US 2012OO15904A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0015904 A1 SHARP et al. (43) Pub. Date: Jan. 19, 2012

(54) BIOMARKERS FOR DIAGNOSIS OF Publication Classification TRANSIENT SCHEMICATTACKS (51) Int. Cl. C40B 30/04 (2006.01) (75) Inventors: Frank SHARP, Davis, CA (US); CI2O I/68 (2006.01) Xinhua ZHAN, Vacaville, CA C40B 40/06 (2006.01) (US); Glen C. JICKLING, A613/60 (2006.01) Sacramento, CA (US); S. Claiborne A6IP 9/10 (2006.01) JOHNSTON, San Francisco, CA A 6LX 3/59 (2006.01) (US) A 6LX 3L/727 (2006.01) A63/37 (2006.01) (73) Assignee: Regents of the University of A6II 3/4439 (2006.01) California, Oakland, CA (US) GOIN 33/53 (2006.01) A63L/4365 (2006.01) (21) Appl. No.: 13/182,630 (52) U.S. Cl...... 514/56; 436/501:506/9; 435/6.12: 506/16; 514/165; 514/301; 514/262. 1: 514/457; (22) Filed: Jul. 14, 2011 514/338 (57) ABSTRACT Related U.S. Application Data The present invention provides methods and compositions for (60) Provisional application No. 61/364,334, filed on Jul. diagnosing and predicting the risk and cause of transient 14, 2010. ischemic attacks (TIA). Patent Application Publication Jan. 19, 2012 Sheet 1 of 4 US 2012/OO15904 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 claims the benefit of U.S. Provi 0008. The present invention provides compositions and sional Application No. 61/364,334, filed on Jul. 14, 2010, the methods for determining the occurrence, predicting the risk entire disclosure of which is hereby incorporated herein by of occurrence and predicting the cause of transient ischemic reference for all purposes. attacks. 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, 0002 This invention was made with Government support wherein an increase or decrease of the level of expression under Grant No. NSO56302, awarded by the National Insti compared to a control indicates that the patient has suffered or tutes of Health. The government has certain rights in this is at risk of experiencing TIA, wherein the plurality of TIA invention. associated biomarkers is selected from the biomarkers set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and 9. FIELD OF THE INVENTION 0010. In some embodiments, the methods further com 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, thee 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 F 1136144, CARDS, 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 2012/OO 15904 A1 Jan. 19, 2012

F1137786, 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///RP11-9412.2, 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, SCAMPS, 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 F1130375, arkers. In some embodiments, the one or more or all endog SCN2A, DKFZP434B061, LTBR, FAMSSD, and IGFBPS 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, PI4 KB, encing TIA. In some embodiments, detection of a decreased CRTC1, HADHA, MAP1LC3B, KAT5, CDC2L1/// level of expression of a biomarker selected from NELL2, CDC2L2, GTSE1, CDC2L1///CDC2L2, TCF25, CHP, APBA2 and MLL indicates that the patient suffered or is at LRRC40, hCG 2003956/1/LYPLA2///LYPLA2P1, DAXX, risk of experiencing TIA. UBE2NL, EIF1, KCMF1, PRKRIP1, CHMP4A, 0.018. In some embodiments, the methods further com TMEM184C, TINF2, PODNL1, FBXO42, LOC441258, prises the step of determining the cause of stroke. In some RRP1, C10orf104, ZDHHC5, C90rf23, LRRC45, NACC1, embodiments, the patient overexpresses a plurality of genes LOC100.133445///LOC115110, PEX16 are determined as a listed in Table 7, indicative of a chronic inflammatory state. In control. Some embodiments, the level of expression of one or more or 0028. In some embodiments, the control is the expression all genes selected from the group consisting of MMP16, level of the same biomarker in a healthy individual. In some US 2012/OO 15904 A1 Jan. 19, 2012

embodiments, the control is the expression level of the same vasculitis, strokes caused by infection, strokes caused by 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, F1130375, 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, US 2012/OO 15904 A1 Jan. 19, 2012 urine, etc. A biological sample is typically obtained from a hybridization of nucleic acids is found in Tijssen, Techniques 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 generally be produced using mechanical synthesis methods conditions will be those in which the salt concentration is less or light directed synthesis methods which incorporate a com than about 1.0 M sodium ion, typically about 0.01 to 1.0 M bination of photolithographic methods and Solid phase Syn sodium ion concentration (or other salts) at Ph 7.0 to 8.3 and thesis methods. Techniques for the synthesis of these arrays the temperature is at least about 30°C. for short probes (e.g., using mechanical synthesis methods are described in, e.g., 10 to 50 nucleotides) and at least about 60°C. for long probes U.S. Pat. No. 5,384.261. Arrays may comprise a planar sur (e.g., greater than 50 nucleotides). Stringent hybridization face or may be nucleic acids or peptides on beads, gels, conditions may also be achieved with the addition of desta polymeric Surfaces, fibers such as fiber optics, glass or any bilizing agents such as formamide. For selective or specific other appropriate Substrate as described in, e.g., U.S. Pat. hybridization, a positive signal is at least two times back Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800, ground, optionally 10 times background hybridization. 992. Arrays may be packaged in Such a manner as to allow for Exemplary stringent hybridization conditions can be as fol diagnostics or other manipulation of an all inclusive device, lowing: 50% formamide, 5xSSC, and 1% SDS, incubating at as described in, e.g., U.S. Pat. Nos. 5,856,174 and 5,922,591. 42°C., or, 5xSSC, 1% SDS, incubating at 65° C., with wash 0039. The term “gene” means the segment of DNA in 0.2XSSC, and 0.1% SDS at 65° C. involved in producing a polypeptide chain; it includes regions 0043. Nucleic acids that do not hybridize to each other preceding and following the coding region (leader and trailer) understringent hybridization conditions are still substantially as well as intervening sequences (introns) between individual identical if the polypeptides which they encode are substan coding segments (exons). tially identical. This occurs, for example, when a copy of a 0040. The terms “nucleic acid and “polynucleotide' are nucleic acid is created using the maximum codon degeneracy used interchangeably herein to refer to deoxyribonucleotides permitted by the genetic code. In Such cases, the nucleic acids or ribonucleotides and polymers thereof in either single- or typically hybridize under moderately stringent hybridization double-stranded form. The term encompasses nucleic acids conditions. Exemplary "moderately stringent hybridization containing known nucleotide analogs or modified backbone conditions’ include a hybridization in a buffer of 40% forma residues or linkages, which are synthetic, naturally occurring, mide, 1 MNaCl, 1% SDS at 37°C., and a wash in 1xSSC at and non-naturally occurring, which have similar binding 45° C. A positive hybridization is at least twice background. properties as the reference nucleic acid, and which are Those of ordinary skill will readily recognize that alternative metabolized in a manner similar to the reference nucleotides. hybridization and wash conditions can be utilized to provide Examples of such analogs include, without limitation, phos conditions of similar stringency. phorothioates, phosphoramidates, methyl phosphonates, 0044) The terms “isolated,” “purified,” or “biologically chiral-methyl phosphonates, 2-O-methyl ribonucleotides, pure” refer to material that is substantially or essentially free peptide-nucleic acids (PNAs). from components that normally accompany it as found in its 0041 Unless otherwise indicated, aparticular nucleic acid native state. Purity and homogeneity are typically determined sequence also encompasses conservatively modified variants using analytical chemistry techniques such as polyacryla thereof (e.g., degenerate codon Substitutions) and comple mide gel electrophoresis or high performance liquid chroma mentary sequences, as well as the sequence explicitly indi tography. A protein that is the predominant species present in cated. Specifically, degenerate codon Substitutions may be a preparation is substantially purified. The term “purified’ achieved by generating sequences in which the third position denotes that a nucleic acid or protein gives rise to essentially of one or more selected (or all) codons is substituted with one band in an electrophoretic gel. Particularly, it means that mixed-base and/or deoxyinosine residues (Batzer et al., the nucleic acid or protein is at least 85% pure, more prefer Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. ably at least 95% pure, and most preferably at least 99% pure. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. 0045. The term "heterologous' when used with reference Probes 8:91-98 (1994)). The term nucleic acid is used inter to portions of a nucleic acid indicates that the nucleic acid changeably with gene, cDNA, mRNA, oligonucleotide, and comprises two or more Subsequences that are not found in the polynucleotide. same relationship to each other in nature. For instance, the 0042. The phrase “stringent hybridization conditions' nucleic acid is typically recombinantly produced, having two refers to conditions under which a probe will hybridize to its or more sequences from unrelated genes arranged to make a target Subsequence, typically in a complex mixture of nucleic new functional nucleic acid, e.g., a promoter from one source acid, but to no other sequences. Stringent hybridization con and a coding region from another source. Similarly, a heter ditions are sequence-dependent and will be different in dif ologous protein indicates that the protein comprises two or ferent circumstances. Longer sequences hybridize specifi more Subsequences that are not found in the same relationship cally at higher temperatures. An extensive guide to the to each other in nature (e.g., a fusion protein). US 2012/OO 15904 A1 Jan. 19, 2012

0046. An "expression vector is a nucleic acid construct, nucleic acid, peptide, polypeptide, or protein sequence which generated recombinantly or synthetically, with a series of alters, adds or deletes a single amino acid or a small percent 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 a 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 Subse analogs have modified R groups (e.g., norleucine) or modi quences that are the same or have a specified percentage fied peptide backbones, but retain the same basic chemical of amino acid residues or nucleotides that are the same structure as a naturally occurring amino acid. “Amino acid (i.e., 60% identity, preferably 65%, 70%, 75%, 80%, mimetics' refers to chemical compounds that have a structure 85%, 90%, or 95% identity over a specified region of a that is different from the general chemical structure of an TIA-associated gene (e.g., a gene set forth in Tables 1, 2, amino acid, but that functions in a manner similar to a natu 5A, 5B, 5C, 5D, 7, 8 and/or 9), when compared and rally occurring amino acid. aligned for maximum correspondence over a compari 0049 Amino acids may be referred to herein by either son window, or designated region as measured using one their commonly known three letter symbols or by the one of the following sequence comparison algorithms or by letter symbols recommended by the IUPAC-IUB Biochemi manual alignment and visual inspection. Such cal Nomenclature Commission. Nucleotides, likewise, may sequences are then said to be “substantially identical.” be referred to by their commonly accepted single-letter codes. This definition also refers to the compliment of a test 0050 “Conservatively modified variants' applies to both sequence. Preferably, the identity exists over a region amino acid and nucleic acid sequences. With respect to par that is at least about 25 amino acids or nucleotides in ticular nucleic acid sequences, conservatively modified Vari length, or more preferably over a region that is 50-100 ants refers to those nucleic acids which encode identical or amino acids or nucleotides in length. essentially identical amino acid sequences, or where the 0063 For sequence comparison, typically one sequence nucleic acid does not encode an amino acid sequence, to acts as a reference sequence, to which test sequences are essentially identical sequences. Because of the degeneracy of compared. When using a sequence comparison algorithm, the genetic code, a large number of functionally identical test and reference sequences are entered into a computer, nucleic acids encode any given protein. For instance, the Subsequence coordinates are designated, if necessary, and codons GCA, GCC, GCG and GCU all encode the amino acid sequence algorithm program parameters are designated. alanine Thus, at every position where an alanine is specified Default program parameters can be used, or alternative by a codon, the codon can be altered to any of the correspond parameters can be designated. The sequence comparison ing codons described without altering the encoded polypep algorithm then calculates the percent sequence identities for tide. Such nucleic acid variations are “silent variations.” the test sequences relative to the reference sequence, based on which are one species of conservatively modified variations. the program parameters. For sequence comparison of nucleic Every nucleic acid sequence herein which encodes a polypep acids and proteins to TIA-associated nucleic acids and pro tide also describes every possible silent variation of the teins, the BLAST and BLAST 2.0 algorithms and the default nucleic acid. One of skill will recognize that each codon in a parameters discussed below are used. nucleic acid (except AUG, which is ordinarily the only codon 0064. A "comparison window', as used herein, includes for methionine, and TGG, which is ordinarily the only codon reference to a segment of any one of the number of contiguous for tryptophan) can be modified to yield a functionally iden positions selected from the group consisting of from 20 to tical molecule. Accordingly, each silent variation of a nucleic 600, usually about 50 to about 200, more usually about 100 to acid which encodes a polypeptide is implicit in each about 150 in which a sequence may be compared to a refer described sequence. ence sequence of the same number of contiguous positions 0051. As to amino acid sequences, one of skill will recog after the two sequences are optimally aligned. Methods of nize that individual substitutions, deletions or additions to a alignment of sequences for comparison are well-known in the US 2012/0015904 A1 Jan. 19, 2012 art. Optimal alignment of sequences for comparison can be acid is less than about 0.2, more preferably less than about conducted, e.g., by the local homology algorithm of Smith & 0.01, and most preferably less than about 0.001. Waterman, Adv. Appl. Math. 2:482 (1981), by the homology 0067. An indication that two nucleic acid sequences or alignment algorithm of Needleman & Wunsch, J. Mol. Biol. polypeptides are substantially identical is that the polypeptide 48:443 (1970), by the search for similarity method of Pearson encoded by the first nucleic acid is immunologically cross & Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by reactive with the antibodies raised against the polypeptide computerized implementations of these algorithms (GAP, encoded by the second nucleic acid, as described below. Thus, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics a polypeptide is typically substantially identical to a second Software Package, Genetics Computer Group, 575 Science polypeptide, for example, where the two peptides differ only 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 US 2012/OO 15904 A1 Jan. 19, 2012 describes any molecule, either naturally occurring or Syn (p=1.35x107) and TIA2 groups (p=2.19x107) and no dif thetic, e.g., protein, oligopeptide (e.g., from about 5 to about ference in MMP16 expression between control subjects and 25 amino acids in length, preferably from about 10 to 20 or 12 TIA2 patients (A2). B. MMP26. There was no difference in to 18 amino acids in length, preferably 12, 15, or 18 amino MMP26 expression for all control subjects compared to all acids in length), Small organic molecule, polysaccharide, TIA patients (B1). There was a significant increase in expres 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 the 1. Introduction lead compound, and evaluating the property and activity of 0077 Although transient ischemic attacks (TIAS) are those variant compounds. Often, high throughput Screening common, the underlying biology remains poorly understood. (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, human patients appear to develop different immune response BRIEF DESCRIPTION OF THE DRAWINGS 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 D 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. US 2012/OO 15904 A1 Jan. 19, 2012

0081. 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, 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, TFP1, 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, US 2012/OO 15904 A1 Jan. 19, 2012

