits can comprise a plurality of nucleic acid probes on Affymetrix Human Genome HG-U133-Plus-2.0 microar that hybridize to a plurality the genes set forth in Tables 1, 2, rays as previously described (18). US 2016/02375O1 A1 Aug. 18, 2016 28

Statistical Analysis TIA patients from controls with 87.5% sensitivity (21 out of 0179 Microarray probeset-level data were log trans 24TIAS correctly classified) and 96.3% specificity (26 out of formed and normalized using Robust Multichip Average 27 controls correctly classified) (FIG. 2). (RMA). Analysis of Covariance (ANCOVA) was conducted in Partek Genomics Suite 6.5 (Partek Inc., St. Louis, Mich. TIA Specific Up-Regulated Genes USA) to identify genes/probes significantly different between TIA and control subjects with adjustment for 0.184 The 325 up-regulated genes that distinguished TIA1 microarray batch effect and age. Genes/probes were consid from TIA2 patients were input into PAM to derive the mini ered significant with a p-values0.05 after Benjamini-Hoch mum number (n=26) of genes that differentiated the two berg multiple-comparison correction, and an absolute fold groups. The 26 genes (Table 5D) distinguished TIA1 from change-1.5. To exclude genes associated with hypertension, TIA2 patients with 100% sensitivity and specificity (FIG. 3). a second comparison was performed for 33 controls with hypertension to controls without hypertension. The Identified No clinical factors were identified that were significantly “hypertension' genes that overlapped with the TIA gene lists different between TIA1 and TIA2 including age, time after were excluded from further analysis. TIA, hypertension, diabetes, ABCD score (Table 6) and 0180 All data are presented as meant-SE. Differences in medications. Notably, Metalloproteinase 16 and Metallopro demographic data between groups were analyzed using Chi teinase 26 were up-regulated in the TIA1 group but not in the square test or t-test as appropriate. Prediction analysis was TIA2 group (FIG. 4). performed using 10-fold leave-one-out cross-validation in Prediction Analysis of Microarrays (PAM). Functional and TABLE 6 pathway analyses were performed using Ingenuity Pathways Analysis (IPA). Demographic Summary of TIA subgroups Results TIA1 (n = 12) TIA2 (n = 12) P value

Subjects Age (yrsi SE) 64.83.7 6378.8 O.91 0181. The demographic information for TIA and control Gender Female (%) 5 (42) 5 (42) 1.OO Subjects showed that age was significantly different between Race TIA and controls (Table 4). Thus, age was adjusted for in the ANCOVA model. Caucasian n (%) 7 (58) 9 (75) O.18 Non-Caucasian n (%) 5 (42) 3 (25) O.18 TABLE 4 Vascular risk factor Demographic Summary of Transient Ischemic Attack (TIA) patients and control Subiects Hypertension n (%) 10 (83) 10 (83) 1.OO Diabetes n (%) 4 (33) 4 (33) 1.OO Controls TIA Hyperlipidemian (%) 6 (50) 7 (58) O.S6 (n = 27) (n = 24) p value Smoken (%) 6 (50) 4 (33) O.22 Age (yrsi SE) SS. 70.8 702 - 2.5 <0.001 Hours since TLA (SE) 28.74.4 29.7 4.3 O.87 Gender Female: n (%) 19 (70.4) 14 (58.3) O.39 Race History of stroken (%) 3 (25) 4 (33) O.S4 CVD in (%) 3 (25) 4 (33) O.S4 Caucasian: n (%) 18 (66.6) 16 (66.6) 1.OO AFn (%) 1 (8) 2 (16) O43 Non-Caucasian: n (%) 9 (33.3) 8 (33.3) 1.OO LVD in (%) 1 (8) 2 (16) O43 ABCD' score (ESE) 5.42 O.29 5.25 + 0.28 O.68 TIA Genomic Profiles CVD: Cardiovascular Disorder; AF: Atrial Fibrillation; LVD: Large Vessel Disease. 0182. A total of 460 genes were differentially expressed There was no any significant difference among two groups analyzed using t-test or Chi square test, between TIA patients and controls (FDRs0.05; fold The factors contributed to the differences in RNA expression between TIA1 and TIA2 changes 1.5) (Tables 5A-D). 135 genes were down-regulated remained unclear, (Table 2 and Table 5A) and 325 were up-regulated (Table 1 and Table 5B) in TIA compared to controls. A Hierarchical cluster analysis of the 460 genes showed that they separated Function Analysis of TIA Specific Genes TIAS from controls (FIG. 1) except that two TIA patients (ID numbers: 57 and 90) clustered in the control group, and three 0185. Functional analysis of the TIA specific genes (460 control patients (ID numbers: 42, 68 and 74) clustered in the genes derived from TIA Vs control) using IPA demonstrated TIA group (FIG. 1). The hierarchical cluster analysis also that they were significantly associated with immune func Suggested the presence of two distinct TIA groups. Most of tions. Amongst the TIA specific genes, a number have been the up-regulated genes in the TIA1 group separated it from associated with autoimmune disease, diabetes, arthritis, rheu the TIA2 group and from controls (FIG. 1). matoid arthritis, atherosclerosis, coronary artery disease and Crohn's disease (Table 7). The significantly regulated genes Prediction Analysis for the TIA1 group compared to the TIA2 group (FDRs0.05; 0183 Cross-correlation performed with PAMusing the 34 fold changes 1.5) are shown in Table 8 along with the most (Table 5C) out of 460 TIA associated genes distinguished significant pathways (Table 9; see discussion below).

US 2016/02375O1 A1 Aug. 18, 2016 30

TABLE 7-continued TIA specific gene-functions Category Function p-value Molecules OVOL2, POU2AF1, RBM14, RORB, SHOX, SHOX2, SIX3, SLC3A1, SMURF2, SOX8, SOX9, SOX11, TFAP2B, TGFB2, TWIST1, ZNF462 Inflam- rheumatic 8.49E-04 ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, CNTN4, DIP2C, matory disease DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, LTBR, LUM, Disease MAPK14, ODZ2, OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 (includes EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B, ZNF438 Inflam- arthritis 7.29E-04 ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, CNTN4, DIP2C, matory DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, LTBR, LUM, Disease MAPK14, ODZ2, OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 (includes EG:6583), TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B, ZNF438 Cellular proliferation 5.91 E-03 ADM, AIM2, BCL6, BMPR1B, CAV1, CCND3, CLTC, COL1A1, DLX6, DPPA4, FOSB, FOXA2, FUS, Growth GRM5, GSTM1, HOXC6, IGFBP5, IL1B, LIFR, MAPK14, MECOM, MEG3 (includes EG:55384), MLL, and NOS3, OSM, PAPPA, PIWIL1, PLSCR1, SHOX2, SOX9, TFPI, TGFB2, TLR5, TNFRSF21 Prolifer ation Cardio- athero- 1.22E-04 ACSL1, AK5, ASTN2 (includes EG:23245), BMPR1B, CARD16, CNTN4, DMRT1, DNAH14, ERAP2, vascular Sclerosis FOSB, FREM2, GRM5, IL1B, IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, NOS3, NTM, Disease ODZ2, OLFM2, PDE1A, ROBO1, RORB, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A, VWA3B inflam- inflam- 5.07E-05 ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), CARD8, DIP2C, DNAH14, ERAP2, FBLN7, matory matory FREM2, GRM5, IL1B, LHX2, LNPEP, LTBR, MECOM, NOS3, ODZ2, OPCML, PAPPA, PDE1A, Disease bowel PPP1R1C, ROBO1, SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, SPON1, TGFB2, disease TLR5, VWA3B, ZNF438 Endocrine non-insulin- 4.48E-04 ADAM30, AK5, ALPL, ALS2CR11, ASTN2 (includes EG:23245), CARD8, CCRL1, CNTLN, CNTN4, System dependent COL1A2, DIP2C, DMRT1, EPHA3, FAT1, FOXA2, GABRB2, IL1B, IQGAP2, ITGBL1, MBNL1, NOS3, Disorders diabetes NTM, ODZ2, PLSCR1, ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SPON1, SRGAP1, TLR5, mellitus UNC84A, VWA3B inflam- rheumatoid 1.54E-03 ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CLTC, CNTN4, DIP2C, DNAH14, EDAR, matory arthritis EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, MAPK14, ODZ2, OSM, PAPPA, Disease PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 (includes EG:6583), TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B, ZNF438 Cardio- coronary 6.94E-05 ACSL1, AK5, ASTN2 (includes EG:23245), BMPR1B, CARD16, CNTN4, DMRT1, DNAH14, ERAP2, vascular artery FREM2, GRM5, IL1B, IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, NOS3, NTM, ODZ2, Disease disease OLFM2, PDE1A, ROBO1, RORB, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A, VWA3B Cell Death cell death 7.84E-03 ADM, AIM2, BCL6, CARD8, CAV1, CCND3, DPPA4, FOSB, FOXA2, FUS, GALNTS, GNAO1, GSTM1, HOXC6, IGFBP5, IL1B, LTBR, MAPK14, MLL, NOS3, PIWIL1, PLSCR1, SHOX, SOX9, TFAP2B, TGFB2, TNFRSF21, TWIST1, UNCSB inflam- Crohn's 2.08E-04 ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), CARD8, DIP2C, DNAH14, ERAP2, FBLN7, matory disease FREM2, GRM5, LHX2, LNPEP, MECOM, ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, ROBO1, Disease SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, SPON1, TGFB2, TLR5, VWA3B, ZNF438 Neurological neuro- 1.57E-62 ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, GABRB2, GRM5, IL1B, MECOM, Disease degenerative NDST3, NOS3, OPCML, RFX2, SCN2A, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, SPON1, disorder TSHZ2, ZNF608 Neurological Alzheimer's 1.72E-02 ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, GABRB2, GRM5, IL1B, MECOM, Disease disease NDST3, NOS3, OPCML, RFX2, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, SPON1, TSHZ2, ZNF608

Discussion compared to controls, TIA patients tend to have increased leukocyte activation and a systemic inflammatory response 0186 TIA is a harbinger of stroke and other vascular events. The present biomarker panels find use for intervention (8-9). Transient ischemic attacks have also been associated in TIA to prevent future vascular events. Prior to the present with a number of systemic inflammatory markers such as invention, there was limited knowledge regarding human TIA CRP (7), and inflammatory conditions such as inflammatory biology, and the development of specific TIA therapies has bowel disease (21-24). Alterations in immune function in been limited. The present biomarker panels provide informa TIAS are further implicated by an association between TIA tion to better understand the immune response in blood that and systemic infection, as well as TIA and periodontal dis occurs inpatients with TIA. By examining the whole genome, ease (25-29). In this study, 63 genes involved in inflammation unique TIA gene expression profiles showing two TIA Sub were differentially expressed in TIA compared to controls types were identified. These findings provide unique insight (Table 7). These genes show patterns of inflammation similar into TIA pathophysiology, and are consistent with the con to that of inflammatory bowel disease (32 genes), rheumatoid clusion that there are specific immune responses that occur arthritis (32 genes), and Crohn's disease (29 genes), Suggest following transient focal cerebral ischemia in humans. They ing that different, but related patterns of inflammation are also suggest diagnostic tests to confirm a TIA diagnosis can associated with TIA. If the expression of these genes changed be developed. in a time-dependent manner after TIA onset, the inflamma tion could be a consequence of TIA. Otherwise, there might be some pre-existing inflammation that did not change with Systemic Inflammation and TIA time that might promote the development of TIA. Therefore, 0187 TIA patients appear to have unique patterns of a time-dependent analysis on the gene expression in the acute inflammation associated with their vascular events. Indeed, phase (blood draw within 24 h of TIA onset; n=11) and the US 2016/02375O1 A1 Aug. 18, 2016

sub acute phase (blood draw between 24 h to 72 h of TIA Limitations of the Study onset; n=13) of TIA was performed. The results showed that 0190. The sample size is small. A control group at very low the large majority of the genes expressed in the acute phase risk of TIA and other vascular events was chosen so that the were similar to those expressed in the sub acute phase (>90% controls would be very unlikely to have silentischemic events similar). Thus, there may be a chronic inflammatory state that would complicate comparison to TIA. By doing so, dif prior to TIA and this could contribute to causing TIAs. ferences due to vascular risk factors are inevitably introduced. Anti-Oxidant Capacity These factors were adjusted for by including age in the ANCOVA model, and excluding genes associated with 0188 GSTM1 and GSTM2 encode cytosolic glutathione hypertension and diabetes. The advantage of comparing TIA S-transferases (GSTs) that belong to the mu class. GST to the controls in this study, therefore, is that the gene expres enzymes function in the detoxification of electrophilic com sion differences between TIA and controls were maximized, pounds, such products of oxidative stress by conjugation with and allowed for the search for TIA subgroups. However, glutathione (30). GSTM1 and GSTM2 were both down-regu future studies will need to compare TIA patients to other lated in TIA patients, Suggesting a decreased anti-oxidant controls to identify “TIA specific gene markers’. These con capacity may exist in patients with TIAS. The resultant trols should include patients with similar vascular risk factors enhanced oxidative stress may in turn promote ischemic vas and “TIA mimic patients with migraine or seizures. cular disease such as TIA. This result is consistent with our 0191 Group heterogeneity is another limitation in the previous animal study that showed a specific GST family study of TIA. Though stringent criteria were used to ensure member (GSTT1) regulated following 10 minutes of brief subjects with TIA were indeed true transientischemic events, focal ischemia simulating human TIAS (5). it is possible that a few TIA patients were in fact TIA mimics. Similarly, though a comparison group at low risk for having Extracellular Matrix Remodeling silent ischemic vascular events was used, it is possible some (0189 Our data Suggest the presence of two subgroups of patients in the control group had silent vascular events. TIA patients. No measured clinical factor was significantly 0.192 This is a discovery type study and thus there is no different between each group. The notion of subtypes of TIA previous study to compare to. Though FDR correction was is not new. For example, TIA subtypes exist based on MRI applied, the only way to account for multiple comparisons is DWI status, ABCD score, or the presence of large vessel to perform a future replication study. PCR verification was disease or atrial fibrillation. In our study, two molecular sub not performed since most changes on Affymetrix arrays have types of TIA were evident based on gene expression profiles. correlated extremely well with PCR in previous studies. In Functional analysis of these two groups suggested over rep addition, PCR would only be needed once this study has been resentation of genes involved in extracellular matrix remod replicated and the PCR confirmed genes were to be used to eling in TIA1 compared to TIA2 including: MMP16, develop clinical tests. MMP19, MMP26, COL1A1, COL1A2, COL3A1, 0193 In summary, patients with recent TIAS can be dif COL10A1, COL11A1, COL25A1, COL27A1, FGFs and ferentiated from controls without previous vascular events EGFR. TIA1 patients may be more prone to extracellular using gene expression profiles in blood. In addition, there matrix breakdown at the blood brain barrier and/or in athero may be different immune response Subtypes following tran Sclerotic plaque. sient ischemic attacks in humans. TABLE 5 TIA associated gene lists (FDRs 0.05, absolute fold change e 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change Table 5A. 135 Downregulated Genes TABLESA

233034 a -2.44997 237597 a -2.4398 15584.09 at -2.26242 1566485 at -2.22393 1556932 at -2.11785 242874 a -2.03355 1561166 a. at — -19781 217671 a -1.9453 1557733 a at - -1910O8 1557580 at -1.85725 1558.410 S at — -17902 242710 a -1.76712 215314 a -1.75283 2296.54 a -1.74432 1560861 at -1.74348 243512 X at — -1.73922 238812 a -1.7O108 232943 a -1.69925 233677 a -168615 244226 s at — -1.685.79 233614 a -168298 US 2016/02375O1 A1 Aug. 18, 2016 32

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 1557581 X at - -1.67676 244860 a -1.67397 23958.8 s at — -1667 244665 a. -165812 243107 a -1.65279 557519 at -1.64084 242564 a -163967 557551 at -163028 238281 a -1.62416 558710 at -1.62037 239646 a -160914 568781 at -160862 234148 a -1.6OO79 233302 a -1595.57 233862 a -1586O4 570329 at -156927 241638 a -156143 232834 a -1.559 236524 a -155759 559723 s at - -155744 5594.01 a. at — -1.SS691 236558 a -155664 237803 x at — -1.SS619 231069 a -1.SS35 557477 at -154943 237953 a -154815 243641 a -1547 555,194 at -1.543O4 217060 a -154232 2394.49 a -154082 237334 a -153953 242074 a -153917 15701.06 at -153564 244674 a -153173 232372 a. -1.52446 238744 a -152032 233127 a -15089 243310 a -1.50605 214309 s at — -1. SO383 244290 a -150381 1562013 a at — -150343 2193O8 is at AKS adenylate kinase 5 -1.95 614 2228.62 s at AK5 adenylate kinase 5 -1.64741 239651 a ANAPCS anaphase promoting complex subunit 5 -155844 209871 S. at APBA2 amyloid beta (A4) precursor protein-binding, family A, -1.56895 member 2 229252 a. ATG9B ATG9 autophagy related 9 homolog B (S. cerevisiae) -1.64694 227372 s at BAIAP2L1 BAI1-associated protein 2-like 1 / hypothetical protein -153271 LOC100128461 LOC100128461 221631 a CACNA1I calcium channel, Voltage-dependent, T type, alpha II -163297 Subunit 239771 a CAND1 cullin-associated and neddylation-dissociated 1 -197531 1553645 at CCDC141 coiled-coil domain containing 141 -162867 1562028 at CCND3 Cyclin D3 (CCND3), transcript variant 3, mRNA -2.OO377 239871 a CLTC Clathrin, heavy chain (He), mRNA (cDNA clone -163031 IMAGE: 4812912) 212504 a DIP2C DIP2 disco-interacting protein 2 homolog C (Drosophila) -1.62614 1553998 at DMRTC1 if DMRT-like family C1 // DMRT-like family C1B -186704 DMRTC1B 220048 a EDAR ectodysplasin A receptor -1.69385 209368 a EPHX2 epoxide hydrolase 2, cytoplasmic -1.62474 1554273 a at ERAP2 endoplasmic reticulum aminopeptidase 2 -1.52883 230792 a. FAAH2 fatty acid amide hydrolase 2 -1.57807 2292.47 a FBLN7 fibulin 7 -1.58734 202768 a FOSB FBJ murine osteosarcoma viral oncogene homolog B -163049 231108 a FUS fusion (involved in t(12; 16) in malignant liposarcoma) -1.56277 1557350 at G3BP1 GTPase activating protein (SH3 domain) binding protein 1 -1.6194 219815 a. GAL3ST4 galactose-3-O-sulfotransferase 4 -15674 156O133 at GIGYF2 GRB10 interacting GYF protein 2 -152626 223.080 a GLS Glutaminase, mRNA (cDNA clone MGC: 33744 -1594.04 IMAGE:5263220) US 2016/02375O1 A1 Aug. 18, 2016 33

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 221288 at GPR22 G protein-coupled receptor 22 -1563O3 215333 x at GSTM1 glutathione S-transferase mu 1 -2.03103 204550 X. at GSTM1 glutathione S-transferase mu 1 -1951.36 204418 x at GSTM2 glutathione S-transferase mu 2 (muscle) -1.95729 232207 at GUSBL2 glucuronidase, beta-like 2 -2.10621 220085 at HELLS helicase, lymphoid-specific -1.67692 241723 at IQGAP2 IQ motif containing GTPase activating protein 2 -1.73571 215750 at KIAA1659 KIAA1659 protein -1.54646 236728 at LNPEP leucyl cystinyl aminopeptidase -1.53387 236621 at LOC100130070 / similar to metallopanstimulin i? similar to rCG63653 fif -1.70558 LOC100130775 i? similar to metallopans LOC100131787 LOC100131905 LOC10O132291 LOC10O1324.88 RPS27 239062 a LOC100131096 hypothetical LOC100131096 -157675 229094 a LOC4O1431 hypothetical gene LOC4.01431 -153069 1565911 at LOC64892.1 MRNA full length insert cDNA clone EUROIMAGE -15498.1 209544 214180 a MAN1C1 mannosidase, alpha, class 1C, member 1 -166631 215663 a MBNL1 muscleblind-like (Drosophila) -153726 212935 a. MCF2L MCF.2 cell line derived transforming sequence-like -153863 207078 a MED6 mediator complex subunit 6 -153.192 242111 a METTL3 methyltransferase like 3 -156742 1559856 S at MLL myeloid lymphoid or mixed-lineage leukemia (trithorax -1592.19 homolog, Drosophila) 243857 a MORF4L2 Mrgx mRNA for MRGX -152328 242191 a NBPF10 / RP11- neuroblastoma breakpoint family, member 10/// -15OO43 94.12.2 hypothetical protein LOC200030 203413 a NELL2 NEL-like 2 (chicken) -1.5281 229.093 a NOS3 nitric oxide synthase 3 (endothelial cell) -153818 223.601 a OLFM2 olfactomedin 2 -15119 214615 a. P2RY1O purinergic receptor P2Y, G-protein coupled, 10 -1.51779 235758 a PNMA6A paraneoplastic antigen like 6A -1.95731 244011 a PPM1 K protein phosphatase 1 K (PP2C domain containing) -1515O1 239635 a. RBM14 RNA binding motif protein 14 -165349 219864 S at RCAN3 RCAN family member 3 -1.6.1977 212699 a SCAMPS secretory carrier membrane protein 5 -154948 232055 a. SFXN1 sideroflexin 1 -1. SO117 239667 a SLC3A1 Solute carrier family 3 (cystine, dibasic and neutral amino -169708 acid transporters, a 553423 a at SLFN13 schlafen family member 13 -153028 232020 a SMURF2 SMAD specific E3 ubiquitin protein ligase 2 -1.57992 560741 at SNRPN Small nuclear ribonucleoprotein polypeptide N -165945 226587 a SNRPN Small nuclear ribonucleoprotein polypeptide N -158OO6 226913 s at SOX8 SRY (sex determining region Y)-box 8 -1.73755 555882 at SPIN3 spindlin family, member 3 -165127 555883 s at SPIN3 spindlin family, member 3 -150348 213993 a SPON1 spondin 1, extracellular matrix protein -1.SS928 218856 a TNFRSF21 tumor necrosis factor receptor Superfamily, member 21 -1.77712 556116 s at TNPO1 Transportin 1, mRNA (cDNA clone MGC: 17116 -1.7577 IMAGE:4178989) 244521 a. TSHZ2 Cell growth-inhibiting protein 7 -1.86.192 206487 a UNC84A unc-84 homolog A (C. elegans) -1. SO376 55.8569 at UNQ6228 MRNA, cDNA DKFZp667K1619 (from clone -163796 DKFZp667K1619) 557450 s at WHDC1L2 WAS protein homology region 2 domain containing 1- -1.75555 like 2 229234 at ZC3H12B Zinc finger CCCH-type containing 12B -1.72127 55872 at ZNFS12B Zinc finger protein 512B -1521.58 568873 at ZNF519 Zinc finger protein 519 -1.70283 Table 5.B. 325 Upregulated Genes TABLESB

563546 at 3.SOO48 559696 at 3.23854 563.033 x at — 3.1635S 563.032 at 2.97.375 558496 at 2.87094 241566 at 2.8.2164 568589 at 2.72.05 215448 at 2.69149 US 2016/02375O1 A1 Aug. 18, 2016 34

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 237479 a 2.68144 234235 a. 2.64462 231074 a 2.63519 1560905 at 2.63286 237871 x at — 2.55976 237937 X at - 2.541 207 731 a 2.52426 240988 x at — 2.46734 243398 a 2.43872 241675 s at — 2.39854 241674 S at — 2.38362 228827 a 2.3697 233944 a 2.36679 227952 a 2.31481 1554225 a. at — 2.30748 1560049 at 2.29877 215962 a 2.28524 1564306 at 2.20443 1557762 at 2.18276 231091 x at — 2.17817 1566862 at 2.1.529 1560760 S at — 2.1184 230959 at 2.10492 238103 at 2.08.283 2428O2 X at — 2.06924 2345.02 at 2.05567 241636 X at — 2.0384 236038 at 2.0344 216406 at 2.02612 566805 a 2.00292 239464 at 2.OOO73 233875 at 99361 561713 a 9693 562480 a 94431 556983 a at — 93605 57.0191 a 93494 243902 a 93045 2O7744 a 923.81 237233 a 90496 561199 a 89756 561902 a 89021 243273 a 88315 238368 a .88178 243666 a 876O1 556989 a 86984 238358 x at — 86,726 229635 a. 8637 238361 s at — 84576 231503 a 84378 229490 s. at — 84229 569344 a at — 83229 234083 a 832O1 243183 a 83176 238405 a. 82494 559336 a 82388 563568 a 81339 237983 a 81,139 563881 a 8O1 242198 a 79799 562613 a 78841 560086 a 78528 237893 a 77856 562992 a 75888 24O112 a 75583 569810 a 75522 566609 a 755O1 243533 x at — 74919 57O152 a. 74489 561112 a .74O3S 231040 at 736O4 559695 a. at - 7325 560296 a 72689 US 2016/02375O1 A1 Aug. 18, 2016 35