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. 0097. In some embodiments, the patient may have coro 0091. 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 0098. In some embodiments, the patient may have Crohn's cludes EG:115669), VWA3B and ZNF438. disease and have increased or decreased expression relative to 0092. In some embodiments, the patient may have arthritis a control level of expression of a plurality of biomarkers and have increased or decreased expression relative to a con selected from the group consisting of ACSL1, AK5, APBA2, trol level of expression of a plurality of biomarkers selected ASTN2 (includes EG:23245), CARD8, DIP2C, DNAH14, from the group consisting of ACSL1, ADM, ASTN2 (in ERAP2, FBLN7, FREM2, GRM5, LHX2, LNPEP. cludes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, MECOM, ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, ROBO1, SFXN1, SLC22A4 (includes EG:6583), SLC26A8, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, SNRPN, SPON1, TGFB2, TLR5, VWA3B and ZNF438. LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, 0099. In some embodiments, the patient may have a neu ROBOT RUNDC3B, S100A12, SLC22A4 (includes rodegenerative disorder and have increased or decreased EG:6583), TNFRSF21, TNPO1, TTC6 (includes expression relative to a control level of expression of a plu EG:115669), VWA3B, ZNF438. rality of biomarkers selected from the group consisting of 0093. In some embodiments, the patient may have athero ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, Sclerosis and have increased or decreased expression relative FOLH1, GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, to a control level of expression of a plurality of biomarkers OPCML, RFX2, SCN2A, SLC22A4 (includes EG:6583), selected from the group consisting of ACSL1, AK5, ASTN2 SLC2A3, SLC3A1, SPON1, TSHZ2 and ZNF608. (includes EG:23245), BMPR1B, CARD16, CNTN4, 0100. In some embodiments, the patient may have Alzhe DMRT1, DNAH14, ERAP2, FOSB, FREM2, GRM5, IL1B, imer's disease and have increased or decreased expression IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, relative to a control level of expression of a plurality of NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, RORB, biomarkers selected from the group consisting of ASTN2 SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, VWA3B. GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, 0094. In some embodiments, the patient may have inflam OPCML, RFX2, SLC22A4 (includes EG:6583), SLC2A3, matory bowel disease and have increased or decreased SLC3A1, SPON1, TSHZ2 and ZNF608. expression relative to a control level of expression of a plu rality of biomarkers selected from the group consisting of 3. Biomarkers Indicative of the Occurrence or Risk ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), of TIA CARD8, DIP2C, DNAH14, ERAP2, FBLN7, FREM2, 0101 Overexpressed biomarkers indicative of the occur GRM5, IL1B, LHX2, LNPEP LTBR, MECOM, NOS3, rence of TIA or useful to predict the risk of experiencing TIA ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, ROBO1, are listed in Table 1. In practicing the present methods, the SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, expression levels of a plurality of biomarkers from Table 1 are SPON1, TGFB2, TLR5, VWA3B and ZNF438. determined, optionally in combination with other TIA-asso 0095. In some embodiments, the patient may have non ciated biomarkers described herein (e.g., in Tables 2, 5A, 5B, insulin-dependent diabetes mellitus and have increased or 5C, 5D, 7, 8 and/or 9) and known in the art. decreased expression relative to a control level of expression 0102 Preferably, the expression levels of a plurality in the of a plurality of biomarkers selected from the group consist range of about 15-85 total biomarkers are determined, for ing of ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes example, about 20-70, 30-60 or 40-50 biomarkers. The EG:23245), CARD8, CCRL1, CNTLN, CNTN4, COL1A2, expression levels of the biomarkers can be concurrently or DIP2C, DMRT1, EPHA3, FAT1, FOXA2, GABRB2, IL1B, sequentially determined. In some embodiments, the expres IQGAP2, ITGBL1, MBNL1, NOS3, NTM, ODZ2, PLSCR1, sion levels of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SPON1, 45, 50, 60, 65,70, 75,80, 85,90, 95, 100, or more, biomarkers SRGAP1, TLR5, UNC84A and VWA3B. listed in Table 1 are determined, optionally in combination 0096. In some embodiments, the patient may have rheu with other TIA-associated biomarkers described herein (e.g., matoid arthritis and have increased or decreased expression in Tables 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9) and known in the relative to a control level of expression of a plurality of art. biomarkers selected from the group consisting of ACSL1, 0103) In patients who have experienced TIA or who are at ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CLTC, risk of developing TIA, the biomarkers of Table 1 are over US 2012/OO 15904 A1 Jan. 19, 2012

expressed in comparison to a control level of expression. A the biomarkers of Table 1 are overexpressed at least 1.5-fold, control level of expression can refer to the level of expression e.g., at least 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, of the same biomarker in an individual who has not had and is 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7- not at risk for a vascular event or the level of expression of a fold, 2.8-fold, 2.9-fold, 3.0-fold, 3.1-fold, 3.2-fold, 3.3-fold, stably expressed endogenous control gene. In patients who 3.4-fold or 3.5-fold, or more, in comparison to a control level have experienced TIA or who are at risk of developing TIA, of expression.

TABLE 1. TIA-associated biomarkers that are upregulated Fold- Fold Change Change (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 TIA up wS Contro (GABA) A receptor, beta 2 NM 021911 227612 at ELAVL3 ELAV (embryonic lethal, NM 001420 3.23425 TIA up wS Contro abnormal vision, NM O32281 Drosophila)-like 3 (Hu antigen C) 1556499 is at COL1A1 collagen, type I, alpha 1 NM OOOO88 2.87107 TIA up wS Contro 210135 S. at SHOX2 short stature homeobox2 NM OO3O3O 2.86893 TIA up wS Contro NM OO6884 242344 at GABRB2 gamma-aminobutyric acid NM 000813 2.72458 TIA up wS Contro (GABA) A receptor, beta 2 NM 021911 213943 at TWIST1 twist homolog 1 NM 000474 2.72279 TIA up wS Contro (Drosophila) 241199 X at DPPA4 developmental NM 0181.89 2.68174 TIA up wS Contro pluripotency associated 4 222253 S at DKFZP434P211 POM121 membrane NR 003714 2.61011 TIA up vs Contro glycoprotein-like 1 pseudogene 206954 a WIT1 Wilms tumor upstream NM O15855 258643 TIA up wS Contro neighbor 1 NR 023920 202935 S. at SOX9 SRY (sex determining NM 000346 2.45928 TIA up wS Contro region Y)-box 9 239309 a DLX6 distal-less homeobox 6 NM OO5222 2.4523 TIA up vs Contro 209369 a ANXA3 annexin A3 NM 005139 241095 TIA up wS Contro 211164 a EPHA3 EPH receptor A3 NM O05233 2.39314 TIA up wS Contro NM 182644 204913 s at SOX11 SRY (sex determining NM OO3108 2.34727 TIA up wS Contro region Y)-box 11 237340 a SLC26A8 solute carrier family 26, NM 052961 2.32491 TIA up vs Contro member 8 NM 138718 220351 a CCRL1 chemokine (C-C motif) NM O16557 2.32444 TIA up vs Contro receptor-like 1 NM 178445 230964 a FREM2 FRAS1 related NM 207361 2.30984 TIA up wS Contro extracellular matrix protein 2 231969 a STOX2 storkhead box2 NM 020225 2.2552 TIA up wS Contro 1555367 at ZNF479 Zinc finger protein 479 NM 033273 2.25193, TIA up wS Contro XM OO1714591 XM OO1719979 1557717 at LOC338862 hypothetical protein 2.22946 TIA up vs Contro LOC338862 1554816 at ASTN2 astrotactin 2 NM 014010 2.22748 TIA up wS Contro NM 1981 86 NM 1981.87 NM 198188 217487 X at FOLH1 folate hydrolase (prostate- NM 001014986 2.19987 TIA up wS Contro specific membrane NM 004476 antigen) 1 241987 X at SNX31 Sorting nexin 31 NM 152628 2.19167 TIA up wS Contro 227250 at KREMEN1 kringle containing NM OO1039570 2.16406 TIA up vs Contro transmembrane protein 1 NM OO1039571 1555368 x at ZNF479 Zinc finger protein 479 NM 033273 2.16203 TIA up vs Contro XM OO1714591 XM OO1719979 1563673 a at ALS2CR11 amyotrophic lateral NM 152525 2.15177 TIA up wS Contro Sclerosis 2 (juvenile) chromosome region, candidate 11 239710 at FIGN fidgetin NM 018086 2.14096 TIA up vs Contro 242385 at RORB RAR-related orphan NM OO6914 2.14023 TIA up vs Contro receptor B US 2012/OO 15904 A1 Jan. 19, 2012 11

TABLE 1-continued TIA-associated biomarkers that are upregulated Fold Fold Change hange (TIA vs. RefSeq, (TIA vs. Control) Probeset ID Gene Symbol Gene Title Transcript ID Control) (Description)

1570009 at LOCA32096 similar to hCG2040240 XM OO1720784 // 2.13184 bws Con O XM OO1725.388 XR 016.064 1559520 at GYPA Glycophorin A NM O02099 2.12904 bws Con O 215783 s at ALPL alkaline phosphatase, NM 000478 2.1006 bws Con O liver/bone/kidney NM OO11275O1 206140 a LHX2 LIM homeobox2 NM OO4789 2.0959 bws Con O 240390 a GALNTS UDP-N-acetyl-alpha-D- NM 014568 2.09257 bws Con O galactosamine:polypeptide N acetylgalactosaminyltransferase 24-1961 a SRDSA2L2 steroid 5 alpha-reductase NM 001010874 2.08494 Au bws Con O 2-like 2 219271 a GALNT14 UDP-N-acetyl-alpha-D- NM O24572 2.076OS Au bws Con O galactosamine:polypeptide N acetylgalactosaminyltransferase 206048 a OVOL2 ovo-like 2 (Drosophila) NM 021220 2.06333 bws Con O 242579 a BMPR1B bone morphogenetic NM 001203 2.05687 bws Con O protein receptor, type IB 226899 a UNCSB unc-5 homolog B (C. elegans) NM 170744 2.04351 bws Con O 231867 a ODZ2 odz, odd Ozften-m NM 00108.0428 2.03143 bws Con O homolog 2 (Drosophila) NM OO1122679 1557924 S at ALPL alkaline phosphatase, NM 000478 2.02022 Au bws Con O liver/bone/kidney NM OO11275O1 217194 a RASAL2 RAS protein activator like 2 NM 004841 2.OO632 Au bws Con O NM 170692 207570 a SHOX short stature homeobox NM 000451 2.OO103 Au bws Con O NM OO6883 235568 a C19Crf59 chromosome 19 open NM 174918 .99789 Au bws Con O reading frame 59 1552946 at ZNF114 Zinc finger protein 114 NM 153608 99445 bws Con O 1554473 at SRGAP1 SLIT-ROBORho GTPase NM O2O762 992O3 bws Con O activating protein 1 228260 at ELAVL2 ELAV (embryonic lethal, NM 004432 9905 bws Con O abnormal vision, Drosophila)-like 2 (Hu antigen B) 1559292 s at NCRNA00032 Clone IMAGE: 2275.835 XM 376821 Au bws Con O C9orf14 mRNA, partial XM 938.938 sequence; alternatively spliced 214984 at LOC440345 hypothetical protein XR O15786 98536 Au bws Con O LOC440345 1557155 a. at FLJ30375 CDNA clone XM OO1724993 Au bws Con O IMAGE: 5301781 XM OO1725199 XM OO1725628 215447 at Tissue factor pathway NM OO 1032281 // Au bws Con O inhibitor (lipoprotein NM OO6287 associated coagulation inhibitor), 228825 at prostaglandin reductase 1 NM 012212 .95262 bws Con O 213194 at roundabout, axon guidance NM OO2941 952O7 bws Con O receptor, homolog 1 NM 133631 (Drosophila) 209119 x at nuclear receptor Subfamily NM 021005 94377 Au bws Con O 2, group F, member 2 206819 at POM121 membrane NR 003714 93567 Au bws Con O glycoprotein-like 1 pseudogene 207235 S. at glutamate receptor, NM OOO842 Au bws Con O metabotropic 5 NM 001143831 201744 s at lumican NM 002345 93131 bws Con O 230999 at CDNA FLJ39051 fis, 926OS bws Con O clone NT2RP701 1452 US 2012/OO 15904 A1 Jan. 19, 2012 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) 229218 at COL1A2 collagen, type I, alpha 2 NM OOOO89 92067 TIA up vs Contro 207500 at CASPS caspase 5, apoptosis- NM 001136109 .91798 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 91158 TIA up vs Contro adhesion molecule-like NM OO2545 1556666 a. at TTC6 tetratricopeptide repeat NM OO1007795 .91015 TIA up vs Contro domain 6 214451 at TFAP2B transcription factor AP-2 NM OO3221 .89347 TIA up vs Contro beta (activating enhancer binding protein 2 beta) 210262 at CRISP2 cysteine-rich Secretory NM OO1142407 .88349 TIA up vs Contro protein 2 NM 001142408 NM 001142417 // NM OO1142435 NM OO3296 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 2290.57 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 if 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 at 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 at CARD8 caspase recruitment NM O14959 78.265 TIA up wS Contro domain family, member 8 235370 at KREMEN1 kringle containing NM OO 1039570 // 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 at FAM149A amily with sequence NM OO1 OO6655 75785 TIA up wS Contro similarity 149, member A NM O15398 US 2012/OO 15904 A1 Jan. 19, 2012 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) 239144 at B3GAT2 beta-1,3- NM 080742 75721 TIA up wS Contro glucuronyltransferase 2 (glucuronosyltransferase S) 235342 at SPOCK3 sparcosteonectin, cwcv NM OO1040159 75.314 TIA up wS Contro and kazal-like domains NM 016950 proteoglycan (testican) 3 1553.024 at G30 protein LG30-like .75094 TIA up wS Contro 214927 at ITGBL1 integrin, beta-like 1 (with NM OO4791 73813 TIA up wS Contro EGF-like repeat domains) 229538 s at IQGAP3 Q motif containing NM 178229 73797 TIA up wS Contro GTPase activating protein 3 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 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 if 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 1.66029 TIA up vs Control XR 041473 205896 at SLC22A4 solute carrier family 22 NM OO3059 1.65918 TIA up vs Control (organic cation ergothioneine transporter), member 4 US 2012/OO 15904 A1 Jan. 19, 2012 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) 226121 at DHRS13 dehydrogenase/reductase NM 144683 165414 TIA up vs Control (SDR family) member 13 21985.0 s at EHF ets homologous factor NM 012153 164412 TIA up vs Control 235.077 at MEG3 maternally expressed 3 NR 002766 1.6384 TIA up vs Control (non-protein coding) NR 003530 NR 003531 214868 at PIWIL1 piwi-like 1 (Drosophila) NM 004764 1.63171 TIA up vs Control 232034 at LOC2O3274 CDNA FLJ31544 fis, 1.631.47 TIA up vs Control clone NT2RI200O865 1556,704 S at LOC10O13392O hypothetical protein NR 024443 1.63O34 TIA up vs Control J. LOC286297 LOC10O13392O XM 001714612 hypothetical protein XM 372109 LOC286297 XM 933054 XM 933058 220493 at DMRT1 doublesex and mab-3 NM O21951 61917 TIA up vs Contro related transcription factor 1 202912 at ADM adrenomedullin NM OO1124 61874 TIA up vs Contro 1561200 at WWA3B von Willebrand factor A NM 144992 618O2 TIA up vs Contro domain containing 3B 1555726 at GAFA3 FGF-2 activity-associated XM OO1715321 // 61768 TIA up vs Contro protein 3 XM OO1722922 XM OO17236.36 211267 at HESX1 HESXhomeobox 1 NM OO3865 613SS TIA up vs 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 vs Contro protein, 22 kDa 215516 at LAMB4 aminin, beta 4 NM OO7356 6.0646 TIA up vs Contro 220205 at TPTE transmembrane NM 1992.59 60S47 TIA up vs Contro phosphatase with tensin NM 19926O homology NM 199261 1555462 at PPP1R1C protein phosphatase 1, NM 001080545 60S42 TIA up vs Contro