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 1561473 at 72375 241654 a 71.535 1557645 at .70892 1566498 at .70831 237399 a 70373 1562811 at 70357 1561448 at .68957 237.933 a 68559 241457 a 67974 242420 a 67555 222342 a. 6753 1556021 at 67385 239984 a 67188 244216 a 67082 234794 a 667.48 215290 a .65929 243279 a 65749 1570268 at 65328 244384 a 65237 238,571 a 64715 237552 a. 64653 241461 a .63938 242718 a 634.17 238392 a 622S2 238354 x at — .62228 1560453 at .62O59 215976 a .62O3S 1564840 at 61.94 1561767 at 61738 1553275 S. at - 612S3 1563.087 at 61106 1566,597 at 59.925 244668 a .59371 216518 a .5937 1563561 at 59351 236571 a S893 216214 a 58555 24O904 a S8293 235494 a S7849 240067 a 57319 237071 a 57301 233306 a S6521 216463 a S6326 237192 a 56114 1560517 s at — 55983 1555,263 at 556 1566968 at SS262 241.173 a S4723 1561351 at S4685 15596.29 at S4679 238395 a S4457 1563026 at S413S 1562610 at S3899 1570506 at 53071 231546 a .52352 240714 a S2183 242495 a S1926 1561642 at S1919 234825 a. S1483 241.247 a S1115 236276 a 50976 23838.6 X at — SO861 241569 a SO674 1564851 at 50551 1556185 a. at — SO4O6 243424 a SO374 238.274 a 5O237 207275 S. at ACSL1 acyl-CoA synthetase long-chain family member 1 S1866 243520 x at ADAM30 ADAM metallopeptidase domain 30 .8O193 206134 a ADAMDEC1 ADAM-like, decysin 1 61274 209.614 a ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide 51397 202912 a ADM adrenomedullin 61874 US 2016/02375O1 A1 Aug. 18, 2016 36

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 206513 at AIM2 absent in melanoma 2 1.60396 215783 s at ALPL alkaline phosphatase, liver/bone/kidney 2.1OO6 1557924 S at ALPL alkaline phosphatase, liver/bone/kidney 2.02022 1563673 a at ALS2CR11 amyotrophic lateral sclerosis 2 (juvenile) chromosome 2.15.177 region, candidate 11 1562292 at ANKRD3OB ankyrin repeat domain 30B 86641 209369 a ANXA3 annexin A3 2.41095 1554816 at ASTN2 astrotactin 2 2.22748 239144 a B3GAT2 beta-1,3-glucuronyltransferase 2 (glucuronosyltransferase 75721 S) 228758 a BCL6 Zinc finger protein .691.27 215990 s. at BCL6 B-cell CLL/lymphoma 6 59315 242579 a BMPR1B bone morphogenetic protein receptor, type IB 2.0S687 232416 a BRUNOLS bruno-like 5, RNA binding protein (Drosophila) 68747 223977 s at C18orf2 chromosome 18 open reading frame 2 S8384 1553652 a. at C18orf54 chromosome 18 open reading frame 54 S4796 235568 a C19Crf59 chromosome 19 open reading frame 59 .99789 1554540 at C1 Orf67 chromosome 1 open reading frame 67 51941 1553329 at C7orfas chromosome 7 open reading frame 45 72974 2392.03 a C7orf53 chromosome 7 open reading frame 53 .55912 1552701 a. at CARD16 caspase recruitment domain family, member 16 59587 232969 a CARD8 caspase recruitment domain family, member 8 .78265 207500 a CASPS caspase 5, apoptosis-related cysteine peptidase .91798 203065 s at CAV1 caveolin 1, caveolae protein, 22 kDa 6O773 220351 a CCRL1 chemokine (C-C motif) receptor-like 1 2.32444 208168 s at CHIT1 chiltinase 1 (chitotriosidase) S6138 239989 a CNTLN centlein, centrosomal protein S3478 229084 a CNTN4 contactin 4 7244 1556499 S at COL1A1 collagen, type I, alpha 1 2.87107 229218 a COL1A2 collagen, type I, alpha 2 92.067 210262 a CRISP2 cysteine-rich Secretory protein 2 88.349 1553.002 at DEFB1OSA defensin, beta 105A defensin, beta 105B 52948 DEFB1OSB 226121 a DHRS13 dehydrogenase/reductase (SDR family) member 13 65414 233092 s at DKFZP434B061 DKFZP434B061 protein .84946 222253 S at DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 2.61011 206819 a DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 93567 239309 a DLX6 distal-less homeobox 6 2.4523 220493 a DMRT1 doublesex and mab-3 related transcription factor 1 61917 241199 X at DPPA4 developmental pluripotency associated 4 2.68174 232360 a EHF ets homologous factor .68951 21985.0 s at EHF ets homologous factor 64.412 228260 a ELAVL2 ELAV (embryonic lethal, abnormal vision, Drosophila)- 9905 ike 2 (Huantigen B) 227612 a ELAVL3 ELAV (embryonic lethal, abnormal vision, Drosophila)- 3.23.425 ike 3 (Huantigen C) 219134 a ELTD1 EGF, latrophilin and seven transmembrane domain .70282 containing 1 211164 a EPHA3 EPH receptor A3 2.393.14 243277 X at EVI1 ecotropic viral integration site 1 S445 230519 a FAM124A amily with sequence similarity 124A S9499 1569025 S at FAM13A1 amily with sequence similarity 13, member A1 55876 222291 a FAM149A amily with sequence similarity 149, member A 75785 222205 X at FAM182B II RP13- family with sequence similarity 182, member B if 70042 401N82 hypothetical gene Supported by 220645 a. FAMSSD amily with sequence similarity 55, member D SS166 201579 a FAT1 FAT tumor suppressor homolog 1 (Drosophila) .67288 239710 a FIGN idgetin 2.14096 238964 a FIGN idgetin S6796 1557155 a. at FLJ30375 CDNA clone IMAGE: 5301781 .974S1 229521 a FLJ36031 hypothetical protein FLJ36031 58,141 1560790 at FLJ36144 hypothetical protein FLJ36144 78391 1558579 at FLJ37786 hypothetical LOC642691 66O29 230999 a FLJ39051 CDNA FLJ39051 fis, clone NT2RP701 1452 926OS 227925 a. FLJ39051 CDNA FLJ39051 fis, clone NT2RP701 1452 86433 217487 x at FOLH1 olate hydrolase (prostate-specific membrane antigen) 1 2.1998.7 217483 a FOLH1 olate hydrolase (prostate-specific membrane antigen) 1 .6895S 40284 at FOXA2 orkhead box A2 8498 1553613 s at FOXC1 orkhead box C1 S3964 230964 a FREM2 FRAS1 related extracellular matrix protein 2 2.30984 1553024 at G30 protein LG30-like .75094 1557122 S at GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 349668 US 2016/02375O1 A1 Aug. 18, 2016 37

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 242344 a GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 2.72.458 1555726 at GAFA3 FGF-2 activity-associated protein 3 61768 219271 a GALNT14 UDP-N-acetyl-alpha-D-galactosamine: polypeptide N- 2.07605 acetylgalactosaminyltransferase 240390 a GALNTS UDP-N-acetyl-alpha-D-galactosamine: polypeptide N- 2.09257 acetylgalactosaminyltransferase 204763 s at GNAO1 guanine nucleotide binding protein (G protein), alpha 5542 activating activity polype 223767 a GPR84 G protein-coupled receptor 84 76044 207235 S. at GRMS glutamate receptor, metabotropic 5 .934S1 1559520 at GYPA Glycophorin A 2.12904 211267 a HESX1 HESXhomeobox 1 61355 227566 a HNT neurotrimin S6SS4 206858. S. at HOXC4 HOXC6 homeobox C4 homeobox C6 70414 219403 s at HPSE heparanase 60481 211959 a GFBP5 insulin-like growth factor binding protein 5 S4S45 205067 a L1B interleukin 1, beta S7884 394.02 at L1B interleukin 1, beta S1316 229538 s at IQGAP3 Q motif containing GTPase activating protein 3 73797 214927 a TGBL1 integrin, beta-like 1 (with EGF-like repeat domains) .73813 238428 a KCNJ15 potassium inwardly-rectifying channel, Subfamily J, .5696S LOC100131955 member 15 i? similar to pot 227250 a KREMEN1 kringle containing transmembrane protein 1 2.16406 235370 a KREMEN1 kringle containing transmembrane protein 1 77475 215516 a LAMB4 aminin, beta 4 60646 206140 a LHX2 LIM homeobox2 2.0959 225571 a LIFR eukemia inhibitory factor receptor alpha 691.68 210582 s at LIMK2 LIM domain kinase 2 S485 1556704 s at LOC100.133920 / hypothetical protein LOC100133920 // hypothetical 63O34 LOC286.297 protein LOC286.297 232034 a LOC2O3274 CDNA FLJ31544 fis, clone NT2RI2O00865 63147 1557717 at LOC338862 hypothetical protein LOC338862 2.22946 1560823 at LOC34.0017 hypothetical protein LOC34.0017 51946 233879 a LOC374491 TPTE and PTEN homologous inositol lipid phosphatase 81019 pseudogene 1558982 at LOC37SO10 hypothetical LOC375010 72485 214984 a LOC440345 hypothetical protein LOC440345 .98536 230902 a LOC645323 CDNA clone IMAGE: 5260726 84336 238850 a LOC645323 hypothetical LOC645323 81SO3 1568933 at LOC646627 phospholipase inhibitor S3874 231434 a LOC728460 similar to FLJ32921 protein 68.733 1570009 at LOC732.096 similar to hCG2040240 2.13184 2308.63 a LRP2 ow density lipoprotein-related protein 2 71146 203005 a LTBR ymphotoxin beta receptor (TNFRSuperfamily, member 58.399 3) 201744 is at LUM unican 93.131 210449 x at MAPK14 mitogen-activated protein kinase 14 57327 211561 x at MAPK14 mitogen-activated protein kinase 14 55337 235.077 at MEG3 maternally expressed 3 (non-protein coding) 6384 240814 at MGC39584 hypothetical gene Supported by BC029568 59341 214087 s at MYBPC1 myosin binding protein C, slow type S8609 237510 at MYNN Myoneurin, mRNA (cDNA clone IMAGE: 4721583) .8SO41 1559292 S at NCRNA00032 Clone IMAGE: 2275835 C9orf14 mRNA, partial .98SS4 sequence; alternatively spliced 220429 at NDST3 N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3 68889 209119 X at NR2F2 nuclear receptor Subfamily 2, group F, member 2 94377 231867 at ODZ2 odz, Odd Oziten-m homolog 2 (Drosophila) 2.03143 214111 at OPCML opioid binding protein cell adhesion molecule-like 91158 230170 at OSM oncostatin M S8899 1553931 at OSTCL oligosaccharyltransferase complex subunit-like 575O1 206048 at OVOL2 ovo-like 2 (Drosophila) 2.06333 1559400 s at PAPPA pregnancy-associated plasma protein A, pappalysin 1 SOOO9 210292 S at PCDH11X protocadherin 11 X-linked fit protocadherin 11 Y-linked 66OS PCDH11 Y 208396 s at PDE1A phosphodiesterase 1A, calmodulin-dependent .68453 214868 at PIWIL1 piwi-like 1 (Drosophila) 63171 202446 s at PLSCR1 phospholipid scramblase 1 S4059 233030 at PNPLA3 patatin-like phospholipase domain containing 3 SO269 1569675 at POU2AF1 POU class 2 associating factor 1, mRNA (cDNA clone 67876 MGC: 45211 IMAGE:5554.134) 1555462 at PPP1R1C protein phosphatase 1, regulatory (inhibitor) subunit 1C 60542 241669 X at PRKD2 protein kinase D2 55139 US 2016/02375O1 A1 Aug. 18, 2016 38

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 220696 a PROO478 PROO478 protein 691.69 228825 a. PTGR1 prostaglandin reductase 1 .95262 217194 a RASAL2 RAS protein activator like 2 2.OO632 226872 a. RFX2 regulatory factor X, 2 (influences HLA class II S8786 expression) 213194 a ROBO1 roundabout, axon guidance receptor, homolog 1 952O7 (Drosophila) 242385 a. RORB RAR-related orphan receptor B 2.14023 1555990 at RP1-127L4.6 hypothetical protein LOC150297 .76603 215321 a RUNDC3B RUN domain containing 3B 60322 205863 a S100A12 S100 calcium binding protein A12 5633 229057 a SCN2A Sodium channel, voltage-gated, type II, alpha Subunit .85129 207570 a SHOX short stature homeobox 2.OO 103 210135 S. at SHOX2 short stature homeobox2 2.86893 208443 x at SHOX2 short stature homeobox2 .7O616 206634 a SIX3 SIXhomeobox 3 78989 205896 a SLC22A4 Solute carrier family 22 (organic cation ergothioneine .65918 transporter), member 4 237340 a SLC26A8. solute carrier family 26, member 8 2.32491 216236 s at SLC2A14 Solute carrier family 2 (facilitated glucose transporter), S1356 SLC2A3 member 14 solute 232547 a SNIP SNAP25-interacting protein 83841 240204 a SNRPN Small nuclear ribonucleoprotein polypeptide N 58295 24-1987 X at SNX31 Sorting nexin 31 2.19167 204913 s at SOX11 SRY (sex determining region Y)-box 11 2.34727 204914 S at SOX11 SRY (sex determining region Y)-box 11 882O1 202935 s at SOX9 SRY (sex determining region Y)-box 9 2.45928 235342 a. SPOCK3 sparcosteonectin, cwcv and kazal-like domains 7S314 proteoglycan (testican) 3 24-1961 a SRDSA2L2 steroid 5 alpha-reductase 2-like 2 2.08494 1554473 at SRGAP1 SLIT-ROBO Rho GTPase activating protein 1 992O3 203759 a ST3GAL4 ST3 beta-galactoside alpha-2,3-sialyltransferase 4 S10O2 231969 a STOX2 storkhead box 2 2.2552 214451 a TFAP2B transcription factor AP-2 beta (activating enhancer 89347 binding protein 2 beta) 215447 a TFPI Tissue factor pathway inhibitor (lipoprotein-associated .96SO9 coagulation inhibitor), 228121 a TGFB2 transforming growth factor, beta 2 .70904 210166 a TLRS ol-like receptor 5 9168 220205 a TPTE transmembrane phosphatase with tensin homology 60S47 206479 a TRPM1 transient receptor potential cation channel, Subfamily M, 57541 member 1 1556666 a. at TTC6 etratricopeptide repeat domain 6 .9101S 213943 a TWIST1 twist homolog 1 (Drosophila) 2.72279 222435 S. at UBE21 ubiquitin-conjugating enzyme E2, J1 (UBC6 homolog, 50758 yeast) 226899 a UNCSB unc-5 homolog B (C. elegans) 2.04351 561200 at WWA3B von Willebrand factor A domain containing 3B 618O2 206954 a WIT1 Wilms tumor upstream neighbor 1 2.58643 552946 at ZNF114 Zinc finger protein 114 99445 229743 a ZNF438 Zinc finger protein 438 S3049 244007 a ZNF462 Zinc finger protein 462 53545 55.5367 at ZNF479 Zinc finger protein 479 2.25193 555368 x at ZNF479 Zinc finger protein 479 2.162O3 2323.03 a ZNF608 Zinc finger protein 608 72629 TABLE SC.34 Genes that differentiate TIA from Control

557580 at -1.85725 559695 a. at - 7325 561767 at 61738 563026 at S413S 563568 at 81339 568589 at 2.72.05 568781 at -160862 216406 at 2.02612 2296.54 at -1.74432 231040 at 736O4 231069 at -1.SS35 231546 at .52352 233306 at S6521 236571 at S893 237597 at -2.4398 US 2016/02375O1 A1 Aug. 18, 2016 39

TABLE 5-continued TIA associated gene lists (FDRs 0.05, absolute fold change a 1.5 compared with control). Fold AFFY ID Gene Symbol Gene Title Change 237953 a -154815 242495 a S1926 242564 a -163967 242710 a -1.76712 244226 s at — -1.685.79 244665 a. -165812 229252 a ATG9B ATG9 autophagy related 9 homolog B (S. cerevisiae) -1.64694 212504 a DIP2C DIP2 disco-interacting protein 2 homolog C (Drosophila) -1.62614 233092 S at DKFZP434B061 DKFZP434B061 protein .84946 220048 a EDAR ectodysplasin A receptor -1.69385 220645 a. FAMSSD amily with sequence similarity 55, member D SS166 1557155 a. at FLJ30375 CDNA clone IMAGE: 5301781 .974S1 215333 x at GSTM1 glutathione S-transferase mu 1 -2.03103 232207 a GUSBL2 glucuronidase, beta-like 2 -2.10621 211959 a IGFBP5 insulin-like growth factor binding protein 5 S4S45 203005 a. LTBR ymphotoxin beta receptor (TNFRSuperfamily, member 3) 58.399 229057 a SCN2A Sodium channel, voltage-gated, type II, alpha Subunit .85129 232020 a SMURF2 SMAD specific E3 ubiquitin protein ligase 2 -1.57992 55872 at ZNFS12B Zinc finger protein 512B -1521.58 TABLE5D. 26 Upregulated Genes that differentiate TIA1 from TLA2 1557122 S at GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 349668 1559696 at 3.23854 227612 a ELAVL3 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 3.23.425 (Huantigen C) 1563.032 at 2.97.375 1558496 at 2.87094 241566 a 2.8.2164 213943 a TWIST1 twist homolog 1 (Drosophila) 2.72279 215448 a 2.69149 241199 x at DPPA4 developmental pluripotency associated 4 2.68174 237479 a 2.68144 234235 a. 2.64462 1560905 at 2.63286 222253 s at DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 2.61011 237937 X at - 2.541 207 731 a 2.52426 239309 a DLX6 distal-less homeobox 6 2.4523 243398 a 2.43872 241675 s at — 2.39854 241674 S at — 2.38362 1555367 at ZNF479 Zinc finger protein 479 2.25193 1554816 at ASTN2 astrotactin 2 2.22748 24-1987 x at SNX31 Sorting nexin 31 2.19167 1557762 at 2.18276 1563673 a at ALS2CR11 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, 2.15.177 candidate 11 214984 at LOC440345 hypothetical protein LOC440345 198536 1556983 a at — 1.9360S

TABLE 8 Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1553422 s at A2BP1 ataxin 2-binding protein 1 1.72186 223593 at AADAT aminoadipate aminotransferase 185564 214829 at AASS aminoadipate-semialdehyde synthase 189032 1552582 at ABCC13 ATP-binding cassette, Sub-family C (CFTR/MRP), member 13 2.62247 1557374 at ABCC9 ATP-binding cassette, Sub-family C (CFTR/MRP), member 9 1.741.38 208462 s at ABCC9 ATP-binding cassette, Sub-family C (CFTR/MRP), member 9 2.03195 220518 at ABI3BP ABI family, member 3 (NESH) binding protein 181797 220061 at ACSMS acyl-CoA synthetase medium-chain family member 5 1.74O6S 89977 at ACSMS acyl-CoA synthetase medium-chain family member 5 2.18846 215613 at ADAM12 Meltrin-S (ADAM12) mRNA, complete cols, alternatively spliced 1790.57 1568970 at ADAM18 ADAM metallopeptidase domain 18 2.48574 207664 at ADAM2 ADAM metallopeptidase domain 2 1.9154 US 2016/02375O1 A1 Aug. 18, 2016 40

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 243520 x at ADAM30 ADAM metallopeptidase domain 30 2.74216 1552266 at ADAM32 ADAM metallopeptidase domain 32 65164 206134 a ADAMDEC1 ADAM-like, decysin 1 3.08521 230040 a ADAMTS18 ADAM metallopeptidase with thrombospondin type 1 motif, 18 68813 1553180 at ADAMTS 19 ADAM metallopeptidase with thrombospondin type 1 motif, 19 2.44377 214913 a ADAMTS3 ADAM metallopeptidase with thrombospondin type 1 motif, 3 58473 220287 a ADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9 97398 209614 a ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide 6OO16 231678. S. at ADH4 alcohol dehydrogenase 4 (class II), pipolypeptide 66033 204120 s at ADK adenosine kinase -1.79666 211491 a ADRA1A adrenergic, alpha-1A-, receptor 6033 204333 s at AGA aspartylglucosaminidase -1.54576 1553447 at AGBL1 ATP/GTP binding protein-like 1 S1198 1554.820 at AGBL3 ATP/GTP binding protein-like 3 794.67 232007 a AGPATS 1-acylglycerol-3-phosphate O-acyltransferase 5 (lysophosphatidic -1.78587 acid acyltrans 205357 s at AGTR1 angiotensin II receptor, type 1 51953 206957 a AGXT alanine-glyoxylate aminotransferase 50599 230630 a. AK3L1 adenylate kinase 3-like 1 if adenylate kinase 3-like 2 52481 AK3L2 207870 a AKAP9 A kinase (PRKA) anchor protein (yotiao) 9 76652 244205 a ALAS2 aminolevulinate, delta-, synthase 2 67115 211617 a ALDOAP2 aldolase A, fructose-bisphosphate pseudogene 2 3.07845 211357 s at ALDOB aldolase B, fructose-bisphosphate 74204 1553261 x at ALS2CR11 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, 2.08857 candidate 11 1553260 s at ALS2CR11 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, 2.81678 candidate 11 1563673 a at ALS2CR11 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, 3.6O798 candidate 11 1553471 at AMAC1 acyl-malonyl condensing enzyme 1 1.53576 236760 at AMMECR1 Alport syndrome, mental retardation, midface hypoplasia and -161791 elliptocytosis chrom 203002 at AMOTL2 angiomotin like 2 1524.46 243799 x at ANGPTL3 Angiopoietin-like 3, mRNA (cDNA clone IMAGE: 3934961) 163129 232606 at ANK2 Ankyrin, Brank-1 protein 1.69608 1553211 at ANKFN1 ankyrin-repeat and fibronectin type III domain containing 1 1.66982 1560370 x at ANKH CDNA FLJ30404 fis, clone BRACE2008481 153577 243181 at ANKIB1 ankyrin repeat and IBR domain containing 1 -1.59952 206029 at ANKRD1 ankyrin repeat domain 1 (cardiac muscle) 1.58224 155.9406 at ANKRD18A ankyrin repeat domain 18A 1.76934 1570255 S at ANKRD20A1 ankyrin repeat domain 20 family, member A1 i? ankyrin repeat 2.65731 ANKRD20A2 domain 20 family, ANKRD20A3 ANKRD2OA4 if ANKRD2OB J. LOC37SO10 J. LOC647595 J. LOCA28371 205706 S. at ANKRD26 ankyrin repeat domain 26 -1.69786 1561079 at ANKRD28 ankyrin repeat domain 28 9663S 1562292 at ANKRD3OB ankyrin repeat domain 30B 25644 1562294 x at ANKRD3OB ankyrin repeat domain 30B 3.18.306 227034 a ANKRD57 ankyrin repeat domain 57 -162847 213553 X at APOC apolipoprotein C-I 51627 215931 S. at ARFGEF2 ADP-ribosylation factor guanine nucleotide-exchange factor 2 -150024 (brefeldin A-inhibi 228368 a ARHGAP2O Rho GTPase activating protein 20 6O28S 1560318 at ARHGAP29 Rho GTPase activating protein 29 4.60468 235412 a ARHGEF7 Rho guanine nucleotide exchange factor (GEF) 7 (ARHGEF7), 63916 transcript variant 2, 242727 a ARLSB ADP-ribosylation factor-like 5B -1.543SS 219094 a ARMC8 armadillo repeat containing 8 -1.57518 227444 a ARMCX4 Armadillo repeat containing, X-linked 4, mRNA (cDNA clone -181523 IMAGE: 5261888) 239147 a ARSK arylsulfatase family, member K 97592 239002 a ASPM asp (abnormal spindle) homolog, microcephaly associated 2.35391 (Drosophila) 1554816 at ASTN2 astrotactin 2 4.64925 233536 a ASXL3 additional sex combs like 3 (Drosophila) 2.11586 1569729 a. at ASZ1 ankyrin repeat, SAM and basic leucine Zipper domain containing 1 1.59531 1559485 at ATG2B ATG2 autophagy related 2 homolog B (S. cerevisiae) 171224 US 2016/02375O1 A1 Aug. 18, 2016 41