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 60396 TIA up vs 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 vs Contro domain family, member 16 NM 052889 230519 at FAM124A family with sequence NM 145019 S9499 TIA up vs Contro similarity 124A 240814 at MGC39584 hypothetical gene XR O17735 S9341 TIA up vs Contro supported by BCO29568 XR O17787 XR 041937 230170 at OSM oncostatin M NM O2O530 S8899 TIA up vs Contro 226872 at RFX2 regulatory factor X, 2 NM OOO635 S8786 TIA up vs Contro (influences HLA class II NM 134433 expression) 214087 s at MYBPC1 myosin binding protein C, NM OO2465 S8609 TIA up vs Contro slow type NM 2068.19 NM 206820 NM 206821 203005 at LTBR lymphotoxin beta receptor NM 002342 S8399 TIA up vs Contro (TNFRSuperfamily, member 3) 223977 s at chromosome 18 open NM 031416 S8384 TIA up vs Contro reading frame 2 NR 023925 NR 023926 NR 023927 NR 023928 240204 at SNRPN Small nuclear NM 003097 1.5829S TIA up vs Control ribonucleoprotein NM 0228.05 polypeptide N NM 022806 NM O22807 NM 0228O8 NR 001289 US 2012/OO 15904 A1 Jan. 19, 2012 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) 229521 at FLJ36O31 hypothetical protein NM 175884 158141 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 1.575O1 TIA up vs Control complex subunit-like 210449 X at MAPK14 mitogen-activated protein NM 001315 157327 TIA up vs Control kinase 14 NM 139012 NM 139013 NM 139014 238428 at KCNJ15 potassium inwardly NM OO2243 1.5696S TIA up vs Control LOC100131955 rectifying channel, NM 170736 Subfamily J, member 15 fif NM 170737 similar to pot XM OO1713900 XM OO1715532 XM O 238964 at FIGN idgetin NM 018086 TIA up vs Contro 227566 at HNT neurotrimin NM OO1048209 // TIA up vs Contro NM O16522 205863 at S100A12 S100 calcium binding NM OO5621 S633 TIA up vs Contro protein A12 208168 s at CHIT1 chiltinase 1 NM 003465 S6138 TIA up vs Contro (chitotriosidase) 2392.03 at C7orf53 chromosome 7 open NMOO1134468 if .55912 TIA up vs Contro reading frame 53 NM 182597 1569025 s at FAM13A1 amily with sequence NM 001015045 55876 TIA up vs Contro similarity 13, member A1 NM O14883 204763 s at guanine nucleotide binding NM O2O988 SS42 TIA up vs Contro protein (G protein), alpha NM 138736 activating activity polype 211561 x at MAPK14 mitogen-activated protein NM 001315 55337 TIA up vs Contro kinase 14 NM 139012 NM 139013 NM 139014 220645 at FAMSSD amily with sequence NM 001077639 SS166 TIA up vs Contro similarity 55, member D NM O17678 241669 x at PRKD2 protein kinase D2 NM 001079880 // 55139 TIA up vs Contro NM 001079881 NM 001079882 NM 016457 210582 s at LIMK2 LIM domain kinase 2 NM OO 1031801 // S485 TIA up vs Contro NM 005569 NM O16733 1553652 a. at C18orf54 chromosome 18 open NM 173529 S4796 TIA up vs Contro reading frame 54 211959 at IGFBP5 insulin-like growth factor NM 000599 S4S45 TIA up vs Contro binding protein 5 243277 X at EVI1 ecotropic viral integration NM 001105077 S445 TIA up vs Contro site 1 NM 001105078 NM O05241 202446 s at PLSCR1 phospholipid scramblase 1 NM 021105 S4059 TIA up vs Contro 1553613 s at FOXC1 forkhead box C1 NM OO1453 S3964 TIA up vs Contro 1568933 at LOC646627 phospholipase inhibitor NM 001085474 S3874 TIA up vs Contro 244007 at ZNF462 Zinc finger protein 462 NM 021224 53545 TIA up vs Contro 239989 at CNTLN centlein, centrosomal NM OO1114395 S3478 TIA up vs Contro protein NM O17738 229743 at ZNF438 Zinc finger protein 438 NM 001143766 TIA up vs Contro NM 001143767 NM 001143768 NM 001143769 // NM 001143770 1553.002 at DEFB1OSA defensin, beta 105A NM OO1040703 S2948 A up vs Control DEFB1OSB defensin, beta 105B NM 152250 1560823 at LOC34.0017 hypothetical protein 51946 A up vs Control LOC34.0017 1554540 at chromosome 1 open NM 144989 51941 A up vs Control reading frame 67 US 2012/OO 15904 A1 Jan. 19, 2012

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) 207275 s at ACSL1 acyl-CoA synthetase long- NM OO1995 51866 TIA up wS Contro chain family member 1 209.614 at ADH1B alcohol dehydrogenase 1B NM OOO668 51397 TIA up wS Contro (class I), beta polypeptide 216236 s at SLC2A14 solute carrier family 2 NM OO6931 51356 TIA up wS Contro SLC2A3 (facilitated glucose NM 153449 transporter), member 14 ft/ solute 394.02 at IL1B interleukin 1, beta NM 000576 S1316 TIA up wS Contro 203759 at ST3GAL4 ST3 beta-galactoside NM OO6278 51OO2 TIA up wS Contro alpha-2,3-Sialyltransferase 4 XM OO1714343 XM OO1726541 // XM OO1726562 222435 S. at UBE21 ubiquitin-conjugating NM 016021 SO758 TIA up wS Contro enzyme E2, J1 (UBC6 homolog, yeast) 233030 at PNPLA3 patatin-like phospholipase NM O25225 SO269 TIA up wS Contro domain containing 3 1559400 S. at PAPPA pregnancy-associated NM OO2581 SOOO9 TIA up wS Contro 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 Control hypothetical protein XM OO1722184 LOC2OOO3O 232055 a. SFXN1 sideroflexin 1 NM O22754 -1.50117 TIA down vs Control 1555883 s at SPIN3 spindlin family, member 3 NM 001010862 -1.50348 TIA down vs Control 206487 a UNC84A unc-84 homolog A (C. elegans) NM 001130965 if -1.50376 TIA down vs NM O25154 Control 2236O1 a OLFM2 olfactomed in 2 NM O581.64 -1.5119 TIA down vs Control 244011 a PPM1K protein phosphatase 1K NM 152542 -1.51501 TIA down vs (PP2C domain containing) Control 214615 a. P2RY1O purinergic receptor P2Y, NM O14499 -151779 TIA down ws G-protein coupled, 10 NM 198333 Control US 2012/OO 15904 A1 Jan. 19, 2012 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) 55872 at ZNFS12B Zinc finger protein 512B NM O2O713 -1.52158 TIA down wS Control 243857 at MORF4L2 Mrgx mRNA for MRGX NM 001142418 if -1.52328 TIA down WS NM 001142419 Control NM 001142420 NM 001142421. If NM 001142422 156O133 at GIGYF2 GRB10 interacting GYF NM 001103146 f -1.52626 TIA down vs protein 2 NM OO1103147 Contro NM OO1103148 NM O15575 1554273 a at ERAP2 endoplasmic reticulum NM OO1130140 -152883 TIA down wS aminopeptidase 2 NM O22350 Contro 1553423 a at SLFN13 schlafen family member 13 NM 144682 -153O28 TIA down wS Contro 229094 at LOC4O1431 hypothetical gene XR 040272 / -153O69 TIA down wS LOC4O1431 XR 040273 Contro XR 040274 XR 040275 207078 at MED6 mediator complex subunit 6 NM OO5466 -1.53192 TIA down vs Contro 227372 s at BAIAP2L1 BAI1-associated protein 2- NM 018842 -153271 TIA down wS LOC100128461 like 1 i? hypothetical XM OO1722656 Contro protein LOC100128461 XM OO1724217 // XM OO1724858 236728 at LNPEP leucyl cystinyl NMOO5575 -153.387 TIA down wS aminopeptidase NM 175920 Contro 215663 at MBNL1 muscleblind-like NM O21038 -153726 TIA down wS (Drosophila) NM 207292 Contro NM 207293 NM 207294 NM 207295 NM 207296 229.093 a NOS3 nitric oxide synthase 3 NM OOO603 -153818 TLA down wS (endothelial cell) Contro 212935 a. MCF2L MCF.2 cell line derived NM 001112732 f -1.53863 TIA down WS transforming sequence-like NM O24979 Contro 215750 a KIAA1659 KIAA1659 protein XM 001723799 f -1.54646 TIA down WS XM OO1725435 // Contro XM OO1726785 212699 a SCAMPS Secretory carrier NM 138967 -1.54948 TIA down vs membrane protein 5 Contro 1565911 at LOC64892.1 MRNA full length insert XM OO1715629 f -1.54981 TIA down vs 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 US 2012/OO 15904 A1 Jan. 19, 2012 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) NM O228O8 NR 001289 2292.47 at FBLN7 fibulin 7 NM OO1128165 f -1.58734 TIA down WS NM 153214 Contro 223.080 at GLS Glutaminase, mRNA NM O14905 -1.594.04 TIA down vs (cDNA clone MGC: 33744 Contro IMAGE:5263220) 1557350 at G3BP1 GTPase activating protein NM OO5754 -1.6.194 TIA down vs (SH3 domain) binding NM 198395 Contro protein 1 219864 S at RCAN3 RCAN family member 3 NM 013441 -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 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 001003406 f -1.63297 TIA down WS dependent, T type, alpha 1 I NMO21096 Contro Subunit 155.8569 at UNQ6228 MRNA, cDNA XM OO1725293 f -1.63796 TIA down vs 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 OO1O10862 -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 O228O8 NR 001289 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 OOO341 -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 OO1722965 LOC10O132291 XM OO1723889 LOC10O1324.88 RPS27 229234 at ZC3H12B Zinc finger CCCH-type NM OO1 010888 -1.72127 TIA down vs containing 12B Control 241723 at IQGAP2 IQ motif containing NM OO6633 -1.73571 TIA down wS GTPase activating protein 2 Control 226913 s at SOX8 SRY (sex determining NM O14587 -1.73755 TIA down wS region Y)-box 8 Control US 2012/OO 15904 A1 Jan. 19, 2012

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) 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 vs 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 239771 at CAND1 cullin-associated and NM 018448 -197531 TIA down wS neddylation-dissociated 1 Contro 1562028 at CCND3 Cyclin D3 (CCND3), NM 001136O17 f -2.00377 TIA down vs transcript variant 3, mRNA NM OO11361.25 Contro NMOO1136126 NM OO1760 215333 x at GSTM1 glutathione S-transferase NM OOO561 -2.03103 TIA down vs mu 1 NM 146421 Contro 232207 at GUSBL2 glucuronidase, beta-like 2 NR OO3660 -2.10621 TIA down vs XR 042150 Contro XR 042151

4. Comparison to a Control Level of Expression tion, peripheral vascular disease, or venous thromboembo lism). The healthy or normal control individual generally 0106 The expression of the TIA-associated biomarkers does not have one or more vascular risk factors (e.g., hyper are compared to a control level of expression. As appropriate, tension, diabetes mellitus, hyperlipidemia, or tobacco Smok the control level of expression can be the expression level of ing) As appropriate, the expression levels of the target TIA the same TIA-associated biomarker in an otherwise healthy associated biomarker in the healthy or normal control individual (e.g., in an individual who has not experienced individual can be normalized (i.e., divided by) the expression and/or is not at risk of experiencing TIA). In some embodi levels of a plurality of stably expressed endogenous reference ments, the control level of expression is the expression level biomarkers. of a plurality of stably expressed endogenous reference biom 0108. In some embodiments, the overexpression or under arkers, as described herein or known in the art. In some expression of a TIA-associated biomarker is determined with embodiments, the control level of expression is a predeter reference to one or more stably expressed endogenous refer mined threshold level of expression of the same TIA-associ ence biomarkers. Internal control biomarkers or endogenous ated biomarker, e.g., based on the expression level of the reference biomarkers are expressed at the same or nearly the biomarker in a population of otherwise healthy individuals. In same expression levels in the blood of patients with stroke or some embodiments, the expression level of the TIA-associ TIAS as compared to control patients. Target biomarkers are ated biomarker and the TIA-associated biomarker in an oth expressed at higher or lower levels in the blood of the stroke erwise healthy individual are normalized to (i.e., divided by), or TIA patients. The expression levels of the target biomarker e.g., the expression levels of a plurality of stably expressed to the reference biomarker are normalized by dividing the endogenous reference biomarkers. expression level of the target biomarker to the expression 0107. In some embodiments, the overexpression or under levels of a plurality of endogenous reference biomarkers. The expression of a TIA-associated biomarker is determined with normalized expression level of a target biomarker can be used reference to the expression of the same TIA-associated biom to predict the occurrence or lack thereof of stroke or TIA, arker in an otherwise healthy individual. For example, a and/or the cause of stroke or TIA. healthy or normal control individual has not experienced 0109. In some embodiments, the expression level of the and/or is not at risk of experiencing TIA. The healthy or TIA-associated biomarker from a patient Suspected of having normal control individual generally has not experienced a or experiencing TIA and from a control patient are normal vascular event (e.g., TIA, ischemic stroke, myocardial infarc ized with respect to the expression levels of a plurality of US 2012/OO 15904 A1 Jan. 19, 2012 20 stably expressed endogenous. The expression levels of the fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold or 3.5-fold, or more, normalized expression of the TIA-associated biomarker is in comparison to the threshold level indicates that the TIA compared to the expression levels of the normalized expres patient has experienced or is at risk of experiencing TIA. If sion of the same TIA-associated biomarker in a control the predetermined threshold level of expression is with patient. The determined fold change in respect to a population of patients known to have experienced expression normalized expression of target biomarker in TIA or known to be at risk for experiencing TIA, then an TIA patient/normalized expression of target biomarker in expression level in the patient Suspected of experiencing TIA control patient. Overexpression or underexpression of the that is approximately equal to the threshold level (or overex normalized TIA-associated biomarker in the TIA patient by at pressed or underexpressed greater than the threshold level of least about 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7- expression), indicates that the TIA patient has experienced or fold, 1.8-fold, 1.9-fold, 2.0-fold, 2.1 fold, 2.2-fold, 2.3-fold, is at risk of experiencing TIA. 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3.0- 0111. With respect to the endogenous reference biomark fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold or 3.5-fold, or more, ers used for comparison, preferably, the endogenous refer in comparison to the expression levels of the normalized ence biomarkers are stably expressed in blood. Exemplary TIA-associated biomarker in a healthy control patient indi endogenous reference biomarkers that find use are listed in cates that the TIA patient has experienced or is at risk of Table 3, below. Further suitable endogenous reference biom experiencing TIA. arkers are published, e.g., in Stamova, et al., BMC Medical 0110. In some embodiments, the control level of expres Genomics (2009) 2:49. In some embodiments, the expression sion is a predetermined threshold level. The threshold level levels of a plurality of endogenous reference biomarkers are can correspond to the level of expression of the same TIA determined as a control. In some embodiments, the expres associated biomarker in an otherwise healthy individual or a sion levels of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, population of otherwise healthy individuals, optionally nor 30, 35, or more, endogenous reference biomarkers, e.g., as malized to the expression levels of a plurality of endogenous listed in Table 3 or known in the art, are determined as a reference biomarkers. After expression levels and normalized control. expression levels of the TIA-associated biomarkers are deter 0112. In some embodiments, the expression levels of the mined in a representative number of otherwise healthy indi endogenous reference biomarkers GAPDH, ACTB, B2M, viduals and individuals predisposed to experiencing TIA, HMBS and PPIB are determined as a control. In some normal and TIA expression levels of the TIA-associated embodiments, the expression levels of 2,3,4,5,6,7,8,9, 10. biomarkers can be maintained in a database, allowing for 15, 20, 25, or more, endogenous reference biomarkers determination of threshold expression levels indicative of the selected from the group consisting of USP7, MAPRE2. presence or absence of risk to experience TIA or the occur CSNK1G2, SAFB2, PRKAR2A, PI4 KB, CRTC1, HADHA, rence of TIA. If the predetermined threshold level of expres MAP1LC3B, KAT5, CDC2L1///CDC2L2, GTSE1, sion is with respect to a population of normal control patients, CDC2L1///CDC2L2, TCF25, CHP, LRRC40, hCG 2003956/ then overexpression or underexpression of the TIA-associ 1/LYPLA2///LYPLA2P1, DAXX, UBE2NL, EIF1, KCMF1, ated biomarker (usually normalized) in the TIA patient by at PRKRIP1, CHMP4A, TMEM184C, TINF2, PODNL1, least about 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7- FBXO42, LOC441258, RRP1, C10orf104, ZDHHC5, fold, 1.8-fold, 1.9-fold, 2.0-fold, 2.1 fold, 2.2-fold, 2.3-fold, C9orf23, LRRC45, NACC1, LOC100.133445///LOC115110, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3.0- 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 (herpes virus associated) 2025O1 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 055083 NR 026570 202573 at CSNK1 G2 casein kinase 1, gamma 2 AL53O441 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 P4KB 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 0561.36 208.630 at HADHA hydroxyacyl-Coenzyme A AI972144 HSS16032 NM OOO182 NP 000173 dehydrogenase, 3 ketoacyl-Coenzyme A US 2012/OO 15904 A1 Jan. 19, 2012 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 thiolasefenoyl-Coenzyme A hydratase (trifunctional protein), alpha Subunit 208786 s at MAP1LC3B microtubule-associated AF1834.17.1 HS.356061 NM 022818 NP 073729 protein 1 light chain 3 beta 209192 X at KATS K(lysine) acetyltransferase BCOOO166.2 HS.397010 NM OO6388 NP OO6379 5 NM 182709 NP 874368 NM 182710 NP 874369 210474 S at CDC2L1 cell division cycle 2-like 1 UO4819.1 HS.651,228 NM 024011 NP 076916 CDC2L2 (PITSLRE proteins) // cell NM 033486 NP 277021 division cycle 2-like 2 NM 033487 NP 277022 (PITSLRE proteins) NM O33488 NP 277023 || NM 033489 NP 277024 NM 03.3492 NP 277027 NM 033493 NP 27.7028 NM 033529 NP 277071 211040 x at GTSE1 G-2 and S-phase BCOO6325.1 HS.386189 NM 016426 NP 057510 expressed 1 211289 x at CDC2L1 cell division cycle 2-like 1 AFO67524.1 HS.651,228 NM 024011 NP 076916 CDC2L2 (PITSLRE proteins) // cell NM O33486 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 f// NM 033493 NP 27.7028 NM O33529 NP 277071 213311 s at TCF25 transcription factor 25 BFOOO2S1 HS.415342 NM O14972 NP O55787 (basic helix-loop-helix) 214665 s at CHP calcium binding protein AKOOOO95.1 HS.406234 NM 007 236 NP O091.67 P22 215063 x at LRRC4O leucine rich repeat AL390149.1 HS.1478.36 NM O17768 NP 060238 containing 40 215200 x at AKO22362.1 HS.663419 215568 X at hCG 2003956 hCG2003956 ALO31295 HS.S33479 NM OO7260 NP O09191 LY PLA2 lysophospholipase II NR OO1444 LYPLA2P1 lysophospholipase II pseudogene 1 216038 X at DAXX death-domain associated BE965715 HS.336916 NM OO1141969 NP OO1135441 protein NM OO1141970 NP OO1135442 NM 001350 NP 001341 NR 024517 217393 X at UBE2NL ubiquitin-conjugating AL1096,22 HS.S85177 NM 001012989 NP 001013 007 enzyme E2N-like 217549 at AWS74933 HS.S27860 217672 X at EIF1 eukaryotic translation BF114906 HS.1SOS8O NM 00:58O1 NP OO5792 initiation factor 1 21793.8 s at KCMF1 potassium channel NM O2O122.1 Hs.654968 NM O2O122 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 O14169.1 Hs.279761 NM 014169 NP O54888 protein 4A 219074 at TMEM184C transmembrane protein NM 018241.1 HS.203896 NM 018241 NP 060711 184C 22005.2 s at TINF2 TERF1 (TRF1)-interacting NM O12461.1 HS.496.191 NM 001099274 NP OO1092744 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.S22384 NM 018994 NP 061867 222207 X at LOC441258 Williams Beuren syndrome AKO246021 HS.711232 chromosome region 19 pseudogene 222733 x at RRP1 ribosomal RNA processing BCOOO380.1 HS.110757 NM 003.683 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 AKO23.130.1 HS.27239 NM O15457 NP 056272 containing 5 US 2012/OO 15904 A1 Jan. 19, 2012 22

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 225403 at C9Crf23 chromosome 9 open AL528.391 HS.15961 NM 148178 NP 680544 reading frame 23 NM 148179 NP 680545 2262.53 at LRRC45 leucine rich repeat BE965418 HS143774 NM 144999 NP 659436 containing 45 227651 at NACC1 nucleus accumbens AI498.126 HS.531.614 NM 052876 NP 443108 associated 1, BEN and BTB (POZ) domain containing 232190 x at LOC100133445/// hypothetical AI393958 HS.132272 NR 026927 LOC115110 LOC10O133445 F. XR 036887 hypothetical protein XR 038144 LOC115110 49878 at PEX16 peroxisomal biogenesis AAS23441 Hs.100915 NM 004813 NP 004804 factor 16 NM 057174 NP 476515

5. Methods of Determining the Cause of TIA expression relative to a control level of expression of a plu 0113 Subsets of the TIA-associated biomarkers described rality of biomarkers selected from the group consisting of herein further find use in predicting or determining the cause ACSL1, ADM, AK5, ASTN2 (includes EG:23245), BCL6, of TIA. BMPR1B, CARD8, CASP5, CCND3, CLTC, CNTN4, 0114 For example, patients that overexpress genes COL1A1, COL1A2, DIP2C, DNAH14, EDAR, ELAVL2, involved in extracellular matrix remodeling including one or EPHA3, EPHX2, FAM124A, FOSB, GABRB2, GIGYF2, more or all genes selected from MMP16, MMP19, MMP26, GNAO1, HOXC6, IL1B, KCNJ15, LAMB4, LIFR, LTBR, COL1A1, COL1A2, COL3A1, COL10A1, COL11A1, LUM, MAPK14, MYBPC1, NOS3, ODZ2, OSM, PAPPA, COL25A1, COL27A1, FGFs and EGFR may have athero PDE1A, ROBO1, RUNDC3B, S100A12, SCN2A, SHOX, Sclerosis. SLC22A4 (includes EG:6583), SOX9, SPOCK3, TLR5, 0115 Individuals can have a risk or predisposition to TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), experiencing TIA, e.g., based on genetics, a related disease TWIST1, UNC5B, VWA3B and ZNF438. condition, environment or lifestyle. For example, in some 0118. In some embodiments, the patient may have an embodiments, the patient Suffers from a chronic inflamma inflammatory disorder and have increased or decreased tory condition, e.g., has an autoimmune disease (e.g., rheu expression relative to a control level of expression of a plu matoid arthritis, Crohn's disease inflammatory bowel dis rality of biomarkers selected from the group consisting of ease), atherosclerosis, hypertension, or diabetes. In some ACSL1, ADM, AK5, ANXA3, APBA2, ASTN2 (includes embodiments, the patient has high LDL-cholesterol levels or EG:23245), BCL6, CARD8, CASP5, CAV1, CCND3, Suffers from a cardiovascular disease (e.g., atherosclerosis, CCRL1, CLTC, CNTN4, DIP2C, DNAH14, EDAR, EPHA3, coronary artery disease). In some embodiments, the patient EPHX2, ERAP2, FAM124A, FBLN7, FOSB, FREM2, has an endocrine system disorder, a neurodegenerative disor GABRB2, GRM5, IL1B, KCNJ15, LAMB4, LHX2, LNPEP. der, a connective tissue disorder, or a skeletal and muscular LRP2, LTBR, LUM, MAPK14, MECOM, MYBPC1, NOS3, disorder. Exemplary disorders associated with, related to, or ODZ2, OPCML, OSM, PAPPA, PDE1A, PPP1R1C, causative of TIA are provided in Table 7. ROBOT, RUNDC3B, S100A12, SCN2A, SFXN1, SLC22A4 0116. In some embodiments, the patient may have a neu (includes EG:6583), SLC26A8, SMURF2, SNRPN, SPON1, rological disorder and have increased or decreased expression TGFB2, TLR5, TNFRSF21, TNPO1, TTC6 (includes relative to a control level of expression of a plurality of EG:115669), TWIST1, UNC5B, VWA3B and ZNF438. biomarkers selected from the group consisting of ACSL1, 0119. In some embodiments, the patient may have a car ADH1B, AK5, ANXA3, APBA2, ASTN2 (includes diovascular disorder and have increased or decreased expres EG:23245), BCL6, BMPR1B, CASP5, CAV1, CNTN4, sion relative to a control level of expression of a plurality of DIP2C, ELAVL2, EPHX2, ERAP2, FAM124A, FAM13A, biomarkers selected from the group consisting of ACSL1, FAM149A, FAT1, FOLH1, FOXC1, GABRB2, GIGYF2, ADM, AK5, ALPL, ASTN2 (includes EG:23245), BCL6, GNAO1, GRM5, GSTM1, HESX1, HOXC6, IGFBP5, IL1B, BMPR1B, C18ORF54, CACNA1 I, CARD16, CAV1, IQGAP2, ITGBL1, LAMB4, LIFR, LTBR, MECOM, CNTN4, DMRT1, DNAH14, EDAR, EPHX2, ERAP2, NBPF10, NDST3, NELL2, NOS3, NTM, ODZ2, OLFM2, FAM13A, FOLH1, FOSB, FREM2, GABRB2, GRM5, OPCML, PDE1A, RFX2, ROBO1, S100A12, SCN2A, GSTM1, IL1B, IQGAP2, LIFR, LTBR, MAN1C1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, SOX9, MAPK14, MBNL1, MCF2L, MECOM, MYBPC1, NOS3, SPOCK3, SPON1, TGFB2, TLR5, TNFRSF21, TRPM1, NTM, ODZ2, OLFM2, OPCML, PAPPA, PDE1A, ROBO1, TSHZ2, TTC6 (includes EG:115669), UNC5B, UNC84A RORB, S100A12, SMURF2, SNRPN, SOX9, SPOCK3, and ZNF608. SPON1, TFPI, TRPM1, UNC84A and VWA3B. 0117. In some embodiments, the patient may have a skel I0120 In some embodiments, the patient may have an etal or muscular disorder and have increased or decreased immunological disorder and have increased or decreased US 2012/OO 15904 A1 Jan. 19, 2012

expression relative to a control level of expression of a plu 0.125. In some embodiments, the patient may have a con rality of biomarkers selected from the group consisting of nective tissue disorder and have increased or decreased ACSL1, ADM, AK5, ANXA3, ASTN2 (includes EG:23245), expression relative to a control level of expression of a plu BCL6, CARD8, CASP5, CCND3, CCRL1, CLTC, CNTN4, rality of biomarkers selected from the group consisting of COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, ACSL1, ADM, ASTN2 (includes EG:23245), BCL6, FAM124A, FAT1, FOSB, GABRB2, GOLGA6L2, GSTM1, CARD8, CASP5, CCND3, CLTC, CNTN4, COL1A1, GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, LTBR, COL1A2, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, MAPK14, MYBPC1, NELL2, NOS3, NTM, ODZ2, FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, OPCML, OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, ROBO1, RUNDC3B, S100A12, SHOX, SLC22A4 (includes S100A12, SLC22A4 (includes EG:6583), SNRPN, SPON1, EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (includes TLR5, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG: 115669), VWA3B and ZNF438. EG: 115669), VWA3B and ZNF438. I0126. In some embodiments, the patient may have rheu 0121. In some embodiments, the patient may have a meta matic disease and have increased or decreased expression bolic disorder and have increased or decreased expression 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, ADM, ASTN2 (includes EG:23245), BCL6, CARD8, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes CASP5, CCND3, CLTC, CNTN4, DIP2C, DNAH14, EDAR, EG:23245), BCL6, CARD8, CASP5, CCRL1, CNTLN, EPHA3, EPHX2, FAM124A, FOSB, GABRB2, IL1B, CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, KCNJ15, LAMB4, LTBR, LUM, MAPK14, ODZ2, OSM, EPHX2, FAT1, FOXA2, GABRB2, GUSBL2, IGFBP5, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, SLC22A4 IL1B, IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, (includes EG:6583), TLR5, TNFRSF21, TNPO1, TTC6 (in NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, cludes EG:115669), VWA3B and ZNF438. ROBO1, SLC22A4 (includes EG:6583), SLC2A3, SLC3A1, I0127. In some embodiments, the patient may have arthritis SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, and have increased or decreased expression relative to a con UNC84A and VWA3B. trol level of expression of a plurality of biomarkers selected 0122. In some embodiments, the patient may have an from the group consisting of ACSL1, ADM, ASTN2 (in endocrine system disorder and have increased or decreased cludes EG:23245), BCL6, CARD8, CASP5, CCND3, CLTC, expression relative to a control level of expression of a plu CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, rality of biomarkers selected from the group consisting of FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, ACSL1, ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (in LTBR, LUM, MAPK14, ODZ2, OSM, PAPPA, PDE1A, cludes EG:23245), BCL6, CARD8, CASP5, CCRL1, ROBO1, RUNDC3B, S100A12, SLC22A4 (includes CNTLN, CNTN4, COL1A2, DIP2C, DMRT1, DNAH14, EG:6583), TNFRSF21, TNPO1, TTC6 (includes EPHA3, FAT1, FOXA2, GABRB2, GUSBL2, IL1B, EG:115669), VWA3B, ZNF438. IQGAP2, ITGBL1, LRP2, LTBR, MAPK14, MBNL1, I0128. In some embodiments, the patient may have athero NELL2, NOS3, NTM, ODZ2, OPCML, PAPPA, PLSCR1, Sclerosis and have increased or decreased expression relative ROBO1, SHOX, SLC22A4 (includes EG:6583), SLC2A3, to a control level of expression of a plurality of biomarkers SMURF2, SNRPN, SPON1, SRGAP1, TLR5, TSHZ2, selected from the group consisting of ACSL1, AK5, ASTN2 UNC84A and VWA3B. (includes EG:23245), BMPR1B, CARD16, CNTN4, 0123. In some embodiments, the patient may have an DMRT1, DNAH14, ERAP2, FOSB, FREM2, GRM5, IL1B, autoimmune disease and have increased or decreased expres IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, MECOM, sion relative to a control level of expression of a plurality of NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, RORB, biomarkers selected from the group consisting of ACSL1, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and ADM, AK5, ASTN2 (includes EG:23245), BCL6, CARD8, VWA3B. CASP5, CCND3, CLTC, CNTN4, COL1A2, DIP2C, I0129. In some embodiments, the patient may have inflam DNAH14, EDAR, EPHA3, EPHX2, FAM124A, FOSB, matory bowel disease and have increased or decreased GABRB2, GUSBL2, IL1B, IQGAP2, KCNJ15, LAMB4, expression relative to a control level of expression of a plu LTBR, MAPK14, MYBPC1, NELL2, ODZ2, OPCML, rality of biomarkers selected from the group consisting of OSM, PAPPA, PDE1A, ROBO1, RUNDC3B, S100A12, ACSL1, AK5, APBA2, ASTN2 (includes EG:23245), SLC22A4 (includes EG:6583), SNRPN, SPON1, TLR5, CARD8, DIP2C, DNAH14, ERAP2, FBLN7, FREM2, TNFRSF21, TNPO1, TSHZ2, TTC6 (includes EG:115669), GRM5, IL1B, LHX2, LNPEP LTBR, MECOM, NOS3, VWA3B and ZNF438. ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, ROBO1, 0.124. In some embodiments, the patient may have diabe SFXN1, SLC22A4 (includes EG:6583), SLC26A8, SNRPN, tes and have increased or decreased expression relative to a SPON1, TGFB2, TLR5, VWA3B and ZNF438. control level of expression of a plurality of biomarkers 0.130. In some embodiments, the patient may have non selected from the group consisting of ACSL1, ADAM30, insulin-dependent diabetes mellitus and have increased or AK5, ALPL. ALS2CR11, ASTN2 (includes EG:23245), decreased expression relative to a control level of expression BCL6, CARD8, CASP5, CCRL1, CNTLN, CNTN4, of a plurality of biomarkers selected from the group consist COL1A2, DIP2C, DMRT1, DNAH14, EPHA3, FAT1, ing of ADAM30, AK5, ALPL. ALS2CR11, ASTN2 (includes 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. US 2012/OO 15904 A1 Jan. 19, 2012 24