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 228190 a ATG4C ATG4 autophagy related 4 homolog C (S. cerevisiae) if Ctr), -15OO66 CTR9 Paf1/RNA polymerase 220920 a ATP1OB ATPase, class V, type 10B 91809 220556 a ATP1B4 ATPase, (Na+)/K+ transporting, beta 4 polypeptide 63153 211137 S at ATP2C1 ATPase, Ca++ transporting, type 2C, member 1 -151541 214594 X at ATP8B1 ATPase, class I, type 8B, member 1 78628 216129 a ATP9A ATPase, class II, type 9A 98899 1560404 a at ATPBD4 ATP binding domain 4 S843 1569796 S. at ATRNL1 attractin-like 1 2.48281 222969 a B3GALT1 UDP-Gal: betaGlcNAc beta 1,3-galactosyltransferase, polypeptide 1 97721 239144 a B3GAT2 beta-1,3-glucuronyltransferase 2 (glucuronosyltransferase S) 2.24315 206233 a B4GALT6 UDP-Gal: betaGlcNAc beta 14-galactosyltransferase, S1182 polypeptide 6 22244.6 s at BACE2 beta-site APP-cleaving enzyme 2 -1.70556 207712 a BAGE B melanoma antigen 65959 15556.05 x at BAGE B melanoma antigen 7285 1555369 at BAGE B melanoma antigen 55591 1555603 at BAGE B melanoma antigen 2.17743 211568 a BAI3 brain-specific angiogenesis inhibitor 3 99551 2196.88 a BBS7 Bardet-Biedl syndrome 7 -1.8488 1555555 at BBS9 Bardet-Biedl syndrome 9 67715 233464 a BCL2L14 BCL2-like 14 (apoptosis facilitator) 5.9747 1560683 at BCL8 B-cell CLL/lymphoma 8 76236 1560684 x at BCL8 B-cell CLL/lymphoma 8 85157 2393.67 a BDNF brain-derived neurotrophic factor 961.76 232368 a BET3L BET3 like (S. cerevisiae) 85928 1569674 at BHLHB9 Clone 23955 mRNA sequence .73214 1569289 at BIVM Full length insert cDNA clone YB21E09 .62223 205431 S. at BMP5 bone morphogenetic protein 5 2.03195 242579 a BMPR1B bone morphogenetic protein receptor, type IB 3.69028 235723 a BNC2 basonuclin 2 .76632 232103 a BPNT1 3'(2),5'-bisphosphate nucleotidase 1 -152974 206044 S at BRAF v-raf murine sarcoma viral oncogene homolog B1 1 KIAA1549 S8869 KIAA1549 1569960 at BRD7P3 bromodomain containing 7 pseudogene 3 3.05416 206787 a BRDT bromodomain, testis-specific 53605 207369 a BRS3 bombesin-like receptor 3 2.10739 238966 a BRUNOL4 bruno-like 4, RNA binding protein (Drosophila) S9417 230497 a BRUNOLS bruno-like 5, RNA binding protein (Drosophila) 81119 232416 a BRUNOLS bruno-like 5, RNA binding protein (Drosophila) 2.98452 202946 s at BTBD3 BTB (POZ) domain containing 3 -1.5.1798 207326 a BTC betacellulin .76063 234243 a BXDCS brix domain containing 5 3.97289 224667 X at C10orf104 chromosome 10 open reading frame 104 S6473 557548 a C10orf108 chromosome 10 open reading frame 108 4.2936 560851 a C10orf136 chromosome 10 open reading frame 136 2.78.294 244435 a. C10orf141 chromosome 10 open reading frame 141 906.79 556648 a. at C10orf240 chromosome 10 open reading frame 40 2.61956 557801 X at C11orf1 chromosome 11 open reading frame 31 -1.50635 561985 a C14orf39 chromosome 14 open reading frame 39 2.08706 224213 at C14orf1 chromosome 14 open reading frame 91 51441 232507 at C15orf241 chromosome 15 open reading frame 41 77387 208109 s at C15orf5 chromosome 15 open reading frame 5 621.18 56O751 a C18orf16 chromosome 18 open reading frame 16 3.41883 223977 s at C18orf2 chromosome 18 open reading frame 2 2.32467 244495 X at C18orf245 chromosome 18 open reading frame 45 .64232 553652 a. at C18orf54 chromosome 18 open reading frame 54 .96326 556288 a C18Orf62 chromosome 18 open reading frame 62 2.60662 55.2908 a C1 orf150 chromosome 1 open reading frame 150 2.85331 554540 a C1 Orf67 chromosome 1 open reading frame 67 74707 233598 at C20orf187 chromosome 20 open reading frame 187 2.12O33 554657 a. at C20orf26 chromosome 20 open reading frame 26 7578 232953 at C20orf59 chromosome 20 open reading frame 69 i? similar to hypothetical 62957 DKFZP434B2016 // protein LOC28470 LOC643670 LOCA281OS if LOCA28323 PCMTD2 234314 at C20orf74 chromosome 20 open reading frame 74 1.68 240068 at C21orf130 chromosome 21 open reading frame 130 2.30653 1557481 a. at C21orf131 chromosome 21 open reading frame 131 2.67119 23.9999 at C21orf34 CDNA FLJ38295 fis, clone FCBBF3012332 1.71918 US 2016/02375O1 A1 Aug. 18, 2016 42

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 240801 at C21orf7 chromosome 21 open reading frame 37 2.52149 552876 at C21orf&9 chromosome 21 open reading frame 89 .74874 244467 at C22:CTA- transmembrane protein 46-like -150447 2SOD10.9 552979 at C2Orfs2 chromosome 2 open reading frame 52 5065 558,519 at C2Orf67 RPE Chromosome 2 open reading frame 67, mRNA (cDNA clone 54141 MGC: 27010 IMAGE:4829661) // 231081 a C2Orf73 chromosome 2 open reading frame 73 83581 24.1998 a C2Orf30 chromosome 2 open reading frame 80 2.15326 554147 s at C3orf15 chromosome 3 open reading frame 15 5927 554528 at C3orf15 chromosome 3 open reading frame 15 2.1.5.191 555719 a. at C3orf15 chromosome 3 open reading frame 15 2.821.89 223990 a C4orf17 chromosome 4 open reading frame 17 61603 231565 a C4orf22 chromosome 4 open reading frame 22 55741 231612 a C4Orf3S chromosome 4 open reading frame 35 55132 555096 at C4Orf37 chromosome 4 open reading frame 37 87794 553106 at CSOrf24 chromosome 5 open reading frame 24 -184772 234457 a C6orf12 chromosome 6 open reading frame 12 2.813S 55.2575 a. at C6orf141 chromosome 6 open reading frame 141 70056 232152 a. C6orf182 chromosome 6 open reading frame 182 chromosome 6 open 2.19633 C6orf182P reading frame 182 pseu 244829 a C6orf218 Chromosome 6 open reading frame 218 (C6orf218), mRNA 24961 211351 a C6orf54 chromosome 6 open reading frame 54 2.04304 1566865 at C7orf58 chromosome 7 open reading frame 38 98885 209446 s at C7orf244 chromosome 7 open reading frame 44 -151989 1553329 at C7orfas chromosome 7 open reading frame 45 2.3417 24.0626 a C8orf15 chromosome 8 open reading frame 15 70317 231380 a C8orf34 chromosome 8 open reading frame 34 78.353 218541 s at C8orf24 chromosome 8 open reading frame 4 99.089 214796 a C8orf79 chromosome 8 open reading frame 79 .71345 1560207 at C8orf&1 chromosome 8 open reading frame 81 3.37061 206727 a C9 complement component 9 66942 230522 S at C9orf100 chromosome 9 open reading frame 100 -155527 1557541 at C9orf122 chromosome 9 open reading frame 122 553O2 208077 a C9Crf38 chromosome 9 open reading frame 38 2.77328 1558.414 at C9orf24 chromosome 9 open reading frame 4 61823 1560558 at C9Crf30 chromosome 9 open reading frame 80 3.13268 1556516 at C9Crf3 CDNA clone IMAGE: 5312512 2.11837 1553433 at C9Crf3 chromosome 9 open reading frame 93 2.37646 1557666 s at C9orf.8 chromosome 9 open reading frame 98 S7862 230976 at C9Crf8 chromosome 9 open reading frame 98 -1.6SSO9 238.636 at CACNA1C calcium channel, Voltage-dependent, L type, alpha 1C Subunit .739S4 244256 at CACNA1E Voltage-operated calcium channel, alpha-1 subunit 2.7O154 2398.84 at CADPS Ca++-dependent Secretion activator 2.05688 219572 at CADPS2 Ca++-dependent Secretion activator 2 64739 201617 x at CALD1 caldesmon 2.15522 235834 at CALD1 Caldesmon, 3' UTR 76734 205525 at CALD1 caldesmon 2.04665 552421 a. at CALR3 cal reticulin 3 S9981 212551 at CAP2 CAP, adenylate cyclase-associated protein, 2 (yeast) 94441 56.9450 at CAPZA2 capping protein (actin filament) muscle Z-line, alpha 2 -1.SS786 553323 a at CATSPER2 cation channel, sperm associated 2 -1.76772 230981 at CATSPER3 cation channel, sperm associated 3 -153O8 555920 at CBX3 Heterochromatin protein HP1Hs-gamma -165486 5.53886 at CCDC108 coiled-coil domain containing 108 2.91507 561477 at CCDC144A coiled-coil domain containing 144A 3.37527 561271 at CCDC144C coiled-coil domain containing 144C 3.46131 243565 at CCDC150 coiled-coil domain containing 150 71562 2374.75 x at CCDC152 coiled-coil domain containing 152 54.515 553849 at CCDC26 coiled-coil domain containing 26 9386 553666 at CCDC34 coiled-coil domain containing 34 8159 233259 at CCDC48 PREDICTED: Homo sapiens similar to hCG20004 2.53391 (LOC729581), mRNA 558893 a at CCDC67 coiled-coil domain containing 67 69471 214710 S. at CCNB1 cyclin B1 -1.54345 220351 at CCRL1 chemokine (C-C motif) receptor-like 1 3.68O23 229900 at CD109 CD109 molecule 62542 215784 at CD1E CD1e molecule 2.06446 1552.509 a at CD300LG CD300 molecule-like family memberg 53768 15545.19 at CD8O CD80 molecule -1.71348 24.1120 S. at CDC2OB Cell division cycle 20 homolog B (S. cerevisiae), mRNA (cDNA 50701 clone IMAGE: 5206729 US 2016/02375O1 A1 Aug. 18, 2016 43

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 24O161 S. at CDC2OB Cell division cycle 20 homolog B (S. cerevisiae), mRNA (cDNA 2.04212 clone IMAGE: 5206729 1555.772 a at CDC25A cell division cycle 25 homolog A (S. pombe) 3.35221 232266 x at CDC2L5 CDNA FLJ35215 fis, clone PROST2000079, highly similar to S2631 Homo sapiens mRNA for C 240735 a. CDC42BPA Ser-thr protein kinase PK428 S3612 22O115 S. at CDH10 cadherin 10, type 2 (T2-cadherin) 2.15879 236179 a CDH11 cadherin 11, type 2, OB-cadherin (osteoblast) 70475 207149 a CDH12 cadherin 12, type 2 (N-cadherin 2) 62637 206898 a CDH19 cadherin 19, type 2 S6233 220679 s at CDH7 cadherin 7, type 2 8O8O1 241911 a CDKL3 cyclin-dependent kinase-like 3 65132 204159 a CDKN2C cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4) -15149 228744 a CEP27 centrosomal protein 27 kDa -1536OS 229208 a CEP27 centrosomal protein 27 kDa -1.51058 241836 x at CEP97 centrosomal protein 97kDa 50275 207874 S at CFHR4 complement factor H-related 4 747O6 235117 a CHAC2 ChaC, cation transport regulator homolog 2 (E. coli) -1.8.177 220619 a CHD7 chromodomain helicase DNA binding protein 7 768.09 1565951 s at CHML choroideremia-like (Rab escort protein 2) -191904 206079 a CHML choroideremia-like (Rab escort protein 2) -164317 214596 a CHRM3 cholinergic receptor, muscarinic 3 2.54248 211587 X at CHRNA3 cholinergic receptor, nicotinic, alpha 3 61917 221107 a CHRNA9 cholinergic receptor, nicotinic, alpha 9 S6409 220026 a CLCA4 chloride channel regulator 4 2.16081 214598 a CLDN8 claudin 8 81.271 219414 a CLSTN2 calsyntenin 2 848.39 1552.588 a. at CNBD1 cyclic nucleotide binding domain containing 1 55.712 1552344 S at CNOT7 CCR4-NOT transcription complex, subunit 7 -1.82468 239989 a CNTLN centlein, centrosomal protein 222761 227209 a CNTN1 Contactin 2 precursor (CNTN1) 77739 229084 a CNTN4 contactin 4 2.67917 207195 a CNTN6 contactin 6 56557 205229 S. at COCH coagulation factor Chomolog, cochlin (Limitius polyphemus) -19015 205941 s at COL10A1 collagen, type X, alpha 1 7013 37892 at COL11A1 collagen, type XI, alpha 1 2.34283 1556499 S at COL1A1 collagen, type I, alpha 1 4.18573 2024.03 s at COL1A2 collagen, type I, alpha 2 61064 229218 at COL1A2 collagen, type I, alpha 2 4.15668 1555.253 at COL25A1 collagen, type XXV, alpha 1 3.31837 225293 at COL27A1 collagen, type XXVII, alpha 1 80939 211161 s at COL3A1 collagen, type III, alpha 1 88O84 215076 s at COL3A1 collagen, type III, alpha 1 84665 232458 at COL3A1 MRNA 3’ region for pro-alpha1 (III) collagen 2.19054 207420 at COLEC10 collectin sub-family member 10 (C-type lectin) S4892 217645 at COX16 COX16 cytochrome c oxidase assembly homolog (S. cerevisiae) -1.59605 227253 at CP ceruloplasmin (ferroxidase) 66O43 1552511 a. at CPA6 carboxypeptidase A6 2.12705 227721 at CPAMD8 C3 and PZP-like, alpha-2-macroglobulin domain containing 8 -2.00772 1555.250 a at CPEB3 cytoplasmic polyadenylation element binding protein 3 57893 204920 at CPS1 carbamoyl-phosphate synthetase 1, mitochondrial 95567 1552714 at CREG2 cellular repressor of E1A-stimulated genes 2 2.09357 2375O2 at CRLS1 Cardiolipin synthase 1 (CRLS1), transcript variant 2, mRNA 62771 1555958 at CRTAC1 cartilage acidic protein 1 S7641 1557143 at CSMD2 CUB and Sushi multiple domains 2 651.98 1553080 at CSN1S2A casein alpha S2-like A 73631 207030 S. at CSRP2 cysteine and glycine-rich protein 2 9.2858 1567912 s at CT45-4 if canceritestis antigen CT45-4 i? cancertestis antigen CT45-6 fif S.90OS4 CT45-6 hypothetical p LOC10O133581 J. RP13-36C9.1 J. RP13-36C9.3 J. RP13-36C9.6

FW88277B6.1 231568 at CT47.7 canceritestis CT47 family, member 7 if cancertestis CT47 1.71304 CT47.8 RP6- family, member 8 fif 166C19.1 RP6-166C19.10 J. RP6 166C19.11 RP6-166C19.2 US 2016/02375O1 A1 Aug. 18, 2016 44

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change

166C19.3 RP6-166C19.4

166C19.5 RP6-166C19.6

166C19.9 213597 s at CTDSPL CTD (carboxy-terminal domain, RNA polymerase II, polypeptide 93739 A) Small phosphatas 209.617 s at CTNND2 catenin (cadherin-associated protein), delta 2 (neural plakophilin- 50335 related arm-r 203917 a CXADR coxsackie virus and adenovirus receptor 2.66.153 231389 a CXorfA1 chromosome X open reading frame 41 97677 1553466 at CXorf59 chromosome X open reading frame 59 2.19023 235991 a CYB5RL cytochrome b5 reductase-like -1.53OSS 216809 a CYLC1 cylicin, basic protein of sperm head cytoskeleton 1 90782 2O7780 a CYLC2 cylicin, basic protein of sperm head cytoskeleton 2 6S232 2408.63 a CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1 2.21129 214235 a. CYP3A5 cytochrome P450, family 3, Subfamily A, polypeptide 5 8O2O3 205939 a CYP3A7 cytochrome P450, family 3, Subfamily A, polypeptide 7 70992 205472 S at DACH1 achshund homolog 1 (Drosophila) 65928 239738 a DACH2 achshund homolog 2 (Drosophila) 51034 1562772 a. at DANDS DAN domain family, member 5 73689 238757 a DBF4B DBF4 homolog B (S. cerevisiae) -1.67188 238508 a DBF4B DBF4 homolog B (S. cerevisiae) -181109 205369 x at DBT ihydrolipoamide branched chain transacylase E2 72887 213865 a DCBLD2 iscoidin, CUB and LCCL domain containing 2 55339 205399 a DCLK1 oublecortin-like kinase 1 .62886 215303 a DCLK1 oublecortin-like kinase 1 3.562O1 201893 x at DCN ecorin 94418 227561 a DDR2 iscoidin domain receptor tyrosine kinase 2 53865 223662 X at DDX59 DEAD (Asp-Glu-Ala-Asp) box polypeptide 59 SSO41 1553.002 at DEFB1OSA efensin, beta 105A defensin, beta 105B 94929 DEFB1OSB 1552411 at DEFB106A, efensin, beta 106A defensin, beta 106B 9024 DEFB106B 1563450 at DEFB107A efensin, beta 107A defensin, beta 107B 3.12379 DEFB107B 1562167 a. at DEFB122 efensin, beta 122 (pseudogene) S82O6 207356 at DEFB4 efensin, beta 4 95828 238917 s at DENNDSB DENN/MADD domain containing 5B -1.877OS 234071 at DEPDC6 DEP domain containing 6 S4924 216947 at DES esmin 4.2O247 1553524 at DGKB iacylglycerol kinase, beta 90 kDa 2.81068 203699 s at DIO2 eiodinase, iodothyronine, type II 61583 1557633 at DKFZp434K191 POM121 membrane glycoprotein-like 1 pseudogene 87034 1569476 at DKFZP434L187 CDNA clone IMAGE: 502.2014 3.78072 206819 at DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 2.57115 222253 S at DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 5.5328 216877 at DKFZp686O1327 EST clone 251800 mariner transposon HSmarl sequence 2.46877 224199 at DKK2 ickkopf homolog 2 (Xenopus laevis) S2116 242631 x at DLC1 eleted in liver cancer 1 .70843 233056 x at DLGAP4 iscs, large (Drosophila) homolog-associated protein 4 S2268 207147 at DLX2 istal-less homeobox2 2.38281 239309 at DLX6 istal-less homeobox 6 4S490S 220493 at DMRT1 oublesex and mab-3 related transcription factor 1 2.29697 237804 at DNAH11 Axonemal dynein heavy chain (DNAH11), partial 71964 1560416 at DNAH11 ynein, axonemal, heavy chain 11 2.87499 220725 x at DNAH3 Dynein, axonemal, heavy chain 3 (DNAH3), mRNA 58728 1552675 at DNAB7 DnaJ (Hsp40) homolog, subfamily B, member 7 69507 1558501 at DNM3 ynamin 3 S6409 21484.4 S at DOK5 ocking portein 5 2.18827 2O778.9 s at DPP6 ipeptidyl-peptidase 6 S1336 231385 at DPPA3 evelopmental pluripotency associated 3 if germ and embryonic 2.12291 STELLAR stem cell enriche 241199 X at DPPA4 evelopmental pluripotency associated 4 4.80564 1557290 at DPY19L2 py-19-like 2 (C. elegans) i? dpy-19-like 2 pseudogene 1 (C. elegans) 62779 DPY19L2P1 fit dpy-1 US 2016/02375O1 A1 Aug. 18, 2016 45

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 24.0218 at DSCAM Down syndrome cell adhesion molecule 1.59287 1552708 a at DUSP19 dual specificity phosphatase 19 2.25968 204014 at DUSP4 dual specificity phosphatase 4 1.67536 1569843 at DYNC1LI1 dynein, cytoplasmic 1, intermediate chain 1 1.78891 1565149 at DYNC2H1 dynein, cytoplasmic 2, heavy chain 1 2.12554 204271 S. at EDNRB endothelin receptor type B 1680O2 1558300 at EFCABS EF-hand calcium binding domain 5 2.24756 233814 a EFNAS Receptor tyrosine kinase ligand LERK-7 precursor (EPLG7) 1.57917 219454 a EGFL6 EGF-like-domain, multiple 6 1.631.59 1565483 at EGFR epidermal growth factor receptor (erythroblastic leukemia viral 1.75454 (v-erb-b) oncoge 21985.0 s at EHF ets homologous factor 2.15949 232360 a EHF ets homologous factor 2.97474 208427 s at ELAVL2 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 2 152696 (Huantigen B) 228260 a ELAVL2 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 2 4.26399 (Huantigen B) 227612 a ELAVL3 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 6.80428 (Huantigen C) 238,073 a ELAVL4 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 4 S4O26 (Huantigen D) 229581 a ELFN extracellular leucine-rich repeat and fibronectin type III domain 841.75 containing 1 1565,254 S at ELL elongation factor RNA polymerase II 2.51255 1557836 at ELMOD2 ELMO/CED-12 domain containing 2 (ELMOD2), mRNA 86O18 219134 a ELTD EGF, latrophilin and seven transmembrane domain containing 1 2.15765 219436 s at EMCN endomlucin 94422 1553672 at ENAH enabled homolog (Drosophila) 64531 205066 s at ENPP ectonucleotide pyrophosphatase/phosphodiesterase 1 .63382 205065 a ENPP ectonucleotide pyrophosphatase/phosphodiesterase 1 S2899 229292 a. EPB41LS erythrocyte membrane protein band 4.1 like 5 -1.50762 20607 O S at EPHA3 EPH receptor A3 2.33775 211164 a EPHA3 EPH receptor A3 4.39517 216837 a EPHAS EPH receptor A5 3.21486 229288 a EPHA7 EPH receptor A7 S6981 216999 a EPOR erythropoietin receptor 2.17646 202454 S at ERBB3 v-erb-b2 erythroblastic leukemia viral Oncogene homolog 3 S8154 (avian) 206794 a ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) 841SS 233498 a ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) 68382 214053 a ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) 3.22256 216440 a ERC1 RAB6 interacting protein 2, mRNA (cDNA clone 2.35068 IMAGE: 4343516) 1569583 at ERE epiregulin 55022 213365 a ERI2 exoribonuclease 2 -1.60968 1564473 at ESCO2 Clone 305-4G mRNA sequence S12O2 235588 a ESCO2 establishment of cohesion 1 homolog 2 (S. cerevisiae) 2.61641 209966 X at ESRRG estrogen-related receptor gamma .74O23 224454 a ETNK1 ethanolamine kinase 1 SOOS8 206501 x at ETV1 ets variant 1 64042 23.0102 a ETV5 Ets-related protein 68286 243277 X at EVI1 ecotropic viral integration site 1 2.35623 208298 a EVIS ecotropic viral integration site 5 2.18273 207327 a EYA4 eyes absent homolog 4 (Drosophila) 248321 1569592 a. at F11 coagulation factor XI 2.291 220575 a. FAM106A amily with sequence similarity 106, member A 54O75 209074 S at FAM107A amily with sequence similarity 107, member A 6318S 1557129 a. at FAM111B amily with sequence similarity 111, member B 202161 212979 S at FAM115A amily with sequence similarity 115, member A .61927 1555944 at FAM12OA amily with sequence similarity 120A -1.588S 1552323 s at FAM122C amily with sequence similarity 122C -154021 1553720 a. at FAM123A amily with sequence similarity 123A S1994 235465 at FAM123A amily with sequence similarity 123A .86652 230496 at FAM123A amily with sequence similarity 123A 2.SO999 231396 s at FAM126A amily with sequence similarity 126, member A -150922 223625 at FAM126A amily with sequence similarity 126, member A -181004 239481 at FAM133A amily with sequence similarity 133, member A 4.33493 1569025 S at FAM13A1 amily with sequence similarity 13, member A1 57074 222291 at FAM149A amily with sequence similarity 149, member A 2.OOO81 214825 at FAM15SA amily with sequence similarity 155, member A 68899 23O869 at FAM15SA amily with sequence similarity 155, member A 4.255.08 242687 at FAM160A1 amily with sequence similarity 160, member A1 63O33 US 2016/02375O1 A1 Aug. 18, 2016 46