0131. In some embodiments, the patient may have rheu protection assays), but measurement of DNA and RNA can matoid arthritis and have increased or decreased expression also be carried out in the absence of electrophoretic separa relative to a control level of expression of a plurality of tion (e.g., by dot blot). Southern blot of genomic DNA (e.g., biomarkers selected from the group consisting of ACSL1, from a human) can be used for Screening for restriction frag ADM, ASTN2 (includes EG:23245), BCL6, CARD8, CLTC, ment length polymorphism (RFLP) to detect the presence of CNTN4, DIP2C, DNAH14, EDAR, EPHA3, EPHX2, a genetic disorder affecting a polypeptide of the invention. All FAM124A, FOSB, GABRB2, IL1B, KCNJ15, LAMB4, forms of RNA can be detected, including, e.g., message RNA MAPK14, ODZ2, OSM, PAPPA, PDE1A, ROBO1, (mRNA), microRNA (miRNA), ribosomal RNA (rRNA) and RUNDC3B, S100A12, SLC22A4 (includes EG:6583), transfer RNA (tRNA). TNFRSF21, TNPO1, TTC6 (includes EG:115669), VWA3B 0.138. The selection of a nucleic acid hybridization format and ZNF438. is not critical. A variety of nucleic acid hybridization formats 0.132. In some embodiments, the patient may have coro are known to those skilled in the art. For example, common nary artery disease and have increased or decreased expres formats include Sandwich assays and competition or dis sion relative to a control level of expression of a plurality of placement assays. Hybridization techniques are generally biomarkers selected from the group consisting of ACSL1, described in Hames and Higgins Nucleic Acid Hybridization, AK5, ASTN2 (includes EG:23245), BMPR1B, CARD16, A Practical Approach, IRL Press (1985); Gall and Pardue, CNTN4, DMRT1, DNAH14, ERAP2, FREM2, GRM5, Proc. Natl. Acad. Sci. U.S.A., 63:378-383 (1969); and Johnet IL1B, IQGAP2, LIFR, MAN1C1, MBNL1, MCF2L, al. Nature, 223:582-587 (1969). MECOM, NOS3, NTM, ODZ2, OLFM2, PDE1A, ROBO1, 0.139. Detection of a hybridization complex may require RORB, SNRPN, SPOCK3, SPON1, TRPM1, UNC84A and the binding of a signal-generating complex to a duplex of VWA3B. target and probe polynucleotides or nucleic acids. Typically, 0133. In some embodiments, the patient may have Crohn's Such binding occurs through ligand and anti-ligand interac disease and have increased or decreased expression relative to tions as between a ligand-conjugated probe and an anti-ligand a control level of expression of a plurality of biomarkers conjugated with a signal. The binding of the signal generation selected from the group consisting of ACSL1, AK5, APBA2, complex is also readily amenable to accelerations by expo ASTN2 (includes EG:23245), CARDS, DIP2C, DNAH14, Sure to ultrasonic energy. ERAP2, FBLN7, FREM2, GRM5, LHX2, LNPEP. 0140. The label may also allow indirect detection of the MECOM, ODZ2, OPCML, PAPPA, PDE1A, PPP1R1C, hybridization complex. For example, where the label is a ROBO1, SFXN1, SLC22A4 (includes EG:6583), SLC26A8, hapten or antigen, the sample can be detected by using anti SNRPN, SPON1, TGFB2, TLR5, VWA3B and ZNF438. bodies. In these systems, a signal is generated by attaching 0134. In some embodiments, the patient may have a neu fluorescent or enzyme molecules to the antibodies or in some rodegenerative disorder and have increased or decreased cases, by attachment to a radioactive label (see, e.g., Tijssen, expression relative to a control level of expression of a plu “Practice and Theory of Enzyme Immunoassays,' Labora rality of biomarkers selected from the group consisting of tory Techniques in Biochemistry and Molecular Biology, Bur ASTN2 (includes EG:23245), CASP5, CNTN4, FAM124A, don and van Knippenberg Eds. Elsevier (1985), pp. 9-20). FOLH1, GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, 0.141. The probes are typically labeled either directly, as OPCML, RFX2, SCN2A, SLC22A4 (includes EG:6583), with isotopes, chromophores, lumiphores, chromogens, or SLC2A3, SLC3A1, SPON1, TSHZ2 and ZNF608. indirectly, Such as with biotin, to which a streptavidin com 0135) In some embodiments, the patient may have Alzhe plex may later bind. Thus, the detectable labels used in the imer's disease and have increased or decreased expression assays of the present invention can be primary labels (where relative to a control level of expression of a plurality of the label comprises an element that is detected directly or that biomarkers selected from the group consisting of ASTN2 produces a directly detectable element) or secondary labels (includes EG:23245), CASP5, CNTN4, FAM124A, FOLH1, (where the detected label binds to a primary label, e.g., as is GABRB2, GRM5, IL1B, MECOM, NDST3, NOS3, common in immunological labeling). Typically, labeled sig OPCML, RFX2, SLC22A4 (includes EG:6583), SLC2A3, nal nucleic acids are used to detect hybridization. Comple SLC3A1, SPON1, TSHZ2 and ZNF608. mentary nucleic acids or signal nucleic acids may be labeled by any one of several methods typically used to detect the 6. Methods of Detecting Biomarkers Associated with presence of hybridized polynucleotides. The most common TIA method of detection is the use of autoradiography with H, 0136 Gene expression may be measured using any I, S, ''C, or P-labeled probes or the like. method known in the art. One of skill in the art will appreciate 0142. Other labels include, e.g., ligands that bind to that the means of measuring gene expression is not a critical labeled antibodies, fluorophores, chemiluminescent agents, aspect of the invention. The expression levels of the biomar enzymes, and antibodies which can serve as specific binding kers can be detected at the transcriptional or translational (i.e., pair members for a labeled ligand. An introduction to labels, protein) level. labeling procedures and detection of labels is found in Polak 0.137 In some embodiments, the expression levels of the and Van Noorden Introduction to Immunocytochemistry, 2nd biomarkers are detected at the transcriptional level. A variety ed., Springer Verlag, NY (1997); and in Haugland Handbook of methods of specific DNA and RNA measurement using of Fluorescent Probes and Research Chemicals, a combined nucleic acid hybridization techniques are known to those of handbook and catalogue Published by Molecular Probes, Inc. skill in the art (see, Sambrook, Supra and Ausubel, Supra) and (1996). may be used to detect the expression of the genes set forth in 0143. In general, a detector which monitors a particular Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. Some methods probe or probe combination is used to detect the detection involve an electrophoretic separation (e.g., Southern blot for reagent label. Typical detectors include spectrophotometers, detecting DNA, Northern blot for detecting RNA, RNAse phototubes and photodiodes, microscopes, Scintillation US 2012/OO 15904 A1 Jan. 19, 2012

counters, cameras, film and the like, as well as combinations product. Coutlee et al. (1989) Analytical Biochemistry 181: thereof. Examples of suitable detectors are widely available 153-162; Bogulayski (1986) et al. J. Immunol. Methods from a variety of commercial Sources known to persons of 89:123-130; Prooijen-Knegt (1982) Exp. Cell Res. 141:397 skill in the art. Commonly, an optical image of a Substrate 407; Rudkin (1976) Nature 265:472-473, Stollar (1970) comprising bound labeling moieties is digitized for Subse Proc. Nat I Acad. Sci. USA 65:993-1000; Ballard (1982) Mol. quent computer analysis. Immunol. 19:793-799; Pisetsky and Caster (1982) Mol. 0144. Most typically, the amount of RNA is measured by Immunol. 19:645-650; Viscidietal. (1988).J. Clin. Microbial. quantifying the amount of label fixed to the Solid Support by 41:199-209; and Kiney et al. (1989).J. Clin. Microbiol. 27:6- binding of the detection reagent. Typically, the presence of a 12 describe antibodies to RNA duplexes, including homo and modulator during incubation will increase or decrease the heteroduplexes. Kits comprising antibodies specific for amount of label fixed to the solid support relative to a control DNA:RNA hybrids are available, e.g., from Digene Diagnos incubation which does not comprise the modulator, or as compared to a baseline established for a particular reaction tics, Inc. (Beltsville, Md.). type. Means of detecting and quantifying labels are well 0150. In addition to available antibodies, one of skill in the known to those of skill in the art. art can easily make antibodies specific for nucleic acid 0145. In preferred embodiments, the target nucleic acid or duplexes using existing techniques, or modify those antibod the probe is immobilized on a solid support. Solid supports ies that are commercially or publicly available. In addition to Suitable for use in the assays of the invention are known to the art referenced above, general methods for producing poly those of skill in the art. As used herein, a solid Support is a clonal and monoclonal antibodies are known to those of skill matrix of material in a Substantially fixed arrangement. in the art (see, e.g., Paul (3rd ed.) Fundamental Immunology 0146 For example, in one embodiment of the invention, Raven Press, Ltd., NY (1993); Coligan, et al., Current Pro microarrays are used to detect the pattern of gene expression. tocols in Immunology, Wiley Interscience (1991-2008); Har Microarrays provide one method for the simultaneous mea low and Lane, Antibodies. A Laboratory Manual Cold Spring Surement of the expression levels of large numbers of genes. Harbor Press, NY (1988); Harlow and Lane. Using Antibod Each array consists of a reproducible pattern of a plurality of ies, Cold Spring Harbor Press, NY (1999); Stites et al. (eds.) nucleic acids (e.g., a plurality of nucleic acids that hybridize Basic and Clinical Immunology (4th ed.) Lange Medical Pub to a plurality of the genes set forth in Tables 1, 2, 5A, 5B, 5C, lications, Los Altos, Calif., and references cited therein; God 5D, 7, 8 and/or 9) attached to a solid support. Labeled RNA or ing Monoclonal Antibodies. Principles and Practice (2d ed.) DNA is hybridized to complementary probes on the array and Academic Press, New York, N.Y., (1986); and Kohler and then detected by laser scanning. Hybridization intensities for Milstein Nature 256: 495-497 (1975)). Other suitable tech each probe on the array are determined and converted to a niques for antibody preparation include selection of libraries quantitative read-out of relative gene expression levels in of recombinant antibodies in phage or similar vectors (see, transient ischemic attacks. Huse et al. Science 246:1275-1281 (1989); and Ward et al. 0147 In some embodiments, a sample is obtained from a Nature 341:544-546 (1989)). Specific monoclonal and poly subject, total mRNA is isolated from the sample and is con clonal antibodies and antisera will usually bind with a K, of verted to labeled cRNA and then hybridized to an array. at least about 0.1 uM, preferably at least about 0.01 uM or Relative transcript levels are calculated by reference to appro better, and most typically and preferably, 0.001 uM or better. priate controls present on the array and in the sample. See, 0151. The nucleic acids used in this invention can be either Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134 positive or negative probes. Positive probes bind to their 1136 (1999). targets and the presence of duplex formation is evidence of 0148. A variety of automated solid-phase assay tech the presence of the target. Negative probes fail to bind to the niques are also appropriate. For instance, very large scale Suspect target and the absence of duplex formation is evi immobilized polymer arrays (VLSIPSTM), available from dence of the presence of the target. For example, the use of a Affymetrix, Inc. (Santa Clara, Calif.) can be used to detect wild type specific nucleic acid probe or PCR primers may changes in expression levels of a plurality of genes involved serve as a negative probe in an assay sample where only the in the same regulatory pathways simultaneously. See, Tijssen, nucleotide sequence of interest is present. supra. Fodor et al. (1991) Science, 251: 767-777; Sheldon et 0152 The sensitivity of the hybridization assays may be al. (1993) Clinical Chemistry39(4): 718–719, and Kozaletal. enhanced through use of a nucleic acid amplification system (1996) Nature Medicine 207): 753-759. Integrated microflu that multiplies the target nucleic acid being detected. idic systems and other point-of-care diagnostic devices avail Examples of such systems include the polymerase chain reac able in the art also find use. See, e.g., Liu and Mathies, Trends tion (PCR) system, in particular RT-PCR, multiplex PCR, Biotechnol. (2009). 27(10):572-81 and Tothill, Semin Cell quantitative PCR or real time PCR, and the ligase chain Dev Biol (2009).20(1):55-62. Microfluidics systems for use in reaction (LCR) system. Other methods recently described in detecting levels of expression of a plurality of nucleic acids the art are the nucleic acid sequence based amplification are available, e.g., from NanoString Technologies, on the (NASBA, Cangene, Mississauga, Ontario) and Q Beta Rep internet at nanostring.com. licase systems. These systems can be used to directly identify 0149 Detection can be accomplished, for example, by mutants where the PCR or LCR primers are designed to be using a labeled detection moiety that binds specifically to extended or ligated only when a selected sequence is present. duplex nucleic acids (e.g., an antibody that is specific for Alternatively, the selected sequences can be generally ampli RNA-DNA duplexes). One preferred example uses an anti fied using, for example, nonspecific PCR primers and the body that recognizes DNA-RNA heteroduplexes in which the amplified target region later probed for a specific sequence antibody is linked to an enzyme (typically by recombinant or indicative of a mutation. High throughput multiplex nucleic covalent chemical bonding). The antibody is detected when acid sequencing or "deep sequencing to detect captured the enzyme reacts with its substrate, producing a detectable expressed biomarker genes also finds use. High throughput US 2012/OO 15904 A1 Jan. 19, 2012 26 sequencing techniques are known in the art (e.g., 454 Purification of oligonucleotides is by either native acrylamide Sequencing on the internet at 454.com). gel electrophoresis or by anion-exchange HPLC as described 0153. An alternative means for determining the level of in Pearson & Reanier, J. Chrom. 255:137-149 (1983). expression of the nucleic acids of the present invention is in 0159. In some embodiments, the expression level of the situ hybridization. In situ hybridization assays are well biomarkers described herein are detected at the translational known and are generally described in Angereret al., Methods or protein level. Detection of proteins is well known in the art, Enzymol. 152:649-660 (1987). In an in situ hybridization and methods for protein detection known in the art find use. assay, cells, preferentially human cells, e.g., blood cells, are Exemplary assays for determining the expression levels of a fixed to a solid support, typically a glass slide. If DNA is to be plurality of proteins include, e.g., ELISA, flow cytometry, probed, the cells are denatured with heat or alkali. The cells mass spectrometry (e.g., MALDI or SELDI), surface plas are then contacted with a hybridization solutionata moderate mon resonance (e.g., BiaCore), microfluidics and other bio temperature to permit annealing of specific probes that are sensor technologies. See, e.g., Tothill, Semin Cell Dev Biol labeled. The probes are preferably labeled with radioisotopes (2009) 20(1):55-62. or fluorescent reporters. 0154) In other embodiments, quantitative RT-PCR is used 7. TIA Reference Profiles to detect the expression of a plurality of the genes set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. A general overview 0160 The invention also provides ischemia reference pro of the applicable technology can be found, for example, in files. The TIA reference profiles comprise information corre A-Z of Ouantitative PCR, Bustin, ed., 2004, International lating the expression levels of a plurality of TIA-associated University Line; Ouantitative PCR Protocols, Kochanowski genes (i.e., a plurality of the genes set forth in Tables 1, 2, 5A, and Reischl, eds., 1999, Humana Press; Clinical Applications 5B, 5C, 5D, 7, 8 and/or 9) to the occurrence or risk of TIA. of PCR, Lo, ed., 2006, Humana Press: PCR Protocols: A The profiles can conveniently be used to diagnose, monitor Guide to Methods and Applications (Innis et al. eds. (1990)) and prognose ischemia. and PCR Technology. Principles and Applications for DNA 0.161 The reference profiles can be entered into a data Amplification (Erlich, ed. (1992)). In addition, amplification base, e.g., a relational database comprising data fitted into technology is described in U.S. Pat. Nos. 4,683,195 and predefined categories. Each table, or relation, contains one or 4,683.202. Methods for multiplex PCR, known in the art, are more data categories in columns. Each row contains a unique applicable to the present invention. instance of data for the categories defined by the columns. For O155 Accordingly, in one embodiment of the invention example, a typical database for the invention would include a provides a reaction mixture comprising a plurality of poly table that describes a sample with columns for age, gender, nucleotides which specifically hybridize (e.g., primers) to a reproductive status, expression profile and so forth. Another plurality of nucleic acid sequences of the genes set forth in table would describe a disease: Symptoms, level, Sample iden Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. In some embodi tification, expression profile and so forth. In one embodiment, ments, the reaction mixture is a PCR mixture, for example, a the invention matches the experimental sample to a database multiplex PCR mixture. of reference samples. The database is assembled with a plu 0156 This invention relies on routine techniques in the rality of different samples to be used as reference samples. An field of recombinant genetics. Generally, the nomenclature individual reference sample in one embodiment will be and the laboratory procedures in recombinant DNA technol obtained from a patient during a visit to a medical profes ogy described below are those well known and commonly sional. Information about the physiological, disease and/or employed in the art. Standard techniques are used for cloning, pharmacological status of the sample will also be obtained DNA and RNA isolation, amplification and purification. Gen through any method available. This may include, but is not erally enzymatic reactions involving DNA ligase, DNA poly limited to, expression profile analysis, clinical analysis, medi merase, restriction endonucleases and the like are performed cal history and/or patient interview. For example, the patient according to the manufacturer's specifications. Basic texts could be interviewed to determine age, sex, ethnic origin, disclosing the general methods of use in this invention symptoms or past diagnosis of disease, and the identity of any include Sambrook et al., Molecular Cloning, A Laboratory therapies the patient is currently undergoing. A plurality of Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expres these reference samples will be taken. A single individual sion: A Laboratory Manual (1990); and Current Protocols in may contribute a single reference sample or more than one Molecular Biology (Ausubel et al., eds., 1994-2008, Wiley sample over time. One skilled in the art will recognize that InterScience)). confidence levels in predictions based on comparison to a 0157 For nucleic acids, sizes are given in either kilobases database increase as the number of reference samples in the (kb) or base pairs (bp). These are estimates derived from database increases. agarose or acrylamide gel electrophoresis, from sequenced 0162 The database is organized into groups of reference nucleic acids, or from published DNA sequences. For pro samples. Each reference sample contains information about teins, sizes are given in kilodaltons (kDa) or amino acid physiological, pharmacological and/or disease status. In one residue numbers. Proteins sizes are estimated from gel elec aspect the database is a relational database with data orga trophoresis, from sequenced proteins, from derived amino nized in three data tables, one where the samples are grouped acid sequences, or from published protein sequences. primarily by physiological status, one where the samples are 0158 Oligonucleotides that are not commercially avail grouped primarily by disease status and one where the able can be chemically synthesized according to the Solid samples are grouped primarily by pharmacological status. phase phosphoramidite triester method first described by Within each table the samples can be further grouped accord Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 ing to the two remaining categories. For example the physi (1981), using an automated synthesizer, as described in Van ological status table could be further categorized according to Devanter et. al., Nucleic Acids Res. 12:6159-6168 (1984). disease and pharmacological status. US 2012/OO 15904 A1 Jan. 19, 2012 27

0163 As will be appreciated by one of skill in the art, the Table 3. For example, the solid support can be a microarray present invention may be embodied as a method, data pro attached to a plurality of nucleic acid probes that hybridize to cessing system or program products. Accordingly, the present a plurality (e.g., two or more, or all) of the genes set forth in invention may take the form of data analysis systems, meth Table 1, and optionally Table 3. In various embodiments, the ods, analysis Software, etc. Software written according to the Solid Support can be a microarray attached to a plurality of present invention is to be stored in some form of computer nucleic acid probes that hybridize to a plurality (e.g., two or readable medium, such as memory, hard-drive, DVD ROM or more, or all) of the genes set forth in Tables 5A, 5B, 5C, and CD ROM, or transmitted over a network, and executed by a 5D, and optionally Table 3. In various embodiments, the solid processor. The present invention also provides a computer Support can be a microarray attached to a plurality of nucleic system for analyzing physiological states, levels of disease acid probes that hybridize to a plurality (e.g., two or more, or states and/or therapeutic efficacy. The computer system com all) of the genes set forth in Table 7, and optionally Table 3. In prises a processor, and memory coupled to said processor various, the Solid Support can be a microarray attached to a which encodes one or more programs. The programs encoded plurality of nucleic acid probes that hybridize to a plurality in memory cause the processor to perform the steps of the (e.g., two or more, or all) of the genes set forth in Table 8, and above methods wherein the expression profiles and informa optionally Table 3. In various, the solid support can be a tion about physiological, pharmacological and disease states microarray attached to a plurality of nucleic acid probes that are received by the computer system as input. Computer hybridize to a plurality (e.g., two or more, or all) of the genes systems may be used to execute the Software of an embodi set forth in Table 9, and optionally Table 3. ment of the invention (see, e.g., U.S. Pat. No. 5,733,729). 0170 In various embodiments, the solid supports are con figured to exclude genes not associated with or useful to the 8. Providing Appropriate Treatment and Prevention diagnosis, prediction or confirmation of a stroke or the causes Regimes to Patient of stroke. For example, genes which are overexpressed or 0164. In some embodiments, the methods further com underexpressed less than 1.5-fold in Subjects having or Sus prise the step of prescribing and providing appropriate treat pected of having TIA, in comparison to a control level of ment and/or prevention regimes to a patient diagnosed as expression can be excluded from the present solid Supports. having TIA or at risk of the occurrence of TIA or stroke. For In some embodiments, genes that are overexpressed or under example, medications and life-style adjustments (e.g., diet, expressed less than 1.2-fold in Subjects with ischemic stroke, including cardioembolic stroke, atherothrombotic stroke, and exercise, stress) to minimize risk factors can be recom stroke Subsequent to atrial fibrillation, in comparison to a mended, including reducing blood pressure and cholesterol control level of expression can be excluded from the present levels, and controlling diabetes. Solid Supports. The Solid Support can comprise a plurality of 0165. In additions, several medications to decrease the nucleic acid probes that hybridize to a plurality (e.g., two or likelihood of a stroke after a transient ischemic attack. The more, orall) of the genes useful for the diagnosis of ischemic medication selected will depend on the location, cause, sever stroke, cardioembolic stroke, carotid Stenosis, and/or atrial ity and type of TIA, if TIA has occurred. fibrillation, as described herein. As appropriate, nucleic acid 0166 In some embodiments, the patient may be pre probes that hybridize to a plurality (e.g., two or more, or all) scribed a regime of an anti-platelet drug. The most frequently of the genes useful for the diagnosis of ischemic stroke, used anti-platelet medication is aspirin. An alternative to aspi cardioembolic stroke, carotid stenosis, and/or atrial fibrilla rin is the anti-platelet drug clopidogrel (Plavix). Some studies tion can be arranged in a predetermined array on the Solid indicate that aspirin is most effective in combination with Support. In various embodiments, nucleic acids not specifi another anti-platelet drug. In some embodiments, the patient cally identified and/or not relating to the diagnosis of and/or is prescribed a combination of low-dose aspirin and the anti not associated with the diagnosis of TIA are not attached to platelet drug dipyridamole (Aggrenox), to reduce blood clot the Solid Support. In various embodiments, nucleic acids not ting. Ticlopidine (Ticlid) is another anti-platelet medication specifically identified and/or not relating to the diagnosis of that finds use to prevent or reduce the risk of stroke in patients and/or not associated with the diagnosis of ischemic stroke, who have experienced TIA. cardioembolic stroke, carotid stenosis, and/or atrial fibrilla 0167. In some embodiments, the patient may be pre tion are not attached to the solid Support. The solid Support scribed a regime of an anticoagulant. Exemplary anticoagul may be a component in a kit. lants include aspirin, heparin, warfarin, and dabigatran. 0168 Patients having a moderately or severely narrowed 0171 The invention also provides kits for diagnosing TIA neck (carotid) artery, may require or benefit from carotid or a predisposition for developing TIA. For example, the endarterectomy. This preventive Surgery clears carotid arter invention provides kits that include one or more reaction ies of fatty deposits (atherosclerotic plaques) before another vessels that have aliquots of some or all of the reaction com TIA or stroke can occur. In some embodiments, the patient ponents of the invention in them. Aliquots can be in liquid or may require or benefit from carotid angioplasty, or stenting. dried form. Reaction vessels can include sample processing cartridges or other vessels that allow for the containment, Carotid angioplasty involves using a balloon-like device to processing and/or amplification of samples in the same ves open a clogged artery and placing a small wire tube (stent) sel. The kits can comprise a plurality of nucleic acid probes into the artery to keep it open. that hybridize to a plurality the genes set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. The probes may be immobi 9. Solid Supports and Kits 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 US 2012/OO 15904 A1 Jan. 19, 2012 28

Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. The kits can also berg multiple-comparison correction, and an absolute fold include written instructions for the use of the kit. change-1.5. To exclude genes associated with hypertension, 0173. In one embodiment, the kits comprise a plurality of a second comparison was performed for 33 controls with antibodies that bind to a plurality of the biomarkers set forth hypertension to controls without hypertension. The Identified in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and/or 9. The antibodies “hypertension' genes that overlapped with the TIA gene lists may or may not be immobilized on a solid Support, e.g., an were excluded from further analysis. ELISA plate. 0180 All data are presented as meant-SE. Differences in demographic data between groups were analyzed using Chi EXAMPLES square test or t-test as appropriate. Prediction analysis was 0.174. The following examples are offered to illustrate, but performed using 10-fold leave-one-out cross-validation in Prediction Analysis of Microarrays (PAM). Functional and not to limit the claimed invention. pathway analyses were performed using Ingenuity Pathways Example 1 Analysis (IPA). Materials and Methods Results Subjects Subjects 0175 TIA and control patients were recruited from the University of California Davis Medical Center, University of 0181. The demographic information for TIA and control California San Francisco Medical Center and Wake Forest Subjects showed that age was significantly different between University Health Sciences. Institutional Review Boards at TIA and controls (Table 4). Thus, age was adjusted for in the each institution approved the study, and written informed ANCOVA model. consent was obtained from all patients. 0176 A total of 27 control patients were compared to 24 TABLE 4 TIA patients studied within 3 to 69 hours (average=29.2 hours) of symptoms onset. The diagnosis of TIA was made by Demographic Summary of Transient Ischemic two independent board certified neurologists with access to Attack (TIA) patients and control subjects all clinical data. TIA was defined as an acute loss of focal Controls TIA cerebral or ocular function lasting <12 hours with a presumed (n = 27) (n = 24) p value ischemic etiology. To be recruited into the study TIA patients Age (yrs + SE) 55.7 O.8 70.22.5 <0.001 were required to have an ABCD scoresc4 to further support Gender Female: n (%) 19 (70.4) 14 (58.3) O.39 the diagnosis of TIA. This ensured that TIA patients at higher Race risk for recurrent vascular events were studied (4, 19). The controls were recruited from the spouses or family members Caucasian: n (%) 18 (66.6) 16 (66.6) 1.00 of TIA patients or people from the community. They were Non-Caucasian: n (%) 9 (33.3) 8 (33.3) 1.00 Subjects free of vascular events such as TIA, ischemic stroke, myocardial infarction, peripheral vascular disease, or venous thromboembolism. Control subjects with hypertension and/ TIA Genomic Profiles or diabetes were also excluded in order to reduce the possi 0182. A total of 460 genes were differentially expressed bility of controls having silent TIA or other vascular events. between TIA patients and controls (FDRsO.05; fold Hypertension and diabetes both increase the probability of change21.5) (Tables 5A-D). 135 genes were down-regulated TIA, as shown by the ABCD score (4, 20). (Table 2 and Table 5A) and 325 were up-regulated (Table 1 and Table 5B) in TIA compared to controls. A Hierarchical RNA Isolation cluster analysis of the 460 genes showed that they separated 0177. A venous blood sample was collected into PAXgene TIAS from controls (FIG. 1) except that two TIA patients (ID vacutainers (PreAnalytiX, Hilden, Germany). Total RNA was numbers: 57 and 90) clustered in the control group, and three isolated according to the manufacturer's protocol. control patients (ID numbers: 42, 68 and 74) clustered in the TIA group (FIG. 1). The hierarchical cluster analysis also Microarray Hybridization Suggested the presence of two distinct TIA groups. Most of the up-regulated genes in the TIAL group separated it from (0178 Biotin-labeled cDNA was synthesized from 50ng of the TIA2 group and from controls (FIG. 1). total RNA using the Ovation Whole Blood Solution (Nugen) kit according to protocol. Each RNA sample was processed Prediction Analysis on Affymetrix Human Genome HG-U133-Plus-2.0 microar rays as previously described (18). 0183 Cross-correlation performed with PAMusing the 34 (Table 5C) out of 460 TIA associated genes distinguished 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 TIA Specific Up-regulated Genes in Partek Genomics Suite 6.5 (Partek Inc., St. Louis, Mich. USA) to identify genes/probes significantly different 0.184 The 325 up-regulated genes that distinguished TIA1 between TIA and control subjects with adjustment for from TIA2 patients were input into PAM to derive the mini microarray batch effect and age. Genes/probes were consid mum number (n=26) of genes that differentiated the two ered significant with a p-values 0.05 after Benjamini-Hoch groups. The 26 genes (Table 5D) distinguished TIA1 from