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 213304 at FAM179B amily with sequence similarity 179, member B -1.60915 230539 at FAM182A amily with sequence similarity 182, member A 57619 216053 X at FAM182A CDNA FLJ38374 fis, clone FEBRA2002552 .70S61 222205 x at FAM182B if amily with sequence similarity 182, member B i? hypothetical 2.46888 RP13-401N8.2 gene Supported by 234945 at FAM54A amily with sequence similarity 54, member A 2.366O2 234331 s at FAM84A amily with sequence similarity 84, member A 85031 1555538 s at FAM9B amily with sequence similarity 9, member B 61504 156.8889 at EANCD2 Fanconi anemia, complementation group D2 62O37 1568891 x at FANCD2 Fanconi anemia, complementation group D2 2.51522 239246 a FARP1 CDEP 90491 201579 a FAT1 FAT tumor Suppressor homolog 1 (Drosophila) 2.291.59 1558964 at FAT3 FAT tumor suppressor homolog 3 (Drosophila) 55.077 1560490 at FAT3 FAT tumor suppressor homolog 3 (Drosophila) 791.33 236029 a FAT3 FAT tumor suppressor homolog 3 (Drosophila) 4.17669 233O87 a FBXL17 F-box and leucine-rich repeat protein 17 834O2 218875 s at FBXO5 F-box protein 5 -16348 2244.02 s at FCRL4 Fc receptor-like 4 666O1 224403 a FCRL4 Fc receptor-like 4 3.64968 1555.136 at FGD6 FYVE, RhoGEF and PH domain containing 6 2.22566 214589 a FGF12 fibroblast growth factor 12 87587 231523 a FGF14 fibroblast growth factor 14 2.OO116 214284 S at FGF18 Fibroblast growth factor 18, mRNA (cDNA clone MGC: 10529 S4O76 MAGE: 3948893) 220394 a FGF2O fibroblast growth factor 20 85663 210311 a FGF5 fibroblast growth factor 5 599.13 205782 a. FGF7 fibroblast growth factor 7 (keratinocyte growth factor) 67479 239710 a FIGN idgetin 4.1857 238964 a FIGN fidgetin 2.65603 1556325 at FILIP1 filamin A interacting protein 1 2.16122 1570515 a. at FILIP1 filamin A interacting protein 1 86592 223667 a FKBP7 FK506 binding protein 7 51179 220828 S. at FLJ11292 hypothetical protein FLJ11292 81486 215187 a FLJ11292 hypothetical protein FLJ11292 2.15766 1564160 at FLJ16686 FLJ16686 protein 795.97 234830 a. FLJ2O518 similar to FSHD region gene 2 protein 2.17839 221172 a FL21075 hypothetical protein FLJ21075 7343 233604 a FLJ22763 hypothetical gene Supported by AK026416 2.69416 217016 x at FLJ23172 fif hypothetical LOC389177 fit transmembrane protein 212 .74S1 TMEM212 553614 a at FLJ25694 hypothetical protein FLJ25694 723 241953 a FLJ25694 hypothetical protein FLJ25694 ft keratin associated protein 21-1 67966 KRTAP21-1 557155 a. at FLJ30375 CDNA clone IMAGE: 5301781 2.6058 241440 a FLJ30375 hypothetical gene Supported by AKO54937 2.70383 236739 a FLJ30594 CDNA FLJ34044 fis, clone FCBBF2007080 3.41974 553775 at FLJ31715 hypothetical protein FLJ31715 -1.57858 553354 a at FLJ31958 hypothetical protein FLJ31958 1.71642 230047 a FLJ32810 hypothetical protein FLJ32810 1.76353 553472 at FLJ32955 hypothetical protein FLJ32955 26SOS4 569378 at FLJ33297 CDNA FLJ33297 fis, clone BNGH42001406 1.76909 553335 x at FLJ34.047 hypothetical protein FLJ34.047 1.59989 5592.77 at FLJ357OO hypothetical protein FLJ35700 166616 557206 at FLJ35848 hypothetical protein FLJ35848 2.97097 566480 x at FLJ35848 Hypothetical protein FLJ35848, mRNA (cDNA clone 2.19166 MAGE: 5402642) 557895 at FLJ35934 FLJ35934 protein 2.05515 561171 a. at FLJ36131 if hypothetical protein FLJ36131 fill hypothetical protein 1.78.937 LOC100131452, . LOC100131452 transmem LOC10O132O2S LOC10O132S66, LOC10O132727 LOC729272 1560790 at FLJ36144 hypothetical protein FLJ36144 2.06719 1556558 s at FLJ36665 hypothetical protein FLJ36665 -1.73079 231527 at FLJ36840 CDNA FLJ36840 fis, clone ASTRO2O11461 1.66566 1558579 at FLJ37786 hypothetical LOC642691 2.45337 242683 at FLJ38028 hypothetical gene Supported by AKO95347 1.51579 242546 at FLJ39632 hypothetical LOC642477 2.2O629 239010 at FLJ39632 CDNA clone IMAGE: 5270501 2.23008 231882 at FLJ39632 hypothetical LOC642477 i? similar to double homeobox A 2.09022 LOC100131139 US 2016/02375O1 A1 Aug. 18, 2016 47

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1566665 at FLJ4O176 hypothetical LOC121951 68357 1568698 at FLJ43O8O hypothetical protein LOC642987 2.07737 1565786 X at FLJ45482 hypothetical LOC645566 6O292 240259 a FLRT2 CDNA FLJ51243 complete cols, highly similar to Leucine-rich 2.20213 repeat transmembrane 219250 S at FLRT3 fibronectin leucine rich transmembrane protein 3 59215 1559244 at FMN2 ormin 2 2.22149 223618 a FMN2 ormin 2 85.606 231231 a FMNL3 KIAA2014 protein 2.66876 226930 a. FNDC1 fibronectin type III domain containing 1 783S4 217483 a FOLH1 olate hydrolase (prostate-specific membrane antigen) 1 241619 217487 x at FOLH1 olate hydrolase (prostate-specific membrane antigen) 1 4.54562 40284 at FOXA2 orkhead box A2 3.21218 1553613 s at FOXC1 orkhead box C1 888.1 206018 a FOXG1 orkhead box G1 85819 235201 a FOXP2 orkhead box P2 2.75837 1555352 at FOXP2 orkhead box P2 71.66 230964 a FREM2 FRAS1 related extracellular matrix protein 2 4.O3728 243689 s at FRG1B Hypothetical protein LOC283788, mRNA (cDNA clone 2.17705 MGC: 23868 IMAGE:4297267) 234949 a FRG1B Hypothetical protein LOC283788, mRNA (cDNA clone 2.27959 MGC: 23868 IMAGE:4297267) 207178 s at F yn-related kinase 187638 1570207 at FRRS1 erric-chelate reductase 1 2.89483 1562625 at FRYL FRY-like 1993.42 244419 a FRZB Fritz 1.54036 230904 a FSD1 L, fibronectin type III and SPRY domain containing 1-like -199072 223985 a FSD1 L, fibronectin type III and SPRY domain containing 1-like 1.83509 207345 a. FST ollistatin 2.76648 203705 s at FZD7 rizzled homolog7 (Drosophila) 1.55517 1553.024 at G30 protein LG30-like 2.51805 22218.7 x at G3BP1 GTPase activating protein (SH3 domain) binding protein 1 16230S 206952 a G6PC glucose-6-phosphatase, catalytic subunit 2.12833 23.8569 a GABBR1 GABA-BR1a (hGB1a) receptor -161754 209990 s. at GABBR2 gamma-aminobutyric acid (GABA) B receptor, 2 1.59875 233437 a GABRA4 gamma-aminobutyric acid (GABA) A receptor, alpha 4 3.25934 207010 a GABRB1 gamma-aminobutyric acid (GABA) A receptor, beta 1 2.42007 242344 a GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 S.10676 1557122 s at GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 8.54122 229724 a GABRB3 gamma-aminobutyric acid (GABA) A receptor, beta 3 1.55943 1563533 at GADL1 glutamate decarboxylase-like 1 4.0883 208283 a GAGE1 Gantigen 1 2.39924 2O7739 s at GAGE1 if Gantigen 1 if G antigen 12F if G antigen 12G // G antigen 12I 2.7548 GAGE12F if G antigen GAGE12G if GAGE12I GAGE12J GAGE2A GAGE2B GAGE2C GAGE2D GAGE2E GAGE3 GAGE4 GAGES GAGE6 GAGE7 GAGE8 237183 at GALNTS CDNA FLJ75131 complete cols, highly similar to Homo sapiens 1.57858 UDP-N-acetyl-alpha-D- 240390 at GALNTS UDP-N-acetyl-alpha-D-galactosamine: polypeptide N- 4.19183 acetylgalactosaminyltransferase 236361 at GALNTL2 UDP-N-acetyl-alpha-D-galactosamine: polypeptide N- 1.9112 acetylgalactosaminyltransferase 22O124 at GAN gigaxonin 1.78227 204,471 at GAP43 growth associated protein 43 1.67109 21995.4 S at GBA3 glucosidase, beta, acid 3 (cytosolic) 1.56599 230788 at GCNT2 glucosaminyl (N-acetyl) transferase 2, I-branching enzyme (I -1.71,043 blood group) 236548 at GIPC2 GIPC PDZ domain containing family, member 2 2.02931 230258 at GLIS3 GLIS family Zinc finger 3 2.8996 244680 at GLRB glycine receptor, beta 190493 235371 at GLT8D4 glycosyltransferase 8 domain containing 4 1.SSO1 US 2016/02375O1 A1 Aug. 18, 2016 48

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1554712 a. at GLYATL2 glycine-N-acyltransferase-like 2 2.06041 204763 s at GNAO1 guanine nucleotide binding protein (G protein), alpha activating 2.09.098 activity polype 229274 at GNAS Adenyl cyclase mRNA 62372 207166 at GNGT1 guanine nucleotide binding protein (G protein), gamma 92.988 transducing activity polyp 204324 S at GOLIM4 golgi integral membrane protein 4 65786 1555199 at GOSR1 golgi SNAP receptor complex member 1 3.06916 1553879 a. at GOT1L1 glutamic-oxaloacetic transaminase 1-like 1 S9882 1553878 at GOT1L1 glutamic-oxaloacetic transaminase 1-like 1 95653 215.554 a GPLD1 glycosylphosphatidylinositol specific phospholipase D1 S4336 236024 a GPM6A glycoprotein M6A 2.04441 212950 a GPR116 G protein-coupled receptor 116 S2S24 212951 a GPR116 G protein-coupled receptor 116 57258 15551 22 at GPR12S G protein-coupled receptor 125 2.42496 233887 a GPR126 G protein-coupled receptor 126 58837 1553.025 at GPR126 G protein-coupled receptor 126 68374 209631 S. at GPR37 G protein-coupled receptor 37 (endothelin receptor type B-like) S6859 219898 a GPR85 G protein-coupled receptor 85 2.09828 238.049 a GRAMD3 GRAM domain containing 3 2.61.185 206204 a GRB14 growth factor receptor-bound protein 14 2.23024 235504 a GREM2 gremlin 2, cysteine knot Superfamily, homolog (Xenopus laevis) SO319 219388 a GRHL2 grainyhead-like 2 (Drosophila) 2.33499 205358 a GRIA2 glutamate receptor, ionotropic, AMPA2 2.02789 206730 a. GRIA3 glutamate receptor, ionotrophic, AMPA 3 2.12652 213845 a. GRIK2 glutamate receptor, ionotrophic, kainate 2 74884 205814 a GRM3 glutamate receptor, metabotropic 3 2.30621 207235 S. at GRMS glutamate receptor, metabotropic 5 2.95593 207548 a GRM7 glutamate receptor, metabotropic 7 64049 216992 S at GRM8 glutamate receptor, metabotropic 8 54.515 235387 a GSTCD glutathione S-transferase, C-terminal domain containing 51561 242656 a GTF2H1 General transcription factor IIH, polypeptide 1, 62 kDa 65352 (GTF2H1), transcript vari 204237 a GULP1 GULP, engulfment adaptor PTB domain containing 1 726 204235 s at GULP1 GULP, engulfment adaptor PTB domain containing 1 67838 215695 S at GYG2 glycogenin 2 67125 1559520 at GYPA Glycophorin A 3.86167 205523 a HAPLN1 hyaluronan and proteoglycan link protein 1 5O177 230895 a HAPLN1 hyaluronan and proteoglycan link protein 1 2.33681 232848 a hCG 1795283 hCG1818.123 60873 232239 a hCG 2024094 hCG2024094 88O82 216229 X at HCG2P7 HLA complex group 2 pseudogene 7 77053 1556351 at HCN1 hyperpolarization activated cyclic nucleotide-gated potassium 2.3437 channel 1 232414 a HEATR1 HEAT repeat containing 1 S2452 210331 a HECW1 HECT, C2 and WW domain containing E3 ubiquitin protein 90413 ligase 1 233075 a. HERC2P7 hect domain and RLD 2 pseudogene 7 S846S 1555318 at HIF3A hypoxia inducible factor 3, alpha Subunit 241676 216548 x at HMG4L high-mobility group (nonhistone chromosomal) protein 4-like 683O8 228772 a HNMT histamine N-methyltransferase .93357 217353 a HNRNPA1 heterogeneous nuclear ribonucleoprotein A1 if heterogeneous 6O11 HNRNPA1L2 nuclear ribonucleop if HNRPA1L-2 if HNRPA1PS J. LOC10O128836 J. LOC12O364 J. LOC391670 J. LOC4O2112 J. LOC44O12S J. LOC642817 J. LOC643O33 J. LOC644037 J. LOC645OO1 J. LOCA2817O J. LOCA28643 LOC7287.32 J. LOCA291.02 J. LOCA29366 J. LOCA3O246 227566 at HNT neurotrimin 2.73516 213793 s at HOMER1 homer homolog 1 (Drosophila) 191311 US 2016/02375O1 A1 Aug. 18, 2016 49

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1566140 at HOPX HOP homeobox .731.84 218959 a HOXC10 homeobox C10 72818 206858. S. at HOXC4 homeobox C4 homeobox C6 2.37146 HOXC6 2294.00 a HOXD10 homeobox D10 2.16969 219985 a HS3ST3A1 heparan Sulfate (glucosamine) 3-O-sulfotransferase 3A1 658O8 232276 a HS6ST3 heparan sulfate 6-O-sulfotransferase 3 2.29584 206639 x at HTN1 histatin 1 S6385 206.786 a HTN3 histatin 3 2.99589 207577 a HTR4 5-hydroxytryptamine (serotonin) receptor 4 SS186 211740 a CA1 islet cell autoantigen 1, 69 kDa 2.1923 213450 s at COSLG inducible T-cell co-stimulator ligand -156491 209291 a D4 inhibitor of DNA binding 4., dominant negative helix-loop-helix 2.00627 protein 236478 a FNAR1 Interferon (alpha, beta and omega) receptor 1, mRNA (cDNA -1.50715 clone IMAGE: 4391580) 209540 a GF1 insulin-like growth factor 1 (Somatomedin C) 221842 211959 a GFBP5 insulin-like growth factor binding protein 5 8742 214973 X at IGHD immunoglobulin heavy constant delta -181338 220567 a KZF2 IKAROS family Zinc finger 2 (Helios) S3299 205992 S at IL15 interleukin 15 -1.73897 220663 a L1RAPL1 interleukin 1 receptor accessory protein-like 1 2.89062 222698 S. at IMPACT Impact homolog (mouse) -154815 222250 S at INTS7 integrator complex subunit 7 -1.53873 228946 a NTU inturned planar cell polarity effector homolog (Drosophila) 66051 1557770 at PO11 importin 11 2.19277 24-1834 a PW imprinted in Prader-Willi syndrome (non-protein coding) 2.05282 229538 s at IQGAP3 IQ motif containing GTPase activating protein 3 2.32378 1553949 at QSEC3 IQ motif and Sec7 domain 3 82434 242694 a QSEC3/// IQ motif and Sec7 domain 3 i? similar to IQ motif and Sec7 2.81166 LOC10O134209 domain-containing pr LOC731035 1568924 a at IQUB IQ motif and ubiquitin domain containing 2.23724 206104 a SL1 ISL LIM homeobox 1 2.04554 242982 x at ITGB8 integrin, beta 8 1.72645 1557080 S at ITGBL1 integrin, beta-like 1 (with EGF-like repeat domains) 1.58327 214927 a TGBL1 integrin, beta-like 1 (with EGF-like repeat domains) 2.53432 242788 a MD2D jumonji domain containing 2D 1.7149 216763 a KANK1 KN motif and ankyrin repeat domains 1, mRNA (cDNA clone 1.90238 MGC: 43128 IMAGE: 5261060) 229125 a. KANK4 KN motif and ankyrin repeat domains 4 2.24666 1555673 at KAP2.1B keratin associated protein 2.1B keratin associated protein 2-4 1991 O7 KRTAP2-4 fit hypotheti LOC6443SO LOC72828S LOC728934 LOC730755 208123 a KCNB2 potassium voltage-gated channel, Shab-related Subfamily, 2.26862 member 2 1555074 a at KCNHS potassium voltage-gated channel, Subfamily H (eag-related), 2.34582 member 5 240591 a KCNIP4 CDNA FLJ59677 complete cols, highly similar to Kv channel- 77751 interacting protein 4 210179 a KCNJ13 potassium inwardly-rectifying channel, Subfamily J, member 13 61478 219564 a KCN16 potassium inwardly-rectifying channel, Subfamily J, member 16 2.4536 208404 x at KCNJS potassium inwardly-rectifying channel, Subfamily J, member 5 S2838 2444.55 a. KCNT2 potassium channel, Subfamily T, member 2 .96504 222664 a KCTD15 potassium channel tetramerisation domain containing 15 -1.52793 222668 a KCTD15 potassium channel tetramerisation domain containing 15 -153961 209781. S. at KHDRBS3 KH domain containing, RNA binding, signal transduction 64262 associated 3 207161 a KIAAO087 KIAAO087 89736 227231 a KIAA1211 KIAA1211 protein 60476 232762 a KIAA1217 KIAA1217 727 235956 a KIAA1377 KIAA1377 S9988 233977 a KIAA1772 KIAA1772 SO426 236518 a KIAA1984 KIAA1984 -158518 244427 a KIF23 Mitotic kinesin-like protein-1 (MKLP-1 gene) 2.120SS 220652 a KIF24 kinesin family member 24 S9148 234307 s at KIF26A kinesin family member 26A -1.736O7 220657 a KLHL11 kelch-like 11 (Drosophila) -1.60971 210634 a KLHL2O kelch-like 20 (Drosophila) -158643 US 2016/02375O1 A1 Aug. 18, 2016 50

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1553873 at KLHL34 kelch-like 34 (Drosophila) 61075 211138 s at KMO kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) -1.69994 205306 X at KMO kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) -1.72294 243998 a KRT222P keratin 222 pseudogene 64083 210662 a KYNU kynureninase (L-kynurenine hydrolase) -2.07S3 1552490 at LACE1 actation elevated 1 753 215516 a LAMB4 aminin, beta 4 2.22608 229953 x at LCA5 Leber congenital amaurosis 5 5775 213371 a LDB3 LIM domain binding 3 4.85498 207409 a LECT2 eukocyte cell-derived chemotaxin 2 3.74939 207092 a LEP eptin 65443 236761 a LHFPL3 ipoma HMGIC fusion partner-like 3 S7304 206140 a LHX2 LIM homeobox2 3.42338 225571 a LIFR eukemia inhibitory factor receptor alpha 2.72636 212328 a LIMCH1 LIM and calponin homology domains 1 .8332 212327 a LIMCH1 LIM and calponin homology domains 1 2.30917 212325 a. LIMCH1 LIM and calponin homology domains 1 61665 232457 a LIMCH1 LIM and calponin homology domains 1, mRNA (cDNA clone 61154 MGC: 16598 IMAGE: 4110496) 2198.23 a LIN28 in-28 homolog (C. elegans) 63702 229349 a LIN28B in-28 homolog B (C. elegans) 2.03446 241957 X at LIN7B in-7 homolog B (C. elegans) -1.54121 219181 a LIPG ipase, endothelial 55778 242178 a LIPI ipase, member I 97767 216543 a LOC100093.698 unknown transcript S3623 217655 a. LOC10O127972 hypothetical LOC100127972 -167943 224095 a LOC100128175 similar to PRO2591 71793 207478 a LOC100128329 similar to PRO2958 77.096 229999 a LOC100128416 Full length insert cDNA clone ZE12A08 -151964 215590 X at LOC100128640 PREDICTED: Homo sapiens hypothetical protein 71347 LOC100128640 (LOC100128640), mRNA 240395 a LOC100128727 hypothetical LOC100128727 SO691 244723 a LOC100129488 hypothetical protein LOC100129488 4.896.76 244518 a LOC10O130452 similar to hCG1777700 67252 1560425 s at LOC10013O868 hypothetical protein LOC100.130868 784 215301 a LOC10O130958 hypothetical protein LOC100.130958 2.02489 1565814 at LOC100131040 hypothetical protein LOC100131040 fit tripartite motif- 71106 fif TRIM36 containing 36 211341 a LOC100131317 similar to hCG1781.072 POU class 4 homeobox 1 S7041 POU4F1 237711 a LOC100131980 similar to zinc finger protein 705A zinc finger protein 705G- .78O11 ZNF705G ike 156117O at LOC10O132O2S transmembrane domain-containing protein ENSP00000320207- 2.28603 ike 236181 a LOC10O1321.81 PREDICTED: Homo sapiens hypothetical protein 2.60614 LOC100132181 (LOC1001321.81), mRNA 243336 a LOC10O132726 hypothetical protein LOC100.132726 -155162 1558.640 a. at LOC10O132788 MRNA (fetal brain cDNA e2 2g) 3.6619 24-1821 a LOC10O132894 hypothetical protein LOC100132894 3.24.026 227631 a LOC10O133283 PREDICTED: Homo sapiens hypothetical protein 1.S8351 LOC100133283 (LOC100133283), mRNA 224110 a LOC10O133319 PRO1804 18742S 1562974 at LOC10O133899 hypothetical protein LOC100.133899 18921 1556.704 s at LOC10O133920 hypothetical protein LOC100.133920 i? hypothetical protein 2.36676 J. LOC286297 LOC286.297 1557617 at LOC100189589 hypothetical LOC100189589 2.06679 229994 at LOC10O190890 MRNA, cDNA DKFZp686.J23256 (from clone 200185 DKFZp686.J23256) 234493 at LOC116437 hypothetical protein LOC116437 1.59059 2424.69 at LOC12O376 Uncharacterized protein LOC120376 (LOC120376), mRNA 1.77817 1555.988 a. at LOC126536 hypothetical protein LOC126536 2.167 22.9178 at LOC145786 hypothetical protein LOC145786 1.58445 229.073 at LOC145786 CDNA FLJ13221 fis, clone NT2RP4002075 3.33323 232450 at LOC149351 hypothetical protein LOC149351 185318 1561343 a at LOC15.0005 hypothetical protein LOC15.0005 186593 239965 at LOC151878 hypothetical protein LOC151878 2.92.204 215978 x at LOC152719 hypothetical protein LOC152719 1.56227 239691 at LOC1964.15 hypothetical protein LOC1964.15 1.53729 232370 at LOC2S4OS7 hypothetical protein LOC254.057 1.63OS 15625O1 at LOC255.177 hypothetical protein LOC255.177 1666.18 1562527 at LOC283O27 hypothetical protein LOC283027 5.38799 156385.4 S at LOC283045 hypothetical protein LOC283045 1.5O235 US 2016/02375O1 A1 Aug. 18, 2016 51