US 2012/OO 15904 A1 Jan. 19, 2012

TABLE 7-continued TIA specific gene-functions Category Function p-value Molecules 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 the large majority of the genes expressed in the acute phase were similar to those expressed in the sub acute phase (>90% 0186 TIA is a harbinger of stroke and other vascular similar). Thus, there may be a chronic inflammatory state events. The present biomarker panels find use for intervention in TIA to prevent future vascular events. Prior to the present prior to TIA and this could contribute to causing TIAs. invention, there was limited knowledge regarding human TIA Anti-Oxidant Capacity biology, and the development of specific TIA therapies has been limited. The present biomarker panels provide informa 0188 GSTM1 and GSTM2 encode cytosolic glutathione tion to better understand the immune response in blood that S-transferases (GSTs) that belong to the mu class. GST occurs inpatients with TIA. By examining the whole genome, enzymes function in the detoxification of electrophilic com unique TIA gene expression profiles showing two TIA Sub pounds. Such products of oxidative stress by conjugation with types were identified. These findings provide unique insight glutathione (30). GSTM1 and GSTM2 were both down-regu into TIA pathophysiology, and are consistent with the con lated in TIA patients, Suggesting a decreased anti-oxidant clusion that there are specific immune responses that occur capacity may exist in patients with TIAS. The resultant following transient focal cerebral ischemia in humans. They enhanced oxidative stress may in turn promote ischemic vas also suggest diagnostic tests to confirm a TIA diagnosis can cular disease such as TIA. This result is consistent with our be developed. previous animal study that showed a specific GST family member (GSTT1) regulated following 10 minutes of brief Systemic Inflammation and TIA focal ischemia simulating human TIAS (5). 0187 TIA patients appear to have unique patterns of Extracellular Matrix Remodeling inflammation associated with their vascular events. Indeed, compared to controls, TIA patients tend to have increased 0189 Our data suggest the presence of two subgroups of leukocyte activation and a systemic inflammatory response TIA patients. No measured clinical factor was significantly (8-9). Transient ischemic attacks have also been associated different between each group. The notion of subtypes of TIA with a number of systemic inflammatory markers such as is not new. For example, TIA subtypes exist based on MRI CRP (7), and inflammatory conditions such as inflammatory DWI status, ABCD score, or the presence of large vessel bowel disease (21-24). Alterations in immune function in disease or atrial fibrillation. In our study, two molecular sub TIAS are further implicated by an association between TIA types of TIA were evident based on gene expression profiles. and systemic infection, as well as TIA and periodontal dis Functional analysis of these two groups suggested over rep ease (25-29). In this study, 63 genes involved in inflammation resentation of genes involved in extracellular matrix remod were differentially expressed in TIA compared to controls eling in TIA1 compared to TIA2 including: MMP16, (Table 7). These genes show patterns of inflammation similar MMP 19, MMP26, COL1A1, COL1A2, COL3A1, to that of inflammatory bowel disease (32 genes), rheumatoid COL10A1, COL11A1, COL25A1, COL27A1, FGFs and arthritis (32 genes), and Crohn's disease (29 genes), Suggest EGFR. TIA1 patients may be more prone to extracellular ing that different, but related patterns of inflammation are matrix breakdown at the blood brain barrier and/or in athero associated with TIA. If the expression of these genes changed Sclerotic plaque. in a time-dependent manner after TIA onset, the inflamma tion could be a consequence of TIA. Otherwise, there might Limitations of the Study be some pre-existing inflammation that did not change with 0190. The sample size is small. A control group at very low time that might promote the development of TIA. Therefore, risk of TIA and other vascular events was chosen so that the a time-dependent analysis on the gene expression in the acute controls would be very unlikely to have silentischemic events phase (blood draw within 24 h of TIA onset; n=11) and the that would complicate comparison to TIA. By doing so, dif sub acute phase (blood draw between 24 h to 72 h of TIA ferences due to vascular risk factors are inevitably introduced. onset; n=13) of TIA was performed. The results showed that These factors were adjusted for by including age in the US 2012/OO 15904 A1 Jan. 19, 2012 32

ANCOVA model, and excluding genes associated with 0.192 This is a discovery type study and thus there is no hypertension and diabetes. The advantage of comparing TIA previous study to compare to. Though FDR correction was to the controls in this study, therefore, is that the gene expres applied, the only way to account for multiple comparisons is sion differences between TIA and controls were maximized, to perform a future replication study. PCR verification was and allowed for the search for TIA subgroups. However, not performed since most changes on Affymetrix arrays have future studies will need to compare TIA patients to other correlated extremely well with PCR in previous studies. In controls to identify “TIA specific gene markers’. These con addition, PCR would only be needed once this study has been trols should include patients with similar vascular risk factors replicated and the PCR confirmed genes were to be used to and “TIA mimic patients with migraine or seizures. develop clinical tests. 0191 Group heterogeneity is another limitation in the 0193 In summary, patients with recent TIAS can be dif study of TIA. Though stringent criteria were used to ensure ferentiated from controls without previous vascular events subjects with TIA were indeed true transientischemic events, using gene expression profiles in blood. In addition, there it is possible that a few TIA patients were in fact TIA mimics. may be different immune response Subtypes following tran Similarly, though a comparison group at low risk for having sient ischemic attacks in humans. silent ischemic vascular events was used, it is possible some (0194 Table 5. TIA associated gene lists (FDRs5.05, patients in the control group had silent vascular events. absolute fold changele 1.5 compared with control).

TABLE 5A Table SA. 135 Downregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 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 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 -1.6OO79 -1595.57 -1586O4 570329 at – -156927 -156143 -1.559 -155759 559723 s at – -155744 5594.01 a. at — -1.SS691 -155664 237803 x at – -1.SS619 -1.SS35 557477 at – -154943 -154815 -1547 555.194 at – -1.543O4 217060 at — -154232 US 2012/OO 15904 A1 Jan. 19, 2012 33

TABLE 5A-continued Table SA. 135 Downregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 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 15601.33 at GIGYF2 GRB10 interacting GYF protein 2 -152626 223O80 a GLS Glutaminase, mRNA (cDNA clone MGC: 33744 -1594.04 IMAGE:5263220) 221288 a 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 a GUSBL2 glucuronidase, beta-like 2 -2.10621 220085 a HELLS helicase, lymphoid-specific -1.67692 241723 a IQGAP2 IQ motif containing GTPase activating protein 2 -1.73571 215750 a KIAA1659 KIAA1659 protein -1.54646 236728 a LNPEP leucyl cystinyl aminopeptidase -1.53387 236621 a LOC100130070 / similar to metallopanstimulin i? similar to rCG63653 fif -1.70558 LOC100130775 i? similar to metallopans LOC100131787 LOC100131905 LOC10O132291 LOC10O1324.88 RPS27 239062 at LOC100131096 hypothetical LOC100131096 -157675 229094 at LOC4O1431 hypothetical gene LOC4.01431 -153069 1565911 at LOC64892.1 MRNA full length insert cDNA clone EUROIMAGE -15498.1 209544 214180 at MAN1C1 mannosidase, alpha, class 1C, member 1 -166631 215663 at MBNL1 muscleblind-like (Drosophila) -153726 212935 at MCF2L MCF.2 cell line derived transforming sequence-like -153863 207078 at MED6 mediator complex subunit 6 -153.192 242111 at METTL3 methyltransferase like 3 -156742 1559856 s at MLL myeloid lymphoid or mixed-lineage leukemia (trithorax -1592.19 homolog, Drosophila) 243857 at MORF4L2 Mrgx mRNA for MRGX -152328 US 2012/OO 15904 A1 Jan. 19, 2012 34

TABLE 5A-continued Table SA. 135 Downregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 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 2198.64 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 5B Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 1563546 at 3.SOO48 1559696 at 3.23854 1563.033 x at — 3.1635S 1563.032 at 2.97.375 1558496 at 2.87094 241566 a 2.8.2164 1568589 at 2.7205 215448 a 2.69149 237479 a 2.68144 234235 a. 2.64462 231074 a 2.63519 1560905 at 2.63286 237871 x at — 2.55976 237937 X at - 2541 2O7731 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 2.366.79 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 US 2012/OO 15904 A1 Jan. 19, 2012 35

TABLE 5B-continued Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 231091 x at — 2.17817 1566862 at 2.1.529 1560760 S at — 2.1184 230959 a 2.10492 238103 a 2.08.283 2428O2 X at — 2.06924 2345.02 a 2.05567 241636 X at — 2.0384 236038 a 2.0344 216406 a 2.02612 566805 a 2.OO292 2394.64 a 2.OOO73 233875 a. 99361 561713 a 9693 562480 a 94431 556983 a at — 936OS 57.0191 a 93494 243902 a .93O45 2O7744 a 923.81 237233 a 90496 561199 a 89756 561902 a 89021 243273 a 883.15 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 81139 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 a 73604 559695 a. at - 7325 560296 a 72689 561473 a 72375 241654 a 71.535 557645 a. .70892 566498 a .70831 237399 a 70373 562811 a 70357 561448 a .68957 237.933 a 68.559 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 US 2012/OO 15904 A1 Jan. 19, 2012 36

TABLE 5B-continued Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 244384 at 65237 238,571 at 64715 237552 at .646.53 241461 at 63938 242718 at 634.17 238392 at 62252 238354 x at — .62228 1560453 at .62O59 215976 at .62O3S 1564840 at 61.94 1561767 at 61738 1553275 S. at - 61253 1563.087 at 61106 1566,597 at 59925 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 S6S21 216463 a S6326 237192 a. 56114 1560517 s at — 55983 1555,263 at .556 1566968 at SS262 241173 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 50237 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 209614 a ADH1B alcohol dehydrogenase 1B (class I), beta polypeptide 51397 202912 a ADM adrenomedullin 61874 206513 a AIM2 absent in melanoma 2 60396 215783 s at ALPL alkaline phosphatase, liver/bone/kidney 2.1006 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 at ANXA3 annexin A3 2.41095 1554816 at ASTN2 astrotactin 2 2.22748 239144 at B3GAT2 beta-1,3-glucuronyltransferase 2 (glucuronosyltransferase 75721 S) 228758 at BCL6 Zinc finger protein .691.27 215990 S. at BCL6 B-cell CLL/lymphoma 6 59315 242579 at BMPR1B bone morphogenetic protein receptor, type IB 2.05687 232416 at 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 at C19Crf59 chromosome 19 open reading frame 59 .99789 US 2012/OO 15904 A1 Jan. 19, 2012 37

TABLE 5B-continued Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 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 .92O67 210262 a CRISP2 cysteine-rich Secretory protein 2 88.349 1553.002 at DEFB1OSA defensin, beta 105A defensin, beta 105B S2948 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 26.1011 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 64412 228260 a ELAVL2 ELAV (embryonic lethal, abnormal vision, Drosophila)- 9905 ike 2 (Huantigen B) 227612 a ELAVL3 ELAV (embryonic lethal, abnormal vision, Drosophila)- 3.2342S 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 .7OO42 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 58141 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 3496.68 242344 a GABRB2 gamma-aminobutyric acid (GABA) A receptor, beta 2 2.72458 1555726 at GAFA3 FGF-2 activity-associated protein 3 61768 219271 a GALNT14 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- 2.076OS 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 1.SS42 activating activity polype 223767 a GPR84 G protein-coupled receptor 84 1.76044 207235 S. at GRMS glutamate receptor, metabotropic 5 1.934S1 1559520 at GYPA Glycophorin A 2.12904 211267 a HESX1 HESXhomeobox 1 1.613SS 227566 a HNT neurotrimin 1S6SS4 206858. S. at HOXC4 HOXC6 homeobox C4 homeobox C6 170414 219403 s at HPSE heparanase 160481 211959 a IGFBP5 insulin-like growth factor binding protein 5 1.54545 US 2012/OO 15904 A1 Jan. 19, 2012 38

TABLE 5B-continued Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 205067 a interleukin 1, beta S7884 394.02 at interleukin 1, beta S1316 229538 s at QGAP3 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, S696S LOC100131955 member 15 i? similar to pot 227250 a KREMEN1 kringle containing transmembrane protein 1 2164O6 235370 a KREMEN1 kringle containing transmembrane protein 1 77475 215516 a LAMB4 aminin, beta 4 6.0646 206140 a LIM homeobox2 2.0959 225571 a LIFR eukemia inhibitory factor receptor alpha 691.68 210582 s at LIMK2 LIM domain kinase 2 S485 1556,704 S at LOC10O13392O hypothetical protein LOC100.133920 i? hypothetical LOC286.297 protein LOC286.297 232034 a LOC2O3274 CDNA FLJ31544 fis, clone NT2RI2O00865 63147 1557717 at LOC338862 ical protein LOC338862 2.22946 1560823 at LOC34.0017 protein LOC34.0017 51946 233879 a LOC374491 TPTE and PTEN homologous inositol lipid phosphatase 81019

1558982 at LOC37SO10 LOC37SO10 72485 214984 a LOC440345 protein LOC440345 98536 230902 a LOC645323 CDNA clone IMAGE: 5260726 84336 238850 a LOC645323 hypothetical LOC645323 81503 1568933 at LOC646627 phospholipase inhibitor S3874 231434 a LOC728460 similar to FLJ32921 protein 68733 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 (TNFR superfamily, member S8399 3) 201744 s at LUM unican 93131 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 214087 s at MYBPC1 myosin binding protein C, slow type 237510 at MYNN Myoneurin, mRNA (cDNA clone IMAGE: 4721583) 1559292 s at NCRNA00032 Clone IMAGE: 2275835 C9orf14 mRNA, partial sequence, alternatively spliced 220429 at NDST3 N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3 6.8889 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, if protocadherin 11 X-linked fit protocadherin 11 Y-linked 6605 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 60S42 241669 x at PRKD2 protein kinase D2 55139 220696 at PROO478 PROO478 protein 691.69 228825 at PTGR1 prostaglandin reductase 1 .95262 217194 at RASAL2 RAS protein activator like 2 2.OO632 226872 at RFX2 regulatory factor X, 2 (influences HLA class II S8786 expression) 213194 at ROBO1 roundabout, axon guidance receptor, homolog 1 (Drosophila) 242385 at RORB RAR-related orphan receptor B 1555990 at RP1-127L4.6 hypothetical protein LOC150297 215321 at RUNDC3B RUN domain containing 3B 205863 at S100A12 S100 calcium binding protein A12 229057 at SCN2A Sodium channel, voltage-gated, type II, alpha Subunit 207570 at SHOX short stature homeobox 210135 s at SHOX2 short stature homeobox2 208443 x at SHOX2 short stature homeobox2 US 2012/OO 15904 A1 Jan. 19, 2012 39

TABLE 5B-continued Table 5.B. 325 Upregulated Genes Fold AFFY ID Gene Symbol Gene Title Change 206634 at SIX3 SIXhomeobox 3 .78989 205896 at SLC22A4 Solute carrier family 22 (organic cation ergothioneine 65918 transporter), member 4 237340 at 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 at SNIP SNAP25-interacting protein 83841 240204 at 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 .75314 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 toll-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 tetratricopeptide repeat domain 6 9101S 213943 a TWIST1 twist homolog 1 (Drosophila) 2.72279 222435 s at UBE2J1 ubiquitin-conjugating enzyme E2, J1 (UBC6 homolog, 50758 yeast) 226899 a UNCSB unc-5 homolog B (C. elegans) 2.04351 1561200 at WWA3B von Willebrand factor A domain containing 3B 618O2 206954 a WIT1 Wilms tumor upstream neighbor 1 2.58643 1552946 at ZNF114 Zinc finger protein 114 99445 229743 a ZNF438 Zinc finger protein 438 S3O49 244007 a ZNF462 Zinc finger protein 462 53545 1555367 at ZNF479 Zinc finger protein 479 2.251.93 1555368 x at ZNF479 Zinc finger protein 479 2.162O3 2323.03 a ZNF608 Zinc finger protein 608 72629