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 558195 a LOC2834.04 hypothetical protein LOC2834.04 2.28078 556425 a. at LOC284219 hypothetical protein LOC284219 2.26468 214162 at LOC284244 hypothetical protein LOC284244 3.07805 563009 a LOC284930 Homo sapiens, clone IMAGE: 5538478, mRNA 86884 557267 s at LOC284952 hypothetical protein LOC284952 61866 557570 a. at LOC285084 hypothetical protein LOC285084 2.389.31 558601 a LOC285.194 hypothetical LOC285.194 54.813 556528 a LOC285326 hypothetical protein LOC285326 57.263 561096 a LOC285419 hypothetical protein LOC285419 77787 557107 a LOC286OO2 hypothetical protein LOC286002 8.8346 556573 s at LOC2861.78 hypothetical protein LOC286.178 76489 556421 a. LOC286189 hypothetical protein LOC286189 2.18301 240545 at LOC286.382 hypothetical protein LOC286382 .91794 557717 a LOC338862 hypothetical protein LOC338862 3.97958 557534 a LOC339862 hypothetical protein LOC339862 S1746 560823 a LOC34.0017 hypothetical protein LOC34.0017 2.06515 563589 a LOC340184 hypothetical protein LOC340184 9 557664 a LOC34O239 PREDICTED: Homo sapiens hypothetical protein LOC340239, 67247 transcript variant 2 (LO 559002 a LOC340544 hypothetical protein LOC340544 -15369 235606 at LOC344595 hypothetical LOC344595 S.656O1 563022 a. LOC34747S UPF0625 coiled-coil domain-containing protein 2.7715 ENSPOOOOO3S9845 558423 a LOC349114 Homo sapiens, clone IMAGE: 4385460, mRNA 6894 233879 at LOC374491 TPTE and PTEN homologous inositol lipid phosphatase 2.23S13 pseudogene 558982 a. LOC37SO10 hypothetical LOC375010 2.624O7 558425 X at LOC388312 hypothetical LOC388312 / hypothetical LOC728417 /// 50876 LOC728417 hypothetical LOC729737 // LOC729737 LOC73O235 56O773 at LOC388458 hypothetical gene Supported by BC040718 991.59 56O119 at LOC389634 hypothetical LOC389634 S6826 226582 at LOC4OOO43 hypothetical gene Supported by BC0093.85 76427 561414 at LOC4O1497 similar to PRO2738 2.43388 561997 at LOC44OO61 PREDICTED: Homo sapiens misc RNA (LOC440061), 61784 miscRNA 240268 at LOC44O117 hypothetical gene Supported by BC037858 82436 214984 at LOC440345 hypothetical protein LOC440345 4.24873 244766 at LOC44O3S4 PI-3-kinase-related kinase SMG-1 pseudogene if PI-3-kinase- 64874 LOCS951O1 if related kinase SMG-1 LOC641298 LOC728423 LOC729513 SMG1 216193 at LOC440366 hect domain and RLD 2 pseudogene 181363 1562558 at LOC44O704 hypothetical gene Supported by BC042042 240362 224426 S. at LOC440888 ARP3 actin-related protein 3 homolog B pseudogene 3.36427 224424 x at LOC440888 ARP3 actin-related protein 3 homolog B pseudogene 2.83853 224425 X at LOC440888 ARP3 actin-related protein 3 homolog B pseudogene 3.33132 229.095 S at LOC440895 LIM and Senescent cell antigen-like domains 3-like 2.24538 222207 X at LOC441258 CDNA: FLJ20949 fis, clone ADSEO1902 1.70745 220771 at LOCS1152 melanoma antigen 2.14963 220893 at LOC57399 uncharacterized gastric protein ZA52P 1.76081 559459 at LOC613266 hypothetical LOC613266 -2.71264 561098 at LOC641365 hypothetical protein LOC641365 1.59224 562223 at LOC642426 hypothetical LOC642426 2.36874 554996 at LOC643955 ; ; ; Zinc finger protein 479 pseudogene if zinc finger protein 479 fif 3.79321 ZNF479 Zinc finger p ZNF727 215625 at LOC644,450 hypothetical protein LOC644450 1S6SO2 566145 S. at LOC6444.50 hypothetical protein LOC644450 2.02346 227976 at LOC644538 hypothetical protein LOC644538 1.58277 230902 at LOC645323 CDNA clone IMAGE: 5260726 2.44976 238850 at LOC645323 hypothetical LOC645323 2.41121 561760 s at LOC645513 CDNA clone IMAGE: 5276804 -1.54359 564200 at LOC646.324 hypothetical LOC646324 1944.25 568933 at LOC646627 phospholipase inhibitor 190895 215467 x at LOC647070 hypothetical LOC647070 1.696.76 561492 at LOC647107 hypothetical protein LOC647107 4.0125 232696 at LOC648SS6 uncharacterized gastric protein ZA43P 2.36O77 US 2016/02375O1 A1 Aug. 18, 2016 52

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 217998 at LOC652993 hypothetical LOC652993 fit pleckstrin homology-like domain, 157414 PHILDA1 amily A, member 1 1557094 at LOC653110 hypothetical LOC653110 S.12803 243124 at LOC653390 RRN3 RNA polymerase I transcription factor homolog (S. cerevisiae) -1.5339 pseudogene 216469 at LOC727867 similar to PRED65 // zinc finger protein ENSPOOOOO344568-like 1.70529 LOC7295O1 if if similar to PR LOC7298.63 ZNF834 1559322 at LOC727916 hypothetical protein LOC727916 1.58056 1564856 S at LOC727924 hypothetical LOC727924 fit olfactory receptor, family 4, 2.1379 OR4N4 Subfamily N, member 4 1558828 S. at LOC728264 CDNA FLJ36638 fis, clone TRACH2O18950 1. SO367 231434 at LOC728460 similar to FLJ32921 protein 2.51418 1559276 at LOC728606 hypothetical LOC728606 1.59845 234562 x at LOC728678 PREDICTED: Homo sapiens misc RNA (LOC728678), 2.04.162 miscRNA 15664.65 at LOC728.987 MRNA, cDNA DKFZp686I1934 (from clone DKFZp686I1934) 2.74.786 214375 at LOC729.222 similar to mKIAA1230 protein ( / PTPRF interacting protein, 3.23314 PPFIBP1 binding protein 1 (1 22O167 s at LOC729355 similar to TP53TG3 protein / TP53 target 3 2.68644 TP53TG3 1563637 at LOC729652 hypothetical protein LOC729652 1.57589 237899 a LOC72.9994 hypothetical LOC72.9994 -150022 233249 a LOC73O2OO PREDICTED: Homo sapiens hypothetical LOC730200 3.67813 (LOC730200), mRNA 237312 a LOC731477 hypothetical protein LOC731477 162866 1570009 at LOC732.096 similar to hCG2040240 4.14937 1563528 at LOC91149 hypothetical protein LOC91149 1.62561 1557523 at LOC92270 V-type proton ATPase subunit S1-like protein 2.32742 2348.61 a LOC93463 hypothetical protein LOC93463 182869 220244 a LOH3CR2A oss of heterozygosity, 3, chromosomal region 2, gene A 2.474.24 235977 a LONRF2 LON peptidase N-terminal domain and ring finger 2 2.03367 206960 a LPAR4 ySophosphatidic acid receptor 4 4.O8642 209866 s at LPHN3 atrophilin 3 3.07.024 23.0644 a LRFNS eucine rich repeat and fibronectin type III domain containing 5 2.28648 2308.63 a LRP2 ow density lipoprotein-related protein 2 2.0802 1562939 at LRRC16A eucine rich repeat containing 1.6A 74525 216149 a LRRC37B2 eucine rich repeat containing 37, member B2 2.36761 232226 a LRRC4C eucine rich repeat containing 4C 2.77481 1556427 s at LRRN4CL LRRN4 C-terminal like 552.75 206144 a MAGI1 membrane associated guanylate kinase, WW and PDZ domain 70898 containing 1 225465 a MAGI1 membrane associated guanylate kinase, WW and PDZ domain 58332 containing 1 226084 a MAP1B microtubule-associated protein 1B 2.916O1 1562440 at MAP3K13 Leucine Zipper bearing kinase 84582 1565131 x at MAP3K2 mitogen-activated protein kinase kinase kinase 2 69787 1552928 s at MAP3K7IP3 mitogen-activated protein kinase kinase kinase 7 interacting -1.70651 protein 3 235066 a MAP4 microtubule-associated protein 4 89346 235141 a MARVELD2 MARVEL domain containing 2 74329 233634 a MARVELD3 MARVEL domain containing 3 65824 205018 s at MBNL2 muscleblind-like 2 (Drosophila) -160512 1554.604 at MBTPS2 membrane-bound transcription factor peptidase, site 2 S1324 214884 a MCF2 DBL mRNA for DBL proto-oncogene splicing variant 1 971.03 1559.427 at MCF2L KIAA0362 gene SSO68 229797 a MCOLN3 mucolipin 3 -2.39333 212732 a MEG3 maternally expressed 3 (non-protein coding) 61766 235.077 a MEG3 maternally expressed 3 (non-protein coding) 2.45959 207480 S. at MEIS2 Meis homeobox2 83267 214077 x at MEIS3P1 Meis homeobox 3 pseudogene 1 9.0099 211424 x at METTL7A methyltransferase like 7A 240031 240814 a MGC39584 hypothetical gene Supported by BCO29568 77085 238.481 a MGP matrix Gla protein 57297 203637 s at MID1 midline 1 (Opitz/BBB syndrome) 2.07411 1552572 a at MIPOL1 mirror-image polydactyly 1 .96747 2394.68 a MKX mohawk homeobox 2.02738 238.257 a MLLT10 Zinc fingerfleucine zipper protein (AF10) 6337 1569998 at MMD2 monocyte to macrophage differentiation-associated 2 60681 207012 a MMP16 matrix metallopeptidase 16 (membrane-inserted) 87224 208166 a MMP16 matrix metallopeptidase 16 (membrane-inserted) 2.SS4O2 204575 s at MMP19 matrix metallopeptidase 19 -1.70549 US 2016/02375O1 A1 Aug. 18, 2016 53

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 220541 at MMP26 matrix metallopeptidase 26 7046 221 636 S. at MOSC2 MOCO Sulphurase C-terminal domain containing 2 -1522 215692 s at MPPED2 metallophosphoesterase domain containing 2 2.926S 205395 s at MRE11A MRE 11 meiotic recombination 11 homolog A (S. cerevisiae) -1.60992 220790 s. at MS4A5 membrane-spanning 4-domains, Subfamily A, member 5 S1834 228473 at MSX1 CDNA FLJ75656 complete cols, highly similar to Homo sapiens 71357 mish homeo box homolog 205932 s at MSX1 msh homeobox. 1 2.16058 210319 X at MSX2 msh homeobox2 6O287 242996 at MTRF1 mitochondrial translational release factor 1 -1.776O1 205675 at MTTP microsomal triglyceride transfer protein 62.218 227241 at MUC15 mucin 15, cell Surface associated 842O6 216188 at MYCNOS v-myc myelocytomatosis viral related oncogene, neuroblastoma .93694 derived (avian) opp 1568926 x at MYLK3 myosin light chain kinase 3 2O3O24 1568925 at MYLK3 myosin light chain kinase 3 89636 1561503 at MYLK4 myosin light chain kinase family, member 4 S1904 237510 a MYNN Myoneurin, mRNA (cDNA clone IMAGE: 4721583) 2.07478 244350 a MYO10 myosin X 2.7656 1554026 a. at MYO10 myosin X 216462 1570141 at MYOSB myosin VB 2.21328 211103 a MYO7A myosin VIIA -164785 216660 a MYO7B myosin VIIB S4433 1554507 at NAALAD2 N-acetylated alpha-linked acidic dipeptidase 2 87347 233815 a. NAALAD2 N-acetylated alpha-linked acidic dipeptidase 2 93112 228.608 a NALCN Sodium leak channel, non-selective 69469 242880 a NALCN Sodium leak channel, non-selective .75222 22O184 a NANOG Nanog homeobox 24O254 242639 a NARG2 NMDA receptor regulated 2 98876 236141 a NBLAOO3O1 NbaOO3O1 84851 237,917 a NBPF8 neuroblastoma breakpoint family, member 8 -1.8445 1563728 at NCRNA00032 non-protein coding RNA32 54507 1559292 S at NCRNA00032 Clone IMAGE: 2275835 C9orf14 mRNA, partial sequence: 2.20902 alternatively splice 231491 a NCRNA00113 non-protein coding RNA 113 2.20943 1569882 at NCRNAOO119 non-protein coding RNA 119 SO636 220429 a NDST3 N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3 2.41867 2294.61 x at NEGR1 neuronal growth regulator 1 53956 204641 a NEK2 NIMA (never in mitosis genea)-related kinase 2 .82S42 206089 a NELL1 NEL-like 1 (chicken) 9916 213438 a NEASC neurofascin homolog (chicken) S1334 214799 a NEASC neurofascin homolog (chicken) .742O7 236471 a NFE2L3 nuclear factor (erythroid-derived 2)-like 3 -194665 213033 s at NFIB nuclear factor IB S8491 233304 a NFIB HMGIC/NFIB fusion protein (HMGIC/NFIB) .71392 209289 a NFIB nuclear factor IB 2.33009 209290 s. at NFIB nuclear factor IB 3.26376 213032 a NFIB nuclear factor IB 3.91895 230291 s at NFIB HMGIC/NFIB fusion protein (HMGIC/NFIB) 2.58971 1555141 a. at NHEDC1 Na+ H+ exchanger domain containing 1 2.544OS 1553633 s at NHEDC1 Na+ H+ exchanger domain containing 1 2.24.905 1564746 at NHEDC2 Na+ H+ exchanger domain containing 2 S816 215228 at NHLH2 nescient helix loop helix 2 86841 15546O1 at NKAIN2 Na+/K+ transporting ATPase interacting 2 .76903 211024 S at NKX2-1 NK2 homeobox 1 7883 205893 at NLGN1 neuroligin 2.23.077 221933 at NLGN4X neuroligin 4, X-linked 7674 234762 x at NLN CDNA FLJ39097 fis, clone NTONG2000977, highly similar to 62853 Neurolysin, mitochondri 1552712 a. at NMNAT2 nicotinamide nucleotide adenylyltransferase 2 52782 206045. S. at NOL4 nucleolar protein 4 2.539 1560974 s at NOS1 nitric oxide synthase 1 (neuronal) 5825 232158 x at NPAL1 NIPA-like domain containing 1 .9677 22O128 S. at NPAL2 NIPA-like domain containing 2 -15032 220316 at NPAS3 neuronal PAS domain protein 3 .69165 229281 at NPAS3 neuronal PAS domain protein 3 8588 230412 at NPAS3 neuronal PAS domain protein 3 2.2537 211585 at NPAT nuclear protein, ataxia-telangiectasia locus 94524 23884.4 S at NPHP1 nephronophthisis 1 (juvenile) 2.41213 225911 at NPNT nephronectin 90656 219789 at NPR3 natriuretic peptide receptor Ciguanylate cyclase C 73795 (atrionatriuretic peptide rec US 2016/02375O1 A1 Aug. 18, 2016 54

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 207443 a NR2E1 nuclear receptor Subfamily 2, group E, member 1 876O7 209119 X at NR2F2 nuclear receptor Subfamily 2, group F, member 2 2.02969 215073 s at NR2F2 nuclear receptor Subfamily 2, group F, member 2 .9613S 209121 x at NR2F2 nuclear receptor Subfamily 2, group F, member 2 7412 208241 a NRG1 neuregulin 1 2.081 61 208062 S at NRG2 neuregulin 2 63978 206879 s at NRG2 neuregulin 2 72088 232771 a NRK Nik related kinase 88.843 209914 S at NRXN1 neurexin 1 67775 2285.47 a NRXN1 neurexin 1 66176 209915 S. at NRXN1 neurexin 1 S3885 229649 a NRXN3 neurexin 3 2.45512 229463 a NTRK2 neurotrophic tyrosine kinase, receptor, type 2 50597 207152 a NTRK2 neurotrophic tyrosine kinase, receptor, type 2 2.OO944 215311 a NTRK3 neurotrophic tyrosine kinase, receptor, type 3 65674 215025 a. NTRK3 neurotrophic tyrosine kinase, receptor, type 3 75126 562775 at NUDT12 nudix (nucleoside diphosphate linked moiety X)-type motif 12 2.25655 219347 a NUDT15 nudix (nucleoside diphosphate linked moiety X)-type motif 15 -1.5.1719 239748 x at OCLAD1 OCIA domain containing 1 SO742 231867 a ODZ2 odz, Odd Oziten-m homolog 2 (Drosophila) 3.26427 554524 a at OLFM3 olfactomedin 3 971.92 207093 s at OMG oligodendrocyte myelin glycoprotein -1904.09 239911 a ONECUT2 one cut homeobox2 56079 214111 a OPCML opioid binding protein cell adhesion molecule-like 3.06809 567657 at OR2H1 olfactory receptor, family 2, Subfamily H, member 1 5335 567656 at OR2H1 Olfactory receptor (6MI-16 gene), exon E variant 2 67337 567246 at ORSH1 olfactory receptor, family 5, Subfamily H, member 1 2.3913S 567247 at ORSH1 olfactory receptor, family 5, Subfamily H, member 1 2.43277 243531 at ORAOV1 oral cancer overexpressed 1 -1.53352 211213 at ORCSL origin recognition complex, Subunit 5-like (yeast) 73358 553931 at OSTCL oligosaccharyltransferase complex subunit-like 2.348O8 555251 a at OTOF otoferlin -190077 238994 at OTUD7B OTU domain containing 7B 54049 206048 at OVOL2 ovo-like 2 (Drosophila) 32046 238409 x at OXR1 oxidation resistance 1 2.67129 243335 at P4HA1 prolyl 4-hydroxylase, alpha polypeptide I 76.53 220403 s at PS3AIP1 p53-regulated apoptosis-inducing protein 1 58587 220402 at P53AIP1 p53-regulated apoptosis-inducing protein 1 2.962SS 242912 at P704P prostate-specific P704P 3.72956 1560770 at PABPC1 Poly(A) binding protein, cytoplasmic 1, mRNA (cDNA clone 63652 MGC: 12727 IMAGE: 4123269 238865 at PABPC4L poly(A) binding protein, cytoplasmic 4-like 2.101.9S 214607 at PAK3 p21 protein (Cdc42, Rac)-activated kinase 3 2.88671 210721 S at PAK7 p21 protein (Cdc42, Rac)-activated kinase 7 74992 228128 x at PAPPA pregnancy-associated plasma protein A, pappalysin 1 2.13807 1559400 S. at PAPPA pregnancy-associated plasma protein A, pappalysin 1 93398 22494.0 s at PAPPA pregnancy-associated plasma protein A, pappalysin 1 4.391.16 205834 S. at PART1 prostate androgen-regulated transcript 1 8141 210292 S at PCDH11X protocadherin 11 X-linked fit protocadherin 11 Y-linked 2.SS484 PCDH11 Y 205656 a PCDH17 protocadherin 17 SO888 227 289 a PCDH17 protocadherin 17 2.04806 225975 a. PCDH18 protocadherin 18 2.301.13 232054 a PCDH2O protocadherin 20 S9426 210273 a PCDHT protocadherin 7 72605 208.205 a PCDHA9 protocadherin alpha 9 54772 232415 a. PCDHB13 protocadherin beta 13 .76909 231726 a PCDHB14 protocadherin beta 14 621.33 232099 a PCDHB16 protocadherin beta 16 2.13788 223927 a PCDHB9 protocadherin beta 9 7009 234515 a. PCGEM1 prostate-specific transcript 1 (non-protein coding) 50251 210650 s at PCLO piccolo (presynaptic cytomatrix protein) 69469 242662 a PCSK6 PACE4A-II 2.30596 233547 X at PDE1A phosphodiesterase 1A, calmodulin-dependent 8O161 231213 a PDE1A phosphodiesterase 1A, calmodulin-dependent .75945 233549 a PDE1A phosphodiesterase 1A, calmodulin-dependent 694.46 208396 s at PDE1A phosphodiesterase 1A, calmodulin-dependent 2.26838 215575 a. PDE4DIP phosphodiesterase 4D interacting protein .793O2 231065 a PDE6D P17 protein -1.SSO18 1554828 at PDGFRA platelet-derived growth factor receptor, alpha polypeptide S3439 232288 a PDXDC1 pyridoxal-dependent decarboxylase domain containing 1 if 65294 PDXDC2 pyridoxal-dependent de US 2016/02375O1 A1 Aug. 18, 2016 55

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 238957 at PDXDC2 MRNA, cDNA DKFZp761H1120 (from clone 2.03644 DKFZp761H1120) 212092 at PEG10 paternally expressed 10 60907 23.0068 s at PEG3 KIAA0287 gene 82316 209243 s at PEG3 ZIM2 paternally expressed 3 Zinc finger, imprinted 2 2.16162 219642 s at PEXSL peroxisomal biogenesis factor 5-like 54143 222O19 at PFDN6 prefoldin subunit 6 -151654 24.0883 at PFKFB1 6-phosphofructo-2-kinasef fructose-2,6-bisphosphatase (EC S229 2.7.1.105, EC 3.1.3.46) 244321 at PGAP1 post-GPI attachment to proteins 1 62493 215179 x at PGF Placenta growth factor 2 (PIGF-2) S3586 1554560 at PGMS phosphoglucomutase 5 4.77525 1560431 at PGMSP1 phosphoglucomutase 5 pseudogene 1 502O7 234405 S at PHAX phosphorylated adaptor for RNA export -166337 1556,369 a. at PHKG2 phosphorylase kinase, gamma 2 (testis) -166594 210919 at PHLPP PH domain and leucine rich repeat protein phosphatase 2.708 217097 s at PHTF2 putative homeodomain transcription factor 2 S4839 237866 at PID1 phosphotyrosine interaction domain containing 1 S2656 1558292 s at PIGW phosphatidylinositol glycan anchor biosynthesis, class W -1.792S7 220041 at PIGZ phosphatidylinositol glycan anchor biosynthesis, class Z -1.7S754 215129 at PIK3C2G phosphoinositide-3-kinase, class 2, gamma polypeptide 96389 214868 at PIWIL1 piwi-like 1 (Drosophila) 2.16549 1563465 at PKD1L1 polycystic kidney disease 1 like 1 2.06488 203895 at PLCB4 phospholipase C, beta 4 68346 203896 S. at PLCB4 phospholipase C, beta 4 2.41741 240033 at PLG plasminogen S6995 207374 at PLSCR2 phospholipid scramblase 2 S6409 224421 X at PMCHL1 pro-melanin-concentrating hormone-like 1 2.02666 224418. X at PMCHL1 pro-melanin-concentrating hormone-like 1 90.155 224419 X at PMCHL1 pro-melanin-concentrating hormone-like 1 2.04898 224422 x at PMCHL2 pro-melanin-concentrating hormone-like 2 91294 206826 at PMP2 peripheral myelin protein 2 2.22591 219926 at POPDC3 popeye domain containing 3 64053 1555.778 a at POSTN periostin, osteoblast specific factor 55784 210809 s at POSTN periostin, osteoblast specific factor 68545 1569675 at POU2AF1 POU class 2 associating factor 1, mRNA (cDNA clone 2.487.84 MGC: 45211 IMAGE:5554.134) 207109 at POU2F3 POU class 2 homeobox 3 72743 207084 at POU3F2 POU class 3 homeobox2 .51578 219195 at PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 2.39587 alpha 232073 at PPFIA2 protein tyrosine phosphatase, receptor type, fpolypeptide 76444 (PTPRF), interacting 204517 at PPIC peptidylprolyl isomerase C (cyclophilin C) 2.51.701 236142 at PPIH U-SnRNP-associated cyclophilin (USA-CyP) -1.72474 223999 at PPIL2 peptidylprolyl isomerase (cyclophilin)-like 2 SOS 16 1555462 at PPP1R1C protein phosphatase 1, regulatory (inhibitor) Subunit 1C 2.33566 240187 at PPP1R3C protein phosphatase 1, regulatory (inhibitor) Subunit 3C S2454 202886 s at PPP2R1B protein phosphatase 2 (formerly 2A), regulatory Subunit A, beta -1.54317 isoform 220673 s at PPP4R4 protein phosphatase 4, regulatory subunit 4 97.256 230311 S. at PRDM6 PR domain containing 6 62777 238441 a PRKAA2 protein kinase, AMP-activated, alpha 2 catalytic Subunit 64369 227892 a. PRKAA2 protein kinase, AMP-activated, alpha 2 catalytic Subunit 67124 1554910 at PRKD3 protein kinase D3 -1.6967 220696 a PROO478 PROO478 protein 2.36786 220883 a PRO2012 hypothetical protein PRO2012 781 208004 a PROL1 proline rich, lacrimal 1 2.6306S 228656 a PROX1 prospero homeobox. 1 83495 242119 a PROX1 Homeodomain protein (Prox 1) .938OS 229376 a PROX1 prospero homeobox. 1 2.244.15 1552455 at PRUNE2 prune homolog 2 (Drosophila) 2.21968 210195 S at PSG1 pregnancy specific beta-1-glycoprotein 1 2.30O34 222796 a PTCD1 pentatricopeptide repeat domain 1 61999 209816 a PTCH1 patched homolog 1 (Drosophila) 75809 1552848 a. at PTCHD1 patched domain containing 1 75618 228825 a. PTGR1 prostaglandin reductase 1 2.7707 210355 a. PTHLH parathyroid hormone-like hormone 52732 1555.324 at PTK7 PTK7 protein tyrosine kinase 7 2.0983S 209465 x at PTN pleiotrophin .77916 211737 x at PTN pleiotrophin 62249 208011 a PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid) 55539 US 2016/02375O1 A1 Aug. 18, 2016 56

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 213362 at PTPRD protein tyrosine phosphatase, receptor type, D 1.SS396 214043 at PTPRD protein tyrosine phosphatase, receptor type, D 4.76051 204944 at PTPRG protein tyrosine phosphatase, receptor type, G 2.03281 235634 at PURG purine-rich element binding protein G 2.04289 215517 at PYGO1 pygopus homolog 1 (Drosophila) 183752 239570 at RAB1A GTP-binding protein (RAB1A) mRNA, 3' untranslated region -161026 24-1977 s at RAB3C RAB3C, member RAS oncogene family (RAB3C), mRNA 193934 224200 s at RAD18 RAD18 homolog (S. cerevisiae) -156083 223417 at RAD18 RAD18 homolog (S. cerevisiae) -1.61243 234662 at RAD21L1 RAD21-like 1 (S. pombe) 2.08749 204146 at RADS1AP1 RAD51 associated protein 1 -197583 206591 at RAG1 recombination activating gene 1 2.08.266 242712 X at RANBP2 RAN binding protein 2 RANBP2-like and GRIP domain 1.6504 RGPD1 containing 1 if RANBP2-li RGPD2, RGPD3 RGPD4 RGPD5 RGPD6 RGPD7 RGPD8 2172.01 a RASAL2 RAS protein activator like 2 84564 1557432 at RASAL2 RAS protein activator like 2 2.14711 217194 a RASAL2 RAS protein activator like 2 348961 1553986 at RASEF RAS and EF-hand domain containing .63337 1553185 at RASEF RAS and EF-hand domain containing 646O1 1553186 X at RASEF RAS and EF-hand domain containing 848 235638 a RASSF6 Ras association (RalGDSAF-6) domain family member 6 2.07978 225846 a RBM3SA RNA binding motif protein 35A 611.78 219121 S at RBM35A RNA binding motif protein 35A 76238 242516 x at RBM46 RNA binding motif protein 46 3.82539 1560322 at RBMS3 RNA binding motif, single stranded interacting protein 6O171 238447 a RBMS3 RNA binding motif, single stranded interacting protein 4.8S901 2094.87 a RBPMS RNA binding protein with multiple splicing 2.17673 232359 a RDH11 Vesicle soluble NSF attachment protein receptor (VT11) 86356 212398 a RDX radixin 899 1561720 at RECQL5 RecQ protein-like 5 3.42158 205923 a RELN reelin S8794 220276 a RERGL RERGRAS-like 7491 203225 S. at RFK riboflavin kinase -166609 223673 a RFX4 regulatory factor X, 4 (influences HLA class II expression) 2.132O6 1556,354 S at RGL3 ral guanine nucleotide dissociation stimulator-like 3 S6724 1568752 s at RGS13 regulator of G-protein signaling 13 2.03693 209071 S. at RGSS regulator of G-protein signaling 5 55719 237719 x at RGS7BP regulator of G-protein signaling 7 binding protein 2.97708 233409 a RHBDL3 rhomboid, veinlet-like 3 (Drosophila) 6217 238906 s at RHOJ ras homolog gene family, member J 71.684 1552922 at RIMS1 regulating synaptic membrane exocytosis 1 S8145 235153 a RNF183 ring finger protein 183 S9993 210931 a RNF6 ring finger protein (C3H2C3 type) 6 9021 226709 a ROBO2 roundabout, axon guidance receptor, homolog 2 (Drosophila) .71534 226766 a ROBO2 roundabout, axon guidance receptor, homolog 2 (Drosophila) .66383 240425 X at ROBO2 Roundabout 2 (robo2) 2.35616 242385 a. RORB RAR-related orphan receptor B 4.22051 1555990 at RP1-127L4.6 hypothetical protein LOC150297 2.08.107 1556.222 at RP11-291L22.2 similar to cell division cycle 10 .74943 235700 a RP13-36C9.6 canceritestis antigen CT45-5 55319 204666 s at RP5-1OOOE10.4 Suppressor of IKK epsilon S818S 235294 a RPS-1OOOE10.4 Suppressor of IKK epsilon -1.58872 230661 a RPESP RPE-spondin (RPESP), mRNA S4O79 238375 a. RPL22 Full open reading frame cDNA clone RZPDo834F116D for gene 6.19279 RPL22, ribosomal prote 238370 X at RPL22 Full open reading frame cDNA clone RZPDo834F116D for gene S.65484 RPL22, ribosomal prote 215249 a RPL3SA ribosomal protein L35a -1.53S49 213459 a RPL37A ribosomal protein L37a -1.577 220738. S. at RPS6KA6 ribosomal protein S6 kinase, 90 kDa, polypeptide 6 1.81745 228.186 s at RSPO3 R-spondin 3 homolog (Xenopus laevis) 2.10349 1553277 at RTTN rotatin 1.SSO66 215321 a. RUNDC3B RUN domain containing 3B 2.53893 205528 S. at RUNX1T1 runt-related transcription factor 1; translocated to, 1 (cyclin D- 2021.37 related) US 2016/02375O1 A1 Aug. 18, 2016 57

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 205529 S. at RUNX1T1 runt-related transcription factor 1; translocated to, 1 (cyclin D- 3.23.118 related) 239150 at S100A1L, Protein S100-A1-like 67335 229273 at SALL1 sal-like 1 (Drosophila) 2.31825 1553411 S. at SALL3 sal-like 3 (Drosophila) 641SS 232847 at SALL3 sal-like 3 (Drosophila) 2.0568 1569443 at SAMDS sterile alpha motif domain containing 5 SO746 228653 at SAMDS sterile alpha motif domain containing 5 52142 1559882 at SAMHD1 Full length insert cDNA clone YP80A10 .63358 1569599 at SAMSN1 SAMSN1 variant b (SAMSN1) mRNA, complete cols; 67178 alternatively spliced 211423 s at SCSDL sterol-C5-desaturase (ERG3 delta-5-desaturase homolog, S. cerevisiae)- -1.784.04 like 206667 s at SCAMP1 Secretory carrier membrane protein 1 3.99037 206021 a SCAND2 SCAN domain containing 2 pseudogene .76903 220232 a. SCD5 stearoyl-CoA desaturase 5 2.02692 1554921 a. at SCEL Sciellin 64729 206884 S at SCEL Sciellin 98.342 597.05 at SCLY Selenocysteine lyase -1.63837 210853 a SCN11A Sodium channel, voltage-gated, type XI, alpha subunit 2.6O2S4 1555.246 a. at SCN1A Sodium channel, voltage-gated, type I, alpha subunit 2.29049 210383 a SCN1A Sodium channel, voltage-gated, type I, alpha subunit 3.19642 229057 a SCN2A Sodium channel, voltage-gated, type II, alpha Subunit 98.264 212157 a SDC2 Syndecan 2 50872 229522 a. SDR42E1 short chain dehydrogenase/reductase family 42E, member 1 -1.52939 206941 x at SEMA3E Sema domain, immunoglobulin domain (Ig), short basic domain, 2.31714 Secreted, (semaphor 226492 a SEMA6D Sema domain, transmembrane domain (TM), and cytoplasmic S2645 domain, (semaphorin) 6D 239889 a SERP2 Stress-associated endoplasmic reticulum protein family member 64374 2, mRNA (cDNA clon 211361 s at SERPINB13 serpin peptidase inhibitor, clade B (ovalbumin), member 13 S4593 217272 s at SERPINB13 serpin peptidase inhibitor, clade B (ovalbumin), member 13 2.91352 24.0709 a SEZ6L seizure related 6 homolog (mouse)-like 861.36 233753 a SFRS15 splicing factor, arginine?serine-rich 15 -1581.65 237,485 a SFRS3 Pre-mRNA splicing factor SRp20, 5'UTR region 63657 230730 a. SGCD sarcoglycan, delta (35 kDa dystrophin-associated glycoprotein) S6939 228.602 a SGCD sarcoglycan, delta (35 kDa dystrophin-associated glycoprotein) 2.64714 231938 a SGOL1 Shugoshin-like 1 (S. pombe), mRNA (cDNA clone 93941 IMAGE: 3861301) 225162 a SH3D19 SH3 domain containing 19 6843 211565 a SH3GL3 SH3-domain GRB2-like 3 6.2489 213307 a SHANK2 SH3 and multiple ankyrin repeat domains 2 2.22882 235238 a SHC4 SHC (Src homology 2 domain containing) family, member 4 248968 207570 a SHOX short stature homeobox 3.56283 208443 x at SHOX2 short stature homeobox2 1.65982 210135 s at SHOX2 short stature homeobox2 4.81277 1554.354 at SIAE sialic acid acetylesterase 1.633S 215856 a SIGLEC15 sialic acid binding Ig-like lectin 15 1.59259 228347 a SIX1 SIXhomeobox 1 1.60659 206634 a SIX3 SIXhomeobox 3 2.19671 206675 S. at SKIL SKI-like oncogene -1.59872 237106 a SLC11A2 NRAMP2 1.57374 220502 s at SLC13A1 solute carrier family 13 (sodium/sulfate symporters), member 1 2.41997 211349 a SLC15A1 Solute carrier family 15 (oligopeptide transporter), member 1 163562 205317 s at SLC15A2 solute carrier family 15 (H+ peptide transporter), member 2 -194245 205234 a SLC16A4 Solute carrier family 16, member 4 (monocarboxylic acid -166979 transporter 5) 220551 a SLC17A6 Solute carrier family 17 (sodium-dependent inorganic phosphate 24O381 cotransporter), m 232232 S at SLC22A16 Solute carrier family 22 (organic cation/carnitine transporter), -2.998.41 member 16 234561 a SLC2A13 Solute carrier family 2 (facilitated glucose transporter), member 1.52225 13 239596 a SLC30A7 solute carrier family 30 (zinc transporter), member 7 1.91435 220796 x at SLC35E1 solute carrier family 35, member E1 167755 228060 a SLC35F1 solute carrier family 35, member F1 2.29249 220786 s at SLC38A4 solute carrier family 38, member 4 167855 1553126 a. at SLC39A12 solute carrier family 39 (zinc transporter), member 12 1.66587 228945 s at SLC39A8 MRNA, 3'UTR, up-regulated by BCG-CWS 167744 210739 X at SLC4A4 Solute carrier family 4, Sodium bicarbonate cotransporter, 16053 member 4 US 2016/02375O1 A1 Aug. 18, 2016 58

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 211494 S at SLC4A4 Solute carrier family 4, Sodium bicarbonate cotransporter, 2.49002 member 4 231424 at SLCSA12 Solute carrier family 5 (sodium glucose cotransporter), member 3.26263 12 1554724 at SLC6A11 solute carrier family 6 (neurotransmitter transporter, GABA), 51255 member 11 1556641 at SLC7A14 Solute carrier family 7 (cationic amino acid transporter, y- SOO49 system), member 14 216604 S at SLC7A8 Solute carrier family 7 (cationic amino acid transporter, y- 76482 system), member 8 1552745 at SLCO6A1 Solute carrier organic anion transporter family, member 6A1 63132 236734 a SLITRK1 SLIT and NTRK-like family, member 1 73464 232481 S. at SLITRK6 SLIT and NTRK-like family, member 6 94.86 215599 a SMA4 glucuronidase, beta pseudogene .96895 207441 a SMR3B Submaxillary gland androgen regulated protein 3B .78909 1556629 a. at SNAP25 HUMSNAP25B(F) 2.68O11 219511 S. at SNCAIP Synuclein, alpha interacting protein 66212 237834 a SNCAIP Synuclein, alpha interacting protein 86,709 232547 a SNIP SNAP25-interacting protein 3.23498 202691 a SNRPD1 Small nuclear ribonucleoprotein D1 polypeptide 16 kDa -1.70602 216850 a SNRPN Small nuclear ribonucleoprotein polypeptide N 74.192 1559545 at SNRPN Small nuclear ribonucleoprotein polypeptide N 224102 240204 a SNRPN Small nuclear ribonucleoprotein polypeptide N 2.35762 220487 a SNTG2 syntrophin, gamma 2 -161256 218705 S at SNX24 Sorting nexin 24 -1.SS845 239739 a SNX24 Sorting nexin 24 .997.04 24-1987 x at SNX31 Sorting nexin 31 3.63912 223666 a SNX5 Sorting nexin 5 -1.61478 1563906 at SOBP sine oculis binding protein homolog (Drosophila) 59114 209648 x at SOCS5 Suppressor of cytokine signaling 5 -152633 1558815 at SORBS2 Sorbin and SH3 domain containing 2 2.73073 204914 S at SOX11 SRY (sex determining region Y)-box 11 2.70367 204913 s at SOX11 SRY (sex determining region Y)-box 11 4.13442 223865 a SOX6 SRY (sex determining region Y)-box 6 87491 1570486 at SOX6 SRY (sex determining region Y)-box 6 85225 202936 S. at SOX9 SRY (sex determining region Y)-box 9 S3496 202935 S. at SOX9 SRY (sex determining region Y)-box 9 3.35729 231178 a SPATA4 spermatogenesis associated 4 61457 2098.91 a SPC25 SPC25, NDC80 kinetochore complex component, homolog (S. cerevisiae) .75386 206318 a SPINLW1 serine peptidase inhibitor-like, with Kunitz and WAP domains 1 7884 (eppin) 235342 a. SPOCK3 sparcosteonectin, cwcv and kazal-like domains proteoglycan 241614 (testican) 3 220456 a SPTLC3 serine palmitoyltransferase, long chain base subunit 3 2.15437 24-1961 a SRDSA2L2 steroid 5 alpha-reductase 2-like 2 3.63908 24-1734 a SRFBP1 serum response factor binding protein 1 -1.SS343 1554473 at SRGAP1 SLIT-ROBO Rho GTPase activating protein 1 2.857O1 228628 a SRGAP2P1 SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1 2.17844 214597 a SSTR2 Somatostatin receptor 2 .799.21 215885 a SSX2 synovial sarcoma, X breakpoint 2 80412 208586 s at SSX4 SSX4B synovial sarcoma, X breakpoint 4 synovial sarcoma, X .7382 breakpoint 4B 206835 a. STATH statherin 86909 204595 s at STC Stanniocalcin 1 67438 204597 X at STC Stanniocalcin 1 3.94696 202695 S at STK17A serine/threonine kinase 17a -153066 223883 s at STK31 serine/threonine kinase 31 S9045 231969 at STOX2 storkhead box 2 3.87778 223245 at STRBP spermatid perinuclear RNA binding protein -159889 23.5180 at STYX serine/threoninetyrosine interacting protein -163483 212354 at SULF1 Sulfatase 1 9771 222940 at SULT1E1 Sulfotransferase family 1E, estrogen-preferring, member 1 .76639 213247 at SVEP1 Sushi, von Willebrand factor type A, EGF and pentraxin domain 778.75 containing 1 1553129 at SVEP1 Sushi, von Willebrand factor type A, EGF and pentraxin domain .98786 containing 1 216917 s at SYCP1 synaptonemal complex protein 1 2.716O1 2O6740 x at SYCP1 synaptonemal complex protein 1 2.SS636 215350 at SYNE spectrin repeat containing, nuclear envelope 1 844O6 202796 at SYNPO synaptopodin -1.54SS3 225720 at SYNPO2 synaptopodin 2 2.47627 US 2016/02375O1 A1 Aug. 18, 2016 59

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 229053 a SYT17 CDNA FLJ56448 complete cols, highly similar to Homo sapiens -2.12139 synaptotagmin XVII (S 202287 s at TACSTD2 tumor-associated calcium signal transducer 2 2.08528 242318 a TAPT1 Transmembrane anterior posterior transformation 1 (TAPT1), 165116 mRNA 214413 a TAT Tyrosine aminotransferase 156842 221858 a TBC1D12 TBC1 domain family, member 12 -1.898.33 1563272 at TBC1D8B TBC1 domain family, member 8B (with GRAM domain) 1.6O724 233633 a TBL1XR1 Transducin (beta)-like 1X-linked receptor 1, mRNA (cDNA 2.06728 clone IMAGE: 4754868) 225544 a TBX3 T-box 3 2.58503 240715 a. TBX5 T-box 5 3.04595 1561254 at teag7.118.8 hypothetical LOC340340 89.091 1562664 at teag7.929 hypothetical protein LOC286009 65909 202823 a TCEB1 transcription elongation factor B (SIII), polypeptide 1 (15 kDa, -1.5985 elongin C) 206286 s at TDGF1 eratocarcinoma-derived growth factor 1 if teratocarcinoma- 64616 TDGF3 derived growth facto 214600 a TEAD1 TEA domain family member 1 (SV40 transcriptional enhancer 68OO1 actor) 204653 a TFAP2A transcription factor AP-2 beta (activating enhancer binding 80715 protein 2 alpha) 214451 a TFAP2B transcription factor AP-2 beta (activating enhancer binding 2.8O3S1 protein 2 beta) 233987 a TFAP2D transcription factor AP-2 delta (activating enhancer binding 665.15 protein 2 delta) 1566931 at TFB2M Transcription factor B2, mitochondrial, mRNA (cDNA clone S3869 MAGE: 5311413) 1566932 x at TFB2M Transcription factor B2, mitochondrial, mRNA (cDNA clone S3363 MAGE: 5311413) 215447 a TFPI Tissue factor pathway inhibitor (lipoprotein-associated 4.OO815 coagulation inhibitor), 228121 a TGFB2 transforming growth factor, beta 2 2.064O7 235653 S at THAP6 THAP domain containing 6 -1.78358 203083 a THEBS2 hrombospondin2 .79394 204776 a THEBS4 hrombospondin 4 -1.51372 219044 a THNSL2 hreonine synthase-like 2 (S. cerevisiae) -1.81461 222835 a. THSD4 hrombospondin, type I, domain containing 4 4.52581 230008 a THSD7A hrombospondin, type I, domain containing 7A 71666 214920 a THSD7A hrombospondin, type I, domain containing 7A 86908 210800 a TIMM8A translocase of inner mitochondrial membrane 8 homolog A 3.55929 (yeast) 202011 a TJP1 ightjunction protein 1 (Zona occludens 1) 2.15499 1555071 at TLL1 olloid-like 1 86,768 215008 a TLL2 olloid-like 2 3.33235 230061 a TM4SF18 MRNA, cDNA DKFZp313N1532 (from clone 61636 DKFZp313N1532) 220639 a TM4SF2O transmembrane 4 L six family member 20 S3906 228.610 a TM9SF3 CDNA FLJ90343 fis, clone NT2RP2002824, highly similar to .792S4 Transmembrane 9 Superfa 1564591 a. at TMC1 transmembrane channel-like 1 87321 1553636 at TMCOSA transmembrane and coiled-coil domains 5A 91589 1554.866 at TMEM13S transmembrane protein 135 .7O2S4 238497 a TMEM136 transmembrane protein 136 66054 239593 a TMEM213 transmembrane protein 213 53796 20965.5 S at TMEM47 transmembrane protein 47 52814 204807 a TMEMS transmembrane protein 5 -1.53392 1569377 at TMEM67 transmembrane protein 67 2.34523 1563646 a. at TMEM67 transmembrane protein 67 2.OSS36 226483 a TMEM68 transmembrane protein 68 -158264 213024 a TMF1 TATA element modulatory factor 1 -1513 220431 a TMPRSS11E, if transmembrane protease, serine 11E if transmembrane protease, 56517 TMPRSS11E2 serine 11E2 1555707 at TNAP TRAFs and NIK-associated protein 2.65475 21.6005 a TNC Tenascin 2.11SO2 216042 a. TNFRSF25 tumor necrosis factor receptor Superfamily, member 25 -1.54437 15572.78 s at TNPO1 Transportin 1, mRNA (cDNA clone MGC: 17116 686 MAGE:4178989) 232750 a TNS1 Tensin 1, mRNA (cDNA clone IMAGE: 4546443) 2.98094 237469 a TOP2A Topoisomerase (DNA) II alpha 170 kDa, mRNA (cDNA clone .75261 MAGE: 4101949) 220205 a TPTE transmembrane phosphatase with tensin homology 2.99568 1556876 s at TPTEps1 TPTE pseudogene 1 3.4786 US 2016/02375O1 A1 Aug. 18, 2016 60

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 2443.34 a TRAM1L1 translocation associated membrane protein 1-like 1 80692 1552791 a. at TRDN triadin .71337 222754 a TRNT1 RNA nucleotidyl transferase, CCA-adding, 1 -1.57097 210814 a TRPC3 transient receptor potential cation channel, Subfamily C, member 3 2.29944 234407 s at TRPC7 transient receptor potential cation channel, Subfamily C, member 7 2.14569 206479 a TRPM1 transient receptor potential cation channel, Subfamily M, member 1 86699 240386 a TRPM1 Homo sapiens, clone IMAGE:4332660, mRNA 91651 216452 a TRPM3 transient receptor potential cation channel, Subfamily M, member 3 .64176 233022 a. TRPM3 transient receptor potential cation channel, Subfamily M, member 3 2.69873 203824 a TSPAN8 etraspanin 8 91.188 21514.6 s at TTC28 etratricopeptide repeat domain 28 S8487 1556666 a. at TTC6 etratricopeptide repeat domain 6 3.47481 240369 a TTC7A Tetratricopeptide repeat domain 7A, mRNA (cDNA clone -1.SS993 MAGE: 5113102) 242771 a TTN Titin -1.82217 210614 a TTPA ocopherol (alpha) transfer protein 58.646 230891 a TUBE1 Tubulin, epsilon 1, mRNA (cDNA clone MGC: 33949 2.16675 MAGE: 5298159) 239742 a. TULP4 Full length insert cDNA clone YU79H10 85499 213943 a TWIST1 twist homolog 1 (Drosophila) 4.94261 220869 a UBA6 ubiquitin-like modifier activating enzyme 6 7396 15692.62 x at UBE2CBP ubiquitin-conjugating enzyme E2C binding protein 2.10912 233327 a UBE2CBP ubiquitin-conjugating enzyme E2C binding protein 2.67633 234163 a UBE3A E6-AP isoform-III 216744 234166 a UBE3A E6-AP isoform-III 65174 1555834 at UCHL1 Protein gene product (PGP) 9.5 73702 221304 a UGT1A10 UDPglucuronosyltransferase 1 family, polypeptide A10 UDP 2.06331 UGT1A6 glucuronosyltransf

UGT1A8 221305 s at UGT1A6 if UDPglucuronosyltransferase 1 family, polypeptide A6 i? UDP 2.18416 UGT1A8 glucuronosyltransfe UGT1A9 211682 X at UGT2B28 UDPglucuronosyltransferase 2 family, polypeptide B28 2.56318 226899 a UNCSB unc-5 homolog B (C. elegans) 2.95198 214640 a UNC93A unc-93 homolog A (C. elegans) 66307 214382 a UNC93A unc-93 homolog A (C. elegans) 71701 1560320 a. at UNQ2963 hypothetical protein LOC283314 -153983 221173 a USH1C Usher syndrome 1C (autosomal recessive, severe) 52879 207706 a USH2A Usher syndrome 2A (autosomal recessive, mild) 87956 232621 a USP48 ubiquitin specific peptidase 48 .77813 1555065 x at USP6 ubiquitin specific peptidase 6 (Tre-2 oncogene) 77628 227399 a WGLL3 vestigial like 3 (Drosophila) 72088 220327 a WGLL3 vestigial like 3 (Drosophila) .88.289 203844 a VHL von Hippel-Lindau tumor suppressor 64-109 203106 S. at VPS41 vacuolar protein sorting 41 homolog (S. cerevisiae) -1.70572 1561200 at WWA3B von Willebrand factor A domain containing 3B .90857 1552430 at WDR17 WD repeat domain 17 2.OS322 219538 a WDRSB WD repeat domain 5B -161334 242162 a WDR69 WD repeat domain 69 S1724 220769 S at WDR78 WD repeat domain 78 2.25954 206954 a WIT1 Wilms tumor upstream neighbor 1 2.72357 213425 a. WNTSA wingless-type MMTV integration site family, member 5A S2O31 205990 s. at WNTSA wingless-type MMTV integration site family, member 5A 2.06024 206067 s at WT1 Wilms tumor 1 .72928 237656 a WWC2 CDNA FLJ51450 complete cols, highly similar to Claudin-22 973.62 207598 X at XRCC2 X-ray repair complementing defective repair in Chinese hamster 696.11 cells 2 214776 X at XYLB Xyluolkinase homolog (H. influenzae) 87664 1569683 at XYLB Xyluolkinase homolog (H. influenzae) 608O8 224895 at YAP1 Yes-associated protein 1, 65 kDa 2.12127 206169 x at ZC3H7B Zinc finger CCCH-type containing 7B 55615 216844 at ZC3H7B Zinc finger CCCH-type containing 7B 2.3575 1553781 at ZC3HAV1L, Zinc finger CCCH-type, antiviral 1-like 2.OOO1 219917 at ZCCHC4 Zinc finger, CCHC domain containing 4 -1.52373 231946 at ZFHX2 Zinc finger homeobox2 S3322 24.1700 at ZFHX4 Zinc finger homeobox 4 74443 222237 S at ZFP112 Zinc finger protein 112 homolog (mouse) -1.SS145 211773 s at ZKSCAN3 Zinc finger with KRAB and SCAN domains 3 -1.52752 1552947 x at ZNF114 Zinc finger protein 114 90546 1552946 at ZNF114 Zinc finger protein 114 2.52625 207402 at ZNF132 Zinc finger protein 132 -158945 US 2016/02375O1 A1 Aug. 18, 2016 61

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1558.184 S at ZNF17 Zinc finger protein 17 -1566.15 1568644 at ZNF208 Zinc finger protein 208 2.2969S 1568646 x at ZNF208 Zinc finger protein 208 3.20902 243456 a ZNF214 Zinc finger protein 214 83302 1557322 at ZNF230 Zinc finger protein 230 -1.76902 1559449 a. at ZNF254 CDNA FLJ58216 complete cols, highly similar to Zinc finger -2.34406 protein 539 215048 a ZNF28OB Zinc finger protein 280B S2294 236328 a ZNF28SA Zinc finger protein 285A -1.73O84 216710 X at ZNF287 Zinc finger protein 287 92695 227680 a ZNF326 Zinc finger protein 326 -1.6O787 224276 a ZNF33A Zinc finger protein 33A .76911 1562743 at ZNF33B Zinc finger protein 33B (ZNF33B), mRNA 50959 2331.69 a ZNF350 Zinc finger protein 350 -1.54751 214761 a ZNF423 Zinc finger protein 423 68652 219848 s at ZNF432 Zinc finger protein 432 -152766 205928 a ZNF443 Zinc finger protein 443 -158322 226575 a. ZNF462 Zinc finger protein 462 2.79327 244007 a ZNF462 Zinc finger protein 462 2.05.007 555368 x at ZNF479 Zinc finger protein 479 3.58093 55.5367 at ZNF479 Zinc finger protein 479 3.75576 559988 at ZNF483 Zinc finger protein 483 2.28434 557616 at ZNF496 Zinc finger protein 496 -1.53S6S 226676 a ZNF521 Zinc finger protein 521 2.SS441 226,592 a ZNF618 Zinc finger protein 618 51197 232272 a ZNF624 Zinc finger protein 624 -160359 553247 a. at ZNF709 Zinc finger protein 709 -1.6001 560201 at ZNF713 Zinc finger protein 713 SOO2 5.53885 x at ZNF99 zinc finger protein 99 66616 228330 a. ZUFSP Zinc finger with UFM1-specific peptidase domain -1.SS835 564685 a. at — 83O44 566896 at 8.1016 238137 a 61463 562201 x at — 69439 241648 a -1.52957 236996 a -154814 567706 at 9772 239082 a 62335 241235 a. -1.5976 244767 a -156631 233424 a 90728 243655 x at — S2941 236395 a -15143 239903 a .61809 566645 a. S476 562341 a 52441 242952 a. 55967 559807 a .70594 23815S a -15566 566550 a S4738 242797 X at — -1862O1 242170 a -1.89134 5700.98 a .82945 559524 a -1.71546 239.606 a -1.53539 566544 a 61104 242133 s at — S6343 556760 a. at — 2.0O828 563461 a 53995 570645 a. SS841 240730 at 61181 236602 at 52.722 24.2122 at -150641 5594.10 a .7089 234100 at -1.52272 239856 at -223215 229243 at -1.73048 231465 at 62758 1562208 a. at — .87O64 1561149 at S2S62 24O642 at -1.71584 1557658 at -161047 US 2016/02375O1 A1 Aug. 18, 2016 62

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 230503 a 6OO16 242494 a 6.192 1561956 at S9298 242495 a 57521 222320 a 61706 237886 a S3331 1565788 at 65726 24O133 X at — .88894 242074 a -1.54665 215029 a -161964 1568785 a. at — S2688 243381 a 63013 216173 a S7894 240688 a S2689 243584 a 76235 231136 a SO646 1569833 at 60643 2301.68 a - 193736 1564744 at .63372 1562010 X at — 50535 228734 a -167929 1560717 at 67536 243356 a 72703 1562935 at 5956 240973 s at — -1.53876 207471 a 75431 222246 a 84054 237102 a 73952 220871 a .8O151 228643 a -16237 233180 a 2.25381 1559709 at 69535 242296 X at — 56148 1562456 at 661.78 1556518 at 537 233579 a 232946 1563531 at 91.261 216757 a 75028 234612 a S48O1 1562835 at 7128 234224 a S186 242115 a. 5505 1569527 at -154022 238415 a. S3.194 226231 a -1.79439 240506 a 6OOO3 240469 a 62514 1557885 at 52753 237356 a 93218 242202 a 573.35 236778 a 6O299 240355 a. -1668.21 242142 a 80096 236038 a 2.10931 1557434 at 53917 227051 a -1.88686 1567304 at 60926 239819 a S6334 1563.054 at 71697 1557921 S at — .68215 242321 a 22O104 1561135 at 73638 1566787 at S9838 239649 a 656.68 214645 a. 55.285 232459 a 8.2556 243236 a -1.70988 1560094 at -168062 237628 a S12O1 244551 a -166189 243345 a. -1.65084 240442 a. 66955 US 2016/02375O1 A1 Aug. 18, 2016 63

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1560372 at 2.10286 1566,504 at S6292 239986 a S3O33 1561319 at 62652 234560 a 68465 1560258 a. at — SO646 2398.63 a -197398 234064 a 2.03588 238718 a 68.987 244O16 a .8O815 217038 a 2.36O71 236659 x at — 57533 1566772 at 61228 1566809 a. at — .79265 244333 a 65689 230294 a -1.SSOO1 1564479 a. at — 72664 215864 a 2.03128 1563477 at 2.05179 1570213 at 98.433 217137 x at — 2.033 237912 a .82S82 24-1220 a S4608 2421.66 a S6101 237134 a 84799 238372 s at — 2.372O1 239536 a -166473 227857 a S6S63 1559664 at 60616 240267 a 51777 1564391 at .97908 236161 a 644O2 233786 a 81531 1567611 at -150961 222298 a S8123 23280S a S9909 236678 a 8314 241057 x at — S6362 1556239 a. at — -1.7364 1558719 S at - -1.86612 240658 a S8761 242564 a -1.77191 241.100 a 89642 236219 a -1.781.49 240245 a. 74041 561328 a 62167 237231 a -150546 558869 a 75081 554.043 a at — -165188 241030 a. 893.93 233306 a 8777 565874 a 63SS8 230874 a -2O6833 569661 a S966S 237742 a. 61044 227985 a -1.82784 566867 a .94122 564773 x at — S4988 562053 a -2.064O2 235.188 a 84682 557512 a -1627 242007 a -1.69897 243455 a. 61.96S 2398.68 a 5129 561417 x at — 60S74 219367 s at — 531.87 236394 a 76477 561134 at S4734 2424.68 a 97864 566994 at 2.10394 210679 x at — SO28 243636 s at — 69661 US 2016/02375O1 A1 Aug. 18, 2016 64

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 234588 a 61426 1566995 at 2.12757 1566096 x at — 2.08387 233.187 s at — -154128 227745 a. -1.73S47 1557443 s at — 608O1 1561161 at 8118S 24O997 a 65329 1561689 at 65238 241163 a S9299 234248 a 55099 1562O65 at 74757 2394.37 a -1.80734 1569208 a. at — 93479 1559737 at 72324 240016 a S8788 235666 a 57665 210914 a S1724 233445 a. 81438 1565825 at S6204 238203 a 701.23 1562327 at S9003 1570316 at .78431 2423.03 a 7273 1563.001 at 56578 1562864 at S4738 222168 a 97664 1562091 at S1347 1566424 at 63682 232962 x at — 69709 235831 a 70453 233861 a 2.22299 215278 a 71066 242599 a 62169 1565879 at 86352 241002 a .693.13 241142 a -167262 232800 a 2.29403 242505 a. S7494 1558714 at 9751 243.014 a 58464 24O101 a -1.75992 232541 a. 55706 241665 X at — 7135 240468 a 92.795 215.405 a .98124 240800 x at — 60351 221120 a S3838 237332 a 5951 1563.036 at 63S32 1557659 a. at - -2.08984 233293 a S1923 242811 X at — .70854 1556439 at 69729 1560453 at 8201S 1569779 at 61263 237525 at S1511 24O989 at 61747 234606 at 54255 234692 at 61537 216756 at 653O4 241637 at 2.17642 1556656 at 68.075 235.017 s at — 7341 233130 at 82787 233779 x at - S1862 237355 at S4889 232850 at 55.839 23.0020 at -1.8275 243454 at 2.15818 237573 at 82449 234036 x at — 8288S US 2016/02375O1 A1 Aug. 18, 2016 65

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 243666 a 2.20715 1568736 s at — 83.385 215539 a 571.74 15565.04 at S1528 221144 a 6864 239459 s at — 2.16772 1552975 X at - 63S6S 1562727 at 87879 233450 a 82759 241.303 X at — S1058 236617 a 2.04757 1562473 at S286S 1556650 at S3931 238395 a .84O75 234597 a 2.57012 240046 a 751.15 237526 a 57771 237492 a 7016S 1563351 at 57794 227140 a 2.59379 21618.7 x at — S8094 236187 s at — 71841 228842 a. -1.51876 234532 a 84698 234219 a 83545 242189 a S8063 241203 a 57795 240580 a 77583 1565576 at S1264 242755 a. 2.01686 1568.648 a. at — .9841S 1562718 at 64374 239.017 a S4796 1563427 at 62296 242857 a -1.7SS1 1557758 at 8066 1559086 at .85777 24.1758 a 67733 23.6564 a -168533 233721 x at — 86315 202015 x at — ..991.69 240640 a S1291 557861 at .75142 240858 a S4478 559695 a. at - 822O2 244891 X at — 6181 240297 a 62.096 5584.44 a 2.92859 570482 a 2.572O1 563.055 a. S8052 56,7303 a 911S 231037 at 77578 564690 a 3.094.08 561129 a 5641 244045 at 2.06161 560352 a 84388 241130 at S8428 232268 at 57907 566768 a 84415 241.173 at 86436 562760 a 72579 562588 a 94416 566763 a 2.04467 569740 a 64645 240290 at 67943 2374.96 at 2.0686S 567379 a 62299 244125 at 2.575.99 235445 at 91.795 555.174 a S8019 216643 at 8921S 569983 a 2.39576 US 2016/02375O1 A1 Aug. 18, 2016 66

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1560429 at 2.04382 1563386 at 76382 244511 a 62772 1570350 at 61993 241487 a .66578 1567913 at 5.71757 1562686 at 74.144 1565860 at 2.969.18 244510 a 2.46633 237622 a. -2.61939 1557780 at 71847 239520 a 53506 243034 a S628 238,571 a 80516 232113 a 2.22875 242641 a 61615 234579 a SS619 1566842 at 75893 21558.7 x at — 53373 236740 a 828S 224.549 X at — 68422 233276 a .62961 561256 at 92386 566094 at 2.44114 224234 a 5266 244098 a 6926 234428 a 2.25705 562720 at 91297 243147 X at — 67593 569344 a at — 2.19681 235560 a 6268 228504 a 72391 556985 at 79627 215628 x at — S6039 562086 at 57298 222372 a 84973 566582 x at — 79715 233.958 a 55915 243008 a 64372 553275 S. at - 890O2 243322 a. 65429 234825 a. 73469 244609 a .8SO48 215615 x at — S3488 1561528 at 55697 24-1852 a 6O268 1558489 at 234982 239672 a 66417 1560.087 a. at — .92O31 1556904 at 2.30213 244724 a 60549 241310 a 2.15657 241655 a. S4O91 234625 a. S8324 231616 a 2.13008 236697 a 5915 235642 a. 70455 241897 a 2.121.9S 236670 s at — 2.10982 240578 a 61716 1562235 S. at — 5.5351 1562687 x at — 8282 15568.05 at 2.61186 237727 a 66SS4 215284 a 2.05102 228740 a 82664 244769 a 95537 227484 a S1603 233755 a. 86698 227126 a 2.10379 224429 X at — 56535 1556796 at 2.47359 US 2016/02375O1 A1 Aug. 18, 2016 67

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 221146 a .7O639 233265 a 84.813 234494 X at — .7031 1556206 at .82973 244384 a 92.957 236466 a 7519 238,536 a 76454 1561591 at 63671 232808 a 87054 1563.052 at 3.05615 1556813 at 666.13 233402 a S3209 238847 a 2.49299 237483 a 2.OOOSS 234753 x at — 87523 220820 a S8991 562332 a 92188 562905 a 56404 561217 a .75568 561121 a. 52528 243762 a 6O241 236650 a 89.552 230577 a 71798 56.9753 a 2.2O368 233224 a -1.51535 241479 a .90387 569491 a .79905 237832 a 2.86311 235733 a 90S22 568803 a 66131 237491 a 2.70143 216151 a S9221 556352 a. .73928 229490 s. at — 2.20922 570596 a 65322 237600 a 64121 211374 x at — 57283 216110 X at — 66876 24O152 a. 2.07123 24O949 X at — 2.6364 1566968 at 8345 216524 x at — 52057 242188 a 67993 1560690 at SO865 240060 a 5O178 237946 a 2.74367 220837 a 76967 229330 a. -152841 1566666 at 2.15745 24.0474 X at — S4O2S 237903 a 681 16 1564567 at 2.86081 227010 a -1.54SS1 1562507 at 2.46383 1562544 at .83332 1560891 a. at — 6O154 233714 a 2.13082 244259 s at — 69439 243279 a 2.034OS 234.755 x at — S2681 241639 a 2.0758 234667 a 61766 216625 a. S4839 244156 a 2.63578 1556683 x at — SO421 230785 a. SO472 232495 X at — 50721 238361 s at — 2.2SO68 217619 x at — 54826 156O111 at 80542 236184 at 2.098.78 235629 at S2947 US 2016/02375O1 A1 Aug. 18, 2016 68

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 242236 a 2.6709 217579 X at - 63O2 233240 a S8366 222296 a 66123 232592 a 67559 237998 a .9SO45 242559 a .73911 243240 a 812 24.1253 a S3832 241069 a 2.1882 238310 a 68.293 1564798 at .741.83 217524 x at — SS266 240427 a 2.394O7 217713 x at — 65536 240450 a 2.21304 237893 a 2.06445 241132 a 2.138O2 237267 a 89267 5.64236 at 69733 558473 at .83OOS 557519 at -1.89371 569231 x at — 6864 241008 a S4943 561445 at 55.856 234571 a 731.78 234.083 a 2.037 241656 a SS124 563.012 X at — SO488 560476 at 2.17694 56.1564 at 2.75205 233118 a 79787 233702 x at — 54804 563091 at 67395 559450 at .77421 244793 a 85576 233622 X at — .51571 241223 X at — 69464 239604 a 2.18244 216158 a 80396 1556817 a. at — 2.10569 1570099 at SO845 1561692 at 2.64312 242795 a 3.20O31 155.9375 S. at - 57452 1569794 at .79312 1562933 at .7812 1561305 at S1196 233502 at 3.43598 244588 at 86.108 240783 at 28921 235.739 at 88.882 233273 at 2.07697 1565873 at 75922 242881 X at — 2.91.173 1563568 at 894.45 1569755 at 86666 242391 at 2.54095 1565637 at 244.504 241657 at 653O4 232957 x at — 2.28244 233683 at 2.15259 237065 s at — -2.23415 1566,597 at 2.38873 239849 at 249616 1564358 at 3.57914 233152 x at — 1.S398 243473 at 18121 216094 at 22O104 1568589 at 2.83131 1555925 at 3.SO923 243572 at 1.7936 US 2016/02375O1 A1 Aug. 18, 2016 69

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 241.186 at 2.07335 239340 at 3.10534 243192 at .79294 1569230 at 89893 215062 at 66817 1561187 at 531.78 243763 x at — 200712 1563329 s at — 93939 238826 x at — 63927 238298 a 924.48 205772 s at — 92683 231482 a 9948 242605 a .68979 1565565 at 67957 1562945 at S1982 1556392 a. at — .882S 243929 a 2.32352 1561509 at .59259 15556O1 at 81067 232324 X at — S3814 238.184 a SO493 1567008 at 2.21042 24.3706 a 82234 23.9514 a 2.26505 234.433 a 2.2O167 240067 a 94901 562263 at 83224 237850 a 60944 222299 X at — 80516 557215 at 8.2993 23.9985 a. 67697 243877 a 65948 569656 at 83943 239344 a S3249 561631 at 67024 237365 a. 70238 243936 x at — 2.23539 216337 a S6682 570423 at 2.37274 558672 at 65888 564580 at 2.5145 562923 at 52114 237951 at 6943 242890 at .885.08 234.805 at .76687 239311 at 55589 565861 at 2.3658 562409 s at — S2328 230130 at 2.07OO3 232833 at 55799 244.507 at 3.42912 561268 at S4475 563331 at 2.23231 224254 X at — 81892 561,346 at 63069 240485 at 61434 238751 at 2.35739 561478 at S6036 2397O6 X at — 2.036.17 240877 x at — 5753 232925 at S8004 558497 a. at — 2.17382 555014 X at — 87282 216101 at .99447 240077 at S1092 234550 at 2.01775 242845 at 6O469 1561778 at 2.41702 242401 X at — 6O26S 1566695 at S7644 1561123 at 2.74.835 1556491 at 2.076.15 US 2016/02375O1 A1 Aug. 18, 2016 70

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 233626 a 684.82 15621.66 at 63935 2424.83 a .556 23074.6 s at — 3.65236 1561437 at 696O4 238,512 a 2.14172 237486 a 64718 215768 a 2.6.1093 1561112 at 2.307 243566 a S4828 242733 a 2.42O57 242171 a .8335 239962 a 94384 1568931 at 68134 239.066 a 90013 1558226 a. at — 2.1.2499 241549 a 54.525 1561962 at 2.0O865 1567009 at 2.338O1 238354 x at — 2.18921 240670 a 2.07815 220729 a 2.066 1563414 at 168084 1562491 at 185416 1566805 at 2.49158 1564819 at 1847SS 1566.848 x at — 1636.36 244503 a 2.28069 244736 a 1.63S28 232795 a 188485 235938 a 2.53577 AFFX- 3.11913 M27830 3 at 233365 a 2.76277 234282 a 2.01659 241667 X at — 17844 243211 a 1.95149 557029 a 1.88354 564878 a 1.97934 242419 a 1546O1 560049 a 3.57O66 243401 a 2.22064 561012 a 3.09703 564451 a 2.88901 563.077 a 2.08269 244637 a 83073 243694 a 56713 237,422 a. 60881 557348 a 3.30543 564097 a 2.32219 24O157 a 802.17 241.222 a. 724O7 216104 a 72674 570506 a 2.2933S 561418 a 2.52035 561658 a 2.77763 243035 a. 77962 234.179 a 4.17162 56O760 S at — 3.16782 231040 a 9811S 24.1387 a 2.261.99 559724 at 82952 232793 a 2.69051 216007 a 91365 238,414 a 93,724 562464 at 2.31276 232582 a 64746 244867 a 2.06707 234652 a 61083 236256 a 97291 232723 a 2.09444 233043 a 2.71.78 US 2016/02375O1 A1 Aug. 18, 2016 71

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 234593 a 866.62 23.3606 a 3.32752 233668 a 2.298.68 1558O19 at 76057 233593 a 64392 1561777 at 2.1.2493 241536 a 2.91919 236962 a. SO896 1564654 at S8649 244821 a 2.3S422 231597 X at — 3.28195 1564807 at 2.09646 1562137 at 8O249 243781 a 69708 244762 a 2.22632 236276 a 2.OO169 238408 a 244824 156O189 at 70373 1561703 at 3.73005 233427 X at — .53672 233828 a 6531 2345.09 a 2.11383 238,411 X at — 3.424.66 244211 a 94329 221174 a 2.05834 15701.25 at 2.23673 233257 a 2.01.104 233406 a 2.43719 1562351 at 179422 237353 a 2.53975 233053 a 2.26447 243424 a 23 1946 237962 x at — 2.492O2 562613 a 2.67097 566846 a 2.74769 231239 a 81363 562311 a S2118 216496 s at — 698.18 562853 x at — 6179 215801 a 2.67753 569809 a S4798 566469 a 2.73721 569858 a 2.28984 563561 a 95.979 562828 a 91629 559.434 a 2.23908 240738 a 68.702 555498 a 8321 561309 x at — 5393 566658 a 884.95 243828 a 87947 239887 a 96566 231315 a. 2.14126 556834 a S.456.17 230959 a 3.63868 237361 a 894O1 24.1769 a 2.05931 244112 X at — 3.84372 1566633 at 96.728 216414 a 87759 231598 x at — 4.5426 237557 a 2.78756 1566969 at 76339 241654 a 2.02175 240522 a. 83066 1562420 at 2.41252 234827 a 91205 216214 a 2.46673 231546 a 98.214 1562820 at 67996 233744 a 99.092 243902 a 2.50007 US 2016/02375O1 A1 Aug. 18, 2016 72

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 2345.31 a 2O8946 1561453 at 686.06 237207 a 2.79429 216595 a 3.777.26 1568611 at 2.16277 1566716 at 92697 240502 a 3.31561 238178 a 87863 1562076 at 2.40574 234581 a 71821 239993 a 6141 1561087 at 2.91713 239303 a 83918 24O788 a .76033 234578 a 933.38 241633 X at — 98.454 24.1509 a 883O7 566938 at 62844 241636 X at — 2.81.114 562169 at 2.81OOS 242715 a. 3.98461 568872 at .7538 556021 at 26888 24.1254 a 2.0837 564083 at 2.39374 564547 x at — 2.681.96 237149 a .70862 233658 a .82247 228732 a 55938 561450 at .708O2 234104 a 61476 563190 at 2.07844 241870 a .8S956 233448 s at — 2.276 561351 at 2.OO141 239970 a 3.00339 559149 at 901.07 569944 at 2.22129 216745 x at — 747 561199 at 3.48145 241583 x at — 90832 234228 at 73472 241287 X at — 75873 23.3853 at 55509 566970 a 2.31372 224.546 at 2.91364 57.0191 a 2.76356 215.810 X at — 56175 231284 at 94763 239025 at 66351 566748 a 2.34934 56.9577 X at - 81.271 562083 a 3.40841 234279 at 75062 236576 at 7866S 562677 a 8276 56O131 a 2.6117 216858 x at — 5146 556622 s at — 2.389.38 244258 at 2.02288 566426 a 2.34526 555365 x at - 2.62O6 561938 a 2.13371 560745 a. 1.79518 234558 at 182691 216764 at 1.78566 57O155 a. 2.22005 561411 a 1.S1791 564070 s at — 164228 233449 at 1.7630S 216286 at 2.06666 240431 at 186816 US 2016/02375O1 A1 Aug. 18, 2016 73

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 244613 at 1.93862 241628 at 2O1118 564134 at 2.32579 555.187 at 1.S2436 566863 at 4.56348 237898 at 1.S1413 563138 at 1.72121 238358 x at — 3.14686 243533 x at — 2.2352 55817O at 2.47388 56.4107 at 2.4479 234773 x at — 185715 556936 at 2.OO32 561143 at 1.531.23 242420 a 2.36834 222325 a. 3.02684 568878 at 2.17186 220874 a 2.17222 222300 a 2.40438 243262 a 186741 570176 at 2.79226 562111 at S.11742 555364 at 2.73119 244668 a 2.52855 233875 a. 2.9792 239959 X at - 60572 215634 a 2.33921 233908 X at — 3.48141 237458 a S91.63 156O775 at 2.48169 239.095 a 2.26387 241044 X at — 2.11189 228731 a 87164 1559360 at 2.731.46 233529 a 63141 238410 X at — 2.90964 234087 a 80534 241061 a 2.21281 230859 a 2.68677 237675 a. S4439 234723 x at — 901.96 1561364 at 3.40486 1561953 at 2.391.51 215849 X at — 72743 1566887 x at — 2.41216 1560517 s at — 2.16789 220851 at 2.14141 238392 at 84284 1566609 at 2.486.79 1564610 at 98.581 215811 at 2.30524 1563396 x at — 65546 24.1584 at 90797 228679 at 2.37OO1 241119 at 2.461.46 237.933 at 2.58.393 1570624 at .7321 242500 at 3.04.026 216575 at 4.14875 1566637 at 2.58398 1566967 at 2.6.1969 2363.89 x at — 1.73264 1563941 at 3.17348 244480 at 3.52279 233372 at 1.65994 1563115 at 2.22091 1562642 at 3.39927 1561473 at 2.4745 238362 at 3.295.08 1564767 at 262248 241200 X at — 1.72239 242532 at 4.O3908 US 2016/02375O1 A1 Aug. 18, 2016 74

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 238297 a 2.10442 1570300 at 2.38986 1562678 at 2.4369 237700 a 2.31864 1561212 at 2.10873 240208 a 173797 238755 a. 2.35516 241883 x at — 167224 243183 a 2.870O8 1559780 at 18O843 237454 a 1849O2 233.133 a 186437 237608 a 167052 215643 a 3.2O534 237399 a 2.5O183 1560144 at 2.65265 220859 a 2.286.17 237049 a 1.59226 216463 a 2.33052 1555373 at 24O199 1561657 at 1.67151 24O921 a 193703 1569409 x at — 162694 237552 a. 2.25696 238390 a 3496.33 220878 a 2.63943 244420 a 2.17474 1561895 at 2.590O3 233373 a 2.31025 232712 a 3.31619 244282 a 64142 215473 a 73547 238.274 a .71931 243041 s at — 3.902 215448 a S.O.9122 241542 a. 2.64253 237480 a 97714 242769 a 2.65101 240956 a 2.82294 242840 a 81443 558048 x at — 4.43301 241094 a 94O22 241945 a. 75756 56.1242 a. 3.36844 216319 a 2.21853 569927 a 2.86702 234096 a 898.63 242645 a. 2.01823 234653 a .92OOS 557778 a .77943 563494 a 61383 215962 a 3.6O791 242652 a 9361 561795 a .78961 566498 a 2.74467 563963 a 2.14216 23838.6 X at — 99773 232817 at 2.194O6 569759 a 2.46257 244885 at 90316 242310 at 91359 56.9596 a 3.39789 241.183 at 2.94.372 230791 at 3.79676 570268 a 2.16933 557832 a. 2.09744 570177 a 2.4673 234655 at 189067 561065 a 1.64279 562480 a 3.83981 557644 a 2.59969 234690 at 169061 US 2016/02375O1 A1 Aug. 18, 2016 75

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 216518 at 1.90215 234794 at 2.89785 240186 at 3.29381 240714 at 2.18363 217 132 at 1.72792 1561881 at 2.35965 1562992 at 2.46132 1568794 at 2.94.OOS 1568936 a. at — 2.0225 1557665 at 2.99.179 233944 a 4.72O23 24016O X at — 1.65O13 231212 X at — 289146 243756 a 2.11775 232944 a 2.10953 243177 a 3.23332 243442 X at — 19452 243897 a 182779 240825 a. 2.47627 1569664 at 4.4506S 228936 a 2.51633 1562353 x at — 1.69798 224237 a 2.90306 2441.69 X at — 3.29.173 241632 X at — 1.59752 228934 x at — 2.47447 220877 a 2.67012 228218 a 2.19026 1561340 at 1.598.17 240988 x at — 3.81.074 234270 a 2.29.525 1570246 at 2.06463 24O904 a 2.724.54 238368 a 4.76547 240364 a 2.02402 233209 a 254469 215290 a 3.33519 233035 a. 1.72582 562997 a. at — 2.34S47 2298.23 a 1.67524 244866 a 2.04538 563546 a 6.23891 233906 a 3.09354 242266 X at — 2.86831 2434.66 a 2.071.49 570623 a 2.34232 243632 a. 2.62996 240864 a 3.791.35 569539 a 5.27322 243489 a 6.03255 2O7744 a 2.86433 237684 a 2.31226 57.0054 a 19518 557025 a. at - 3.49339 566115 a. 2.72849 561069 a 3.10071 564840 a 2.471.98 215976 at 2.16509 563660 a 4.23944 216290 x at — 190371 233401 at 4.47S35 233653 at 1.6959 234015 at 2.59514 1563026 at 2.232 210893 at 2.14379 1563316 at 410042 1554225 a. at — 3.18715 1562071 at 173705 1561754 at 5.09305 232453 at 2.65615 243273 at 2.91.387 244300 at 1.81931 US 2016/02375O1 A1 Aug. 18, 2016 76

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 238381 X at — 1.850.34 1561713 at 3.415 234213 at 15293 231494 at 4.23233 1560025 at 3.35764 217617 at 2.45438 1570152 at 2.42411 235079 at 2.2S4O1 1564841 at 3.20049 237871 x at — 3.55396 236881 at 186195 233932 at 3.68719 234137 S at — 2.30775 568660 a. at — 3.72993 222339 x at — 2.47329 563.033 x at — 6.31222 559814 a 2.7905 556794 a 2.98S74 560002 a 1936.16 561879 a 2.39371 237.596 a 3.34796 561513 a 18622 241673 X at — 2.8O804 561767 a 2.33844 228827 a 4.64642 563332 a 195777 562800 a 2.06622 23.7530 a. 2.59509 244412 a 2.89052 232538 a 3.79966 561543 a 5.85562 555926 a. at — 3.01372 238407 a 2.73065 24O112 a 2.66998 556989 a 2.84888 24.1506 a 2.4216 563.038 a 2.87832 237983 a 3.01582 5631.87 a 3.70922 559697 a. at - 3.36172 557762 a. 5.09552 564631 a 2.34427 239984 at 2.4818 556935 a. 4.49148 233793 at 3.15092 561902 a 3.08744 232935 at 2.11436 244051 at 1.SS456 562797 a 3.02768 563.032 a 6.9936S 242232 at 3.47935 563189 a 4.43695 228502 at 3.37897 222288 at 6.71681 556983 a at — 3.928.04 558496 a 5.841.22 566600 a 199013 557645 a. 2.36718 231227 at 190383 238384 x at — 3.07283 240331 at 6.6OOO3 569818 a 2.5437 562084 a 4.883O8 238103 at 2.96539 561448 a 2.8O876 24O992 at 170856 568812 a 2.82372 562276 a 4.36824 564964 a S.68325 233330 s at — 4.92758 233282 at 3.534O2 233331 at 2.994.13 US 2016/02375O1 A1 Aug. 18, 2016 77

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 241649 a 1987O1 1568711 a. at — 1.88935 215736 a 3.18179 1553498 at 3.65853 1559696 at 7.OO732 241569 a 2.15149 241770 x at — 2.354.49 238956 a 1.77345 234105 a 2.45775 241026 a 2.03428 1560533 at 183344 1559336 at 3.17434 238852 a 1851.11 244626 a 3.61861 231687 a 2.06469 243974 a 2.23O29 1561642 at 2.17232 233611 a 2.79902 1569545 at 2.96746 1569853 at 2.348O8 217569 x at — 22O119 244216 a 3.52052 234057 a 3.12494 216406 a 3.25332 241676 x at — 3.07696 234906 a 2.942S1 563881 a 2.97996 237937 X at - 7.10043 561856 a 8.77012 561529 a 1932S6 230.064 a 2.99589 564676 a. at — 3.7315 562755 a. 4.87812 235494 a 26SSO9 568871 a 1.71949 562873 a 1.93S11 561214 a 4.07318 242718 a 2.S6091 562811 a 2.21403 241457 a 2.64311 564851 a 2.15494 217085 a 2.04989 241566 a 4.90225 562916 a 4.O1294 564306 a 3.50683 243398 a 4.93S21 241.247 a 2.4O905 561213 a 2.01136 569810 a 3.1075 5666.22 a. 3.07274 241312 a 3.10323 241567 a 2.31223 560905 a 5.46696 560086 a 3.09926 556263 s at — 2.85.076 244612 a 5.78514 560296 a 3.17524 231503 a 3.63922 222342 a. 2.8616 56.6638 a 190699 561926 a 3.80796 563O87 a 242998 234601 X at — 168879 216728 at 3.901.74 562610 a 1.96876 2345.02 at 3.82276 242198 at 2.81983 234235 at 5.71387 241675 s at — 6.66189 1555,263 at 2.30475 1566862 at 3.92941 207 731 at 7.5.127 US 2016/02375O1 A1 Aug. 18, 2016

TABLE 8-continued Table 8- Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change a 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 231074 at 5.19962 237233 at 4.19082 233279 at 2.6O1 237479 at 6.74O27 2428O2 X at — 4621.83 234800 at 188126 231091 x at — 3.87591 241674 S at — 6.55087

TABLE 9 TIA subtype specific genes: pathways Ingenuity Canonical i Pathways p-value Molecules Molecules Axonal Guidance 2.48E-O3 32 LRRC4C, BDNF, ARHGEF7, UNCSB, PGF, IGF1, Signaling SDC2, SRGAP1, EFNA5, ROBO2, SEMA3E, EPHA7, ADAM2, SHANK2, PTCH1, PIK3C2G, EPHA3, BMP5, ADAM18, GNAS, PLCB4, ADAM30, NTRK2, PAK3, ADAM12, NTRK3, SEMA6D, GNAO1, EPHA5, PAK7, WNTSA, FZD7 Hepatic Fibrosis, 151E-O2 13 LEP, EDNRB, IGFBP5, PGF, COL1A2, COL1A1, Hepatic Stellate Cell GF1, PDGFRA, TGFB2, IFNAR1, AGTR1, Activation COL3A1, EGFR Human Embryonic 1.34E-O2 13 BDNF, TDGF1, PIK3C2G, BMP5, GNAS, BMPR1B, StemCell NANOG, NTRK2, NTRK3, PDGFRA, TGFB2, Pluripotency FZD7, WNT5A Neuropathic Pain 9.78E-03 11 GRM5, GRM7, PLCB4, NTRK2, GPR37, BDNF, Signaling In Dorsal GRM8, GRM3, PIK3C2G, GRIA2, GRIA3 Horn Neurons Bladder Cancer S.O8E-03 11 FGF18, MMP26, MMP16, FGF14, FGF12, FGF20, Signaling FGF7, PGF, EGFR, MMP19, FGF5 Amyotrophic Lateral 2.02E-O2 10 NOS1, CACNA1E, IGF1, HECW1, PIK3C2G, Sclerosis Signaling GRIA2, CACNA1C, GRIK2, PGF, GRIA3 Glutamate Receptor 2.74E-O3 9 GRM5, GRM7, SLC17A6, GRM8, GRM3, GRLA2, Signaling GRIK2, HOMER1, GRIA3 GABA Receptor 2.23E-O3 8 SLC6A11, GABBR2, GABRB3, GABRA4, Signaling GABRB1, GABBR1, MYOSB, GABRB2 Agrin Interactions at 2.35E-02 8 NRG2, PAK3, ARHGEF7, ERBB4, NRG1, PAK7, Neuromuscular ERBB3, EGFR Junction Maturity Onset 2.46E-O2 4 CACNA1E, ALDOB, FOXA2, CACNA1C Diabetes of Young (MODY) Signaling

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Lowe G D, Campbell DJ et al. gested to persons skilled in the art and are to be included Associations of inflammatory and hemostatic variables within the spirit and purview of this application and scope of with the risk of recurrent stroke. Stroke. 2005; 36:2143 the appended claims. All publications, sequence accession 2147 numbers, patents, and patent applications cited herein are 0208 15. Kang D. W. Yoo SH, Chun Set al. Inflammatory hereby incorporated by reference in their entirety for all pur and hemostatic biomarkers associated with early recurrent poses. ischemic lesions in acute ischemic stroke. Stroke. 2009; 1-47. (canceled) 40:1653-1658 48. A solid Support comprising a plurality of nucleic acids 0209 16. Moore DF, Li H, Jeffries Netal. Using periph that hybridize to a plurality of genes comprising ATG9B, eral blood mononuclear cells to determine a gene expres DIP2C, DKFZP434B061, EDAR, FAM55D, FLJ30375, sion profile of acute ischemic stroke: a pilot investigation. GSTM1, GUSBL2, IGFBP5, LTBR, SCN2A, SMURF2, Circulation. 2005; 111:212-221 ZNF512B, wherein genes which are overexpressed or under 0210, 17. Tang Y. Xu H, Du X et al. Gene expression in expressed less than 1.5-fold in Subjects having or Suspected of blood changes rapidly in neutrophils and monocytes after having TIA, in comparison to a control level of expression are ischemic stroke in humans: a microarray study. J Cereb excluded. Blood Flow Metab. 2006; 26:1089-1102 49. (canceled) 0211 18. Xu H, Tang Y. Liu DZetal. Gene expression in 50. The solid support of claim 48, further comprising a peripheral blood differs after cardioembolic compared plurality of nucleic acids that hybridize to a plurality of the with large-vessel atherosclerotic stroke: biomarkers for the genes selected from the group consisting of SNIP. BXDC5, etiology of ischemic stroke. J Cereb Blood Flow Metab. FAT3, LECT2, THSD4, CCDC144C///LOC100134159, 2008; 28:1320-1328 OVOL2, SPTLC3, CLEC4E, GLYATL1, RBMS3, SPIB, 0212 19. Giles MF, Rothwell PM. Systematic review and DKFZP434L187, GADL1, SHOX, TBX5, UNC5B, PGM5, pooled analysis of published and unpublished validations TIMP2, ELL2, CXADR, and RNF141. of the ABCD and ABCD2 transient ischemic attack risk 51. The solid support of claim 48, further comprising a scores. Stroke. 2010:41:667-673 plurality of nucleic acids that hybridize to a plurality of the 0213 20. Cucchiara B L. Messe S R. Sansing L et al. genes selected from the group consisting of RPL22, SNIP. D-dimer, magnetic resonance imaging diffusion-weighted SH3GL3, MCTP1, FAT3, SPTLC3, RBMS3, SNRPN, and imaging, and ABCD2 score for transient ischemic attack TIMP2. risk stratification.J Stroke Cerebrovasc Dis. 2009; 18:367 52. The solid support of claim 48, further comprising a 373 plurality of nucleic acids that hybridize to a plurality of the 0214) 21. Andersohn F. Waring M, Garbe E. Risk of genes selected from the group consisting of FGD4, F5. ischemic stroke in patients with Crohn's disease: A popu ABCA1., LOC100290.882, LTB4R, UBXN2B, CKLF, lation-based nested case-control study. Inflamm Bowel Dis. CLEC4E, PHTF1, ENTPD1, OSBPL1A, RRAGD, CPEB2, 2009 CKLF, BST1, and CKLF. US 2016/02375O1 A1 Aug. 18, 2016

53. The solid support of claim 48, further comprising a 60. The solid support of claim 48, further comprising a plurality of nucleic acids that hybridize to a plurality of the plurality of nucleic acids that hybridize to a plurality of the genes selected from the group consisting of ZNF608, genes selected from the group consisting of USP7, MAPRE2. FCHO2, ST3GAL6, ABCA1, THED, AMN1, QKI, CSNK1G2, SAFB2, PRKAR2A, PI4KB, CRTC1, HADHA, KIAA0319, MCTP1, VNN3, UBR5, FAR2, RBM25, MAP1LC3B, KAT5, CDC2L1///CDC2L2, GTSE1, TCF25, CHMP1B, LAMP2, VAPA, IFRD1, HNRNPH2, REM2, and CHP, LRRC40, hCG 2003956///LYPLA2///LYPLA2P1, GAB1. DAXX, UBE2NL, EIF1, KCMF1, PRKRIP1, CHMP4A, 54. The solid support of claim 48, further comprising a TMEM184C, TINF2, PODNL1, FBXO42, LOC441258, plurality of nucleic acids that hybridize to a plurality of the RRP1, C10orf104, ZDHHC5, C90rf23, LRRC45, NACC1, genes selected from the group consisting of THSD4, SNRPN, LOC100.133445///LOC115110, PEX16. ASTN2, SNIP, FAT3, TIMM8A, CCDC144C/// 61. The solid support of claim 48, wherein the solid support LOC100134159, ANKRD28, TBX5, PGM5, SCD5, FCRL4, is a microarray. SHOX, CCRL1, LECT2, PTPRD, CCDC144A, LDB3, 62. The solid support of claim 48, wherein genes that are LOC729222///PPFIBP1, RBMS3, P704P, GYPA, PRTG, overexpressed or underexpressed less than 1.2-fold in sub GABRB2, HNRNPUL2, ELAVL2, SPTLC3, FOXA2, jects with ischemic stroke, including cardioembolic stroke, DLX6, ALDOAP2, and FLJ35934. atherothrombotic stroke, and stroke Subsequent to atrial 55. The solid support of claim 48, further comprising a fibrillation, in comparison to a control level of expression are plurality of nucleic acids that hybridize to a plurality of the excluded. genes selected from the group consisting of RPL22, 63. The solid support of claim 48, wherein the solid support LOC100129488, LOC283027, LOC344595, THSD4, FAT3, comprises 100 or fewer nucleic acids. and P704P. 64. The solid support of claim 48, further comprising a 56. The solid support of claim 48, further comprising a plurality of nucleic acids comprising Affymetrix probeset ID plurality of nucleic acids that hybridize to a plurality of the numbers 1557580 at, 1559695 a at, 1561767 at 1563026 genes selected from the group consisting of SNIP. BXDC5, at, 1563568 at 1568589 at, 1568781 at, 21.6406 at, FAT3, LECT2, THSD4, CCDC144C///LOC100134159, 2296.54 at, 231040 at, 231069 at, 231546 at, 233306 at, OVOL2, SPTLC3, CLEC4E, GLYATL1, RBMS3, SPIB, 236571 at 237597 at 237953 at 242495 at 242564 at, DKFZP434L187, GADL1, SHOX, TBX5, UNC5B, PGM5, 242710 at, 244226 s at, and 244665 at. TIMP2, ELL2, CXADR, RNF141, RPL22, SH3GL3, 65. A solid Support comprising a plurality of nucleic acids MCTP1, SNRPN, FGD4, F5, ABCA1., LOC100290882, that hybridize to a plurality of genes comprising only ATG9B, LTB4R, UBXN2B, CKLF, PHTF1, ENTPD1, OSBPL1A, DIP2C, DKFZP434B061, EDAR, FAM55D, FLJ30375, RRAGD, CPEB2, CKLF, BST1, ZNF608, FCHO2, GSTM1, GUSBL2, IGFBP5, LTBR, SCN2A, SMURF2, ST3GAL6, THBD, AMN1, QKI, KIAA0319, MCTP1, ZNF512B, SNIP, BXDC5, FAT3, LECT2, THSD4, VNN3, UBR5, FAR2, RBM25, CHMP1B, LAMP2, VAPA, CCDC144C///LOC100134159, OVOL2, SPTLC3, IFRD1, HNRNPH2, REM2, GAB1, ASTN2, TIMM8A, CLEC4E, GLYATL1, RBMS3, SPIB, DKFZP434L187, CCDC144C///LOC100134159, ANKRD28, SCD5, FCRL4, GADL1, SHOX, TBX5, UNC5B, PGM5, TIMP2, ELL2, CCRL1, LECT2, PTPRD, CCDC144A, LDB3, CXADR, RNF141, RPL22, SH3GL3, MCTP1, FAT3, LOC729222///PPFIBP1, P704P, GYPA, PRTG, GABRB2, SPTLC3, RBMS3, SNRPN, FGD4, F5, ABCA1, HNRNPUL2, ELAVL2, FOXA2, DLX6, ALDOAP2, LOC100290882, LTB4R, UBXN2B, CLEC4E, PHTF1, FLJ35934, LOC100129488, LOC283027, and LOC344595. ENTPD1, OSBPL1A, RRAGD, CPEB2, CKLF, BST1, 57. The solid support of claim 48, further comprising a ZNF608, FCHO2, ST3GAL6, ABCA1, THBD, AMN1, QKI, plurality of nucleic acids that hybridize to a plurality of the KIAA0319, MCTP1, VNN3, UBR5, FAR2, RBM25, genes selected from the group consisting of EBF1, GRM5, CHMP1B, LAMP2, VAPA, IFRD1, HNRNPH2, REM2, TSKS, ENPP2, AP3S2, LRRC37A3, C16orf68, GAB1, THSD4, SNRPN, ASTN2, FAT3, TIMM8A, LOC284751, IRF6, LHFP, BANK1, ARHGEF5, ZNF254, CCDC144C///LOC100134159, ANKRD28, TBX5, PGM5, TFDP1, COL13A1, GSTK1, ADAMTSL4, P2RX5, LHFP. SCD5, FCRL4, SHOX, CCRL1, LECT2, PTPRD, PIK3C2B, CHURC1, EXT2, HLA-DOA, OOEP, ZNF185, CCDC144A, LDB3, LOC729222///PPFIBP1, RBMS3, TMEM19, FCRL1, FLJ4.0125, ARHGEF12, CLEC18A, P704P, GYPA, PRTG, GABRB2, HNRNPUL2, ELAVL2, CD46, PTPN20A/PTPN2OB, and C19orf28. SPTLC3, FOXA2, DLX6, ALDOAP2, FLJ35934, RPL22, 58. The solid support of claim 48, further comprising a LOC100129488, LOC283027, LOC344595, THSD4, FAT3, plurality of nucleic acids that hybridize to a plurality of the P704P, BXDC5, FAT3, LECT2, THSD4, CCDC144C/// genes selected from the group consisting of EBF1, FLJ31945, LOC100134159, OVOL2, SPTLC3, CLEC4E, GLYATL1, C16orf68, SLC20A1, DOPEY2, COL13A1, LHFP. RBMS3, SPIB, DKFZP434L187, GADL1, SHOX, TBX5, LOC284751, GRM5, LOC10014.4603, MTBP, SHOX2, UNC5B, PGM5, TIMP2, ELL2, CXADR, RNF141, RPL22, ARHGEF5, RNF7, CLASP2, GIPC2, RANBP10, CMBL, SH3GL3, MCTP1, SNRPN, FGD4, F5, ABCA1, LOC100.127980, CYTH3, PROCR, LOC146880, SLC6A19, LOC100290882, LTB4R, UBXN2B, PHTF1, ENTPD1, ICAM4, C12orfA2, ARHGEF12, PRSS35, NT5E, OSBPL1A, RRAGD, CPEB2, BST1, ZNF608, FCHO2, LOC100271832, LHFP. NT5E and AKR1C3. ST3GAL6, THBD, AMN1, QKI, KIAA0319, MCTP1, 59. The solid support of claim 48, further comprising a VNN3, UBR5, FAR2, RBM25, CHMP1B, LAMP2, VAPA, plurality of nucleic acids that hybridize to a plurality of the IFRD1, HNRNPH2, REM2, GAB1, ASTN2, TIMM8A, genes selected from the group consisting of CMTM1, CCDC144C///LOC100134159, ANKRD28, SCD5, FCRL4, COL13A1, SDC4, C60rf164, GPR176, BRUNOL6, CCRL1, LECT2, PTPRD, CCDC144A, LDB3, SNORA68, MIF///SLC2A11, DUSP16, HIPK2, TTC7A, LOC729222///PPFIBP1, P704P GYPA, PRTG, HNRN PPIE, GRLF1, MAP3K7IP1, LOC100129034, PER3, PUL2, FOXA2, DLX6, ALDOAP2, FLJ35934, SMC1A, and LRRC43. LOC100129488, LOC283027, LOC344595, EBF1, GRM5,