TABLE SC TABLE 5C-continued

34 Genes that differentiate TLA from Control 34 Genes that differentiate TIA from Control

Fold- Fold AFFY ID Gene Symbol Gene Title Change AFFY ID Gene Symbol Gene Title Change 1557580 at - -1.85725 244226 s at — -168579 1559695 a. at - 7325 1561767 at 61738 244665 at -165812 1563026 at S413S 229252 at ATG9B ATG9 autophagy -1.64694 1S63568 at 81339 related 9 homolog B 1568589 at - 2.7205 (S. cerevisiae) 1568781 at -160862 212504 at DIP2C DIP2 disco-interacting -1.62614 216406 at 2.02612 protein 2 homolog C 2296.54 at -1.74432 (Drosophila) 231040 at 73604 233092 s at DKFZP434B061 DKFZP434B061 protein 1.84946 231069 at -1.SS35 220048 at EDAR ectodysplasin A receptor -1.693.85 231546 at .52352 220645 at FAMSSD family with sequence 1.SS166 233306 at S6S21 similarity 55, member D 236571 at S893 1557155 a. at FLJ30375 CDNA clone IMAGE: 1974S1 237597 at -2.4398 5301781 237953 at -154815 215333 x at GSTM1 glutathione S-transferase -2.03103 242495 at S1926 mu 1 242564 at -163967 232207 at GUSBL2 glucuronidase, beta-like -2.10621 242710 at -1.76712 2 US 2012/OO 15904 A1 Jan. 19, 2012

TABLE 5C-continued TABLE 5D-continued 34 Genes that differentiate TLA from Control 26 Upregulated Genes that differentiate TIAl from TIA2 Fold- Fold AFFY ID Gene Symbol Gene Title Change AFFY ID Gene Symbol Gene Title Change 211959 at IGFBP5 insulin-like growth factor 1.54545 241566 at 2.8.2164 binding protein 5 213943 at TWIST1 twist homolog 1 2.72279 203005 at LTBR lymphotoxin beta 1.58.399 (Drosophila) receptor (TNFR 215448 at 2.69149 Superfamily, member 3) 241199 X at DPPA4 developmental pluripotency 2.68174 229057 at SCN2A Sodium channel, voltage- 1851.29 associated 4 gated, type II, alpha 237479 at 2.68144 Subunit 234235 at 2.64462 232020 at SMURF2 SMAD specific E3 -1.57992 1560905 at 2.63286 ubiquitin protein ligase 2 222253 s at DKFZP434P211 POM121 membrane 2.61011 55872 at ZNFS12B Zinc finger protein 512B -1521.58 glycoprotein-like 1 pseudogene 237937 X at - 2.541 2O7731 at 2.52426 TABLE5D 239309 at DLX6 distal-less homeobox 6 2.4523 243398 at 2.43872 26 Upregulated Genes that differentiate TIA1 from TIA2 : 27, 3. Fold- 1555367 at ZNF479 Zinc finger protein 479 2.2S193 AFFY ID Gene Symbol Gene Title Change 1554816 at ASTN2 astrotactin 2 2.22748 241987 X at SNX31 sorting nexin 31 2.19167 1557122 S at GABRB2 gamma-aminobutyric acid 3.49668 1557762 at - 2.18276 (GABA) A receptor, beta 2 1563673 a at ALS2CR11 amyotrophic lateral 2.15.177 1559696 at - 3.23854 sclerosis 2 (juvenile) 227612 at ELAVL3 ELAV (embryonic lethal, 3.23425 chromosome region, abnormal vision, candidate 11 Drosophila)-like 3 214984 at LOC440345 hypothetical protein 198536 (Huantigen C) LOC440345 1563.032 at 2.97.375 1556983 a at — 19360S 1558496 at 2.87094

TABLE 8 Table 8 - Significant genes between TIAl and TIA2 (FDRs 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1553.422 S at A2BP1 ataxin 2-binding protein 1 72186 223593 a AADAT aminoadipate aminotransferase 85564 214829 a AASS aminoadipate-semialdehyde synthase 89.032 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 .741.38 208462 s at ABCC9 ATP-binding cassette, Sub-family C (CFTR/MRP), member 9 2.03195 220518 a ABI3BP ABI family, member 3 (NESH) binding protein 81797 220061 a ACSMS acyl-CoA synthetase medium-chain family member 5 7406S 89977 at ACSMS acyl-CoA synthetase medium-chain family member 5 2.18846 215613 a ADAM12 Meltrin-S (ADAM12) mRNA, complete cols, alternatively spliced 79057 1568970 at ADAM18 ADAM metallopeptidase domain 18 2.48574 207664 a ADAM2 ADAM metallopeptidase domain 2 .9154 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 ADAMTS19 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), pi polypeptide 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 US 2012/OO 15904 A1 Jan. 19, 2012 41

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 230630 at AK3L1 adenylate kinase 3-like 1 / adenylate kinase 3-like 2 152481 AK3L2 207870 at AKAP9 A kinase (PRKA) anchor protein (yotiao) 9 1.76652 244205 at ALAS2 aminolevulinate, delta-, synthase 2 1.6711S 211617 at ALDOAP2 aldolase A, fructose-bisphosphate pseudogene 2 3.07845 211357 s at ALDOB aldolase B, fructose-bisphosphate 174204 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 domain 20 family, ANKRD2OA2

ANKRD2OA3

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 ASZ, ankyrin repeat, SAM and basic leucine Zipper domain containing 1 1.59531 1559485 at ATG2B ATG2 autophagy related 2 homolog B (S. cerevisiae) 171224 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 1.91809 220556 a ATP1B4 ATPase, (Na+)/K+ transporting, beta 4 polypeptide 1.631.53 211137 s at ATP2C1 ATPase, Ca++ transporting, type 2C, member 1 -151541 214594 X at ATP8B1 ATPase, class I, type 8B, member 1 1.78628 216129 a ATP9A ATPase, class II, type 9A 198899 1560404 a at ATPBD4 ATP binding domain 4 1.5843 1569796 S. at ATRNL1 attractin-like 1 2.48281 222969 a B3GALT1 UDP-Gal:betaGlcNAc beta1,3-galactosyltransferase, polypeptide 1 197721 239144 a B3GAT2 beta-1,3-glucuronyltransferase 2 (glucuronosyltransferase S) 2.24315 206233 a B4GALT6 UDP-Gal:betaGlcNAc beta 14-galactosyltransferase, 1.S1182 polypeptide 6 US 2012/OO 15904 A1 Jan. 19, 2012 42

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 202946s 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 a C14orf1 chromosome 14 open reading frame 91 51441 232507 a 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 24.0068 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 240801 at C21orf7 chromosome 21 open reading frame 37 2.52149 1552876 at C21orf&9 chromosome 21 open reading frame 89 1.74874 244467 at C22:CTA- transmembrane protein 46-like -150447 2SOD10.9 1552979 at C2Orfs2 chromosome 2 open reading frame 52 1.506S 15585.19 at C2orf67 RPE Chromosome 2 open reading frame 67, mRNA (cDNA clone 154141 MGC: 27010 IMAGE:4829661) // 231081 at C2Orf73 chromosome 2 open reading frame 73 183581 24.1998 at C2Orf30 chromosome 2 open reading frame 80 2.15326 1554147 s at C3orf15 chromosome 3 open reading frame 15 1.5927 1554528 at C3orf15 chromosome 3 open reading frame 15 2.1.5.191 1555.719 a. at C3orf15 chromosome 3 open reading frame 15 2.821.89 US 2012/OO 15904 A1 Jan. 19, 2012 43

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 1555096 at C4Orf37 chromosome 4 open reading frame 37 87794 1553106 at CSOrf24 chromosome 5 open reading frame 24 -184772 234457 a C6orf12 chromosome 6 open reading frame 12 2.813S 1552575 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 15565.16 at C9Crf3 CDNA clone IMAGE: 5312512 2.11837 1553433 at C9Crf3 chromosome 9 open reading frame 93 2.37646 1557666 sat 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 1 C 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 552.509 a. at CD3OOLG CD300 molecule-like famil memberg 53768 554519 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 24O161 S. at CDC2OB Cell division cycle 20 homolog B (S. cerevisiae), mRNA (cDNA 2.04212 clone IMAGE: 5206729 555772 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 152631 Homo sapiens mRNA for C 240735 at CDC42BPA Ser-thr protein kinase PK428 1.53612 22O115 S. at CDH10 cadherin 10, type 2 (T2-cadherin) 2.15879 236179 at CDH11 cadherin 11, type 2, OB-cadherin (osteoblast) 170475 207149 at CDH12 cadherin 12, type 2 (N-cadherin 2) 162637 206898 at CDH19 cadherin 19, type 2 1.56233 220679 s at CDH7 cadherin 7, type 2 18O8O1 US 2012/OO 15904 A1 Jan. 19, 2012 44

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 1553.080 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? cancer/testis antigen CT45-6 fif S.90OS4 CT45-6 hypothetical p LOC10O133581 J. RP13-36C9.1 J. RP13-36C9.3 J. RP13-36C9.6 XX FW88277B6.1 231568 at CT47.7 canceritestis CT47 family, member 7 i? cancertestis CT47 1.71304 CT47.8/// RP6- family, member 8 /// 66C19.1 RP6-166C19.10 J. RP6 66C19.11 RP6-166C19.2 J. RP6 66C19.3 RP6-166C19.4 J. RP6 66C19.5 RP6-166C19.6 J. RP6 66C19.9 213597 s at CTDSPL CTD (carboxy-terminal domain, RNA polymerase II, polypeptide 193739 A) Small phosphatas US 2012/OO 15904 A1 Jan. 19, 2012 45

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 802O3 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) S1034 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 S386S 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 i? defensin, beta 107B 3.12379 DEFB107B 1562167 a. at DEFB122 efensin, beta 122 (pseudogene) S82O6 207356 a DEFB4 efensin, beta 4 95828 238917 s at DENNDSB DENN/MADD domain containing 5B -1.877OS 234071 a DEPDC6 DEP domain containing 6 54924 216947 a 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: 5022014 3.78072 206819 a DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 2.57115 222253 s at DKFZP434P211 POM121 membrane glycoprotein-like 1 pseudogene 5.5328 216877 a DKFZp686O1327 EST clone 251800 mariner transposon HSmar1 sequence 2.46877 224199 a 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 a DLX2 istal-less homeobox2 2.38281 239309 a DLX6 istal-less homeobox 6 4S490S 220493 a DMRT1 oublesex and mab-3 related transcription factor 1 2.29697 237804 a 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) dpy-19-like 2 pseudogene 1 (C. elegans) 62779

DPY19L2P4 24.0218 at DSCAM Down syndrome cell adhesion molecule 59287 1552708 a at DUSP19 dual specificity phosphatase 19 2.25968 204014 at DUSP4 dual specificity phosphatase 4 67536 1569843 at DYNC1LI1 dynein, cytoplasmic 1, intermediate chain 1 78891 1565149 at DYNC2H1 dynein, cytoplasmic 2, heavy chain 1 2.12554 204271 S. at EDNRB endothelin receptor type B 68OO2 1558300 at EFCABS EF-hand calcium binding domain 5 2.24756 233814 at EFNAS Receptor tyrosine kinase ligand LERK-7 precursor (EPLG7) 57917 219454 at EGFL6 EGF-like-domain, multiple 6 .631.59 US 2012/OO 15904 A1 Jan. 19, 2012 46

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 sat 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 a FAM123A amily with sequence similarity 123A .86652 230496 a FAM123A amily with sequence similarity 123A 2.SO999 231396 s at FAM126A amily with sequence similarity 126, member A -150922 223625 a. FAM126A amily with sequence similarity 126, member A -181004 239481 a FAM133A amily with sequence similarity 133, member A 4.33493 1569025 S at FAM13A1 amily with sequence similarity 13, member A1 57074 222291 a FAM149A amily with sequence similarity 149, member A 2.OOO81 214825 a. FAM15SA amily with sequence similarity 155, member A 68899 23O869 a FAM15SA amily with sequence similarity 155, member A 4.255.08 242687 a FAM160A1 amily with sequence similarity 160, member A1 63O33 213304 a FAM179B amily with sequence similarity 179, member B -1.60915 230539 a FAM182A amily with sequence similarity 182, member A 57619 216053 X at FAM182A CDNA FLJ38374 fis, clone FEBRA2002552 .70S61 222205 X at FAM182B amily with sequence similarity 182, member B i? hypothetical 2.46888 RP13-401N8.2 gene Supported by 234945 a. 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 US 2012/OO 15904 A1 Jan. 19, 2012 47

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 156.8889 at EANCD2 Fanconi anemia, complementation group D2 .62037 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 233087 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 IMAGE: 10529 S4O76 MAGE: 3948893) 220394 a FGF2O fibroblast growth factor 20 .85663 210311 a FGF fibroblast growth factor 5 S9913 205782 a FGF7 fibroblast growth factor 7 (keratinocyte growth factor) 67479 239710 a FIGN idgetin 4.1857 238964 a FIGN idgetin 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 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 55.3775 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 FLJ34047 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 similar to double homeobox A 2.09022 LOC100131139 US 2012/OO 15904 A1 Jan. 19, 2012 48

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 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 Fyn-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 1553024 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 207739 S at GAGE1 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 (1 -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 US 2012/OO 15904 A1 Jan. 19, 2012 49

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 244680 at GLRB glycine receptor, beta 90493 235371 at GLT8D4 glycosyltransferase 8 domain containing 4 55O1 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 -162372 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 2O6204 a GRB14 growth factor receptor-bound protein 14 2.23024 23SSO4 a GREM2 gremlin 2, cysteine knot Superfamily, homolog (Xenopus laevis) SO319 219388 a GRHL2 grainyhead-like 2 (Drosophila) 2.33499 2OS358 a GRIA2 glutamate receptor, ionotropic, AMPA 2 2.02789 2O6730 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 -151561 242656 a GTF2H1 General transcription factor IIH, polypeptide 1, 62 kDa -1.653.52 (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 -1.88O82 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 -1.93357 217353 a HNRNPA1 heterogeneous nuclear ribonucleoprotein A1 if heterogeneous 6O11 HNRNPA1L2 nuclear ribonucleop if HNRPA1L-2 if HNRPA1PS

LOC100128836 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 US 2012/OO 15904 A1 Jan. 19, 2012 50

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change J. LOCA29366 J. LOCA3O246 227566 a HNT neurotrimin 2.73516 213793 s at HOMER1 homer homolog 1 (Drosophila) 91311 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 a 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 ICOSLG 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 L15 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 NTS7 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 LOC100134209 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 KLAA1217 727 235956 a KIAA1377 KLAA1377 S9988 233977 a KIAA1772 KLAA1772 SO426 236518 a KIAA1984 KLAA1984 -158518 US 2012/OO 15904 A1 Jan. 19, 2012 51

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 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) 1552490 at LACE1 actation elevated 1 215516 a LAMB4 aminin, beta 4 229953 X at LCAS Leber congenital amaurosis 5 213371 a LDB3 LIM domain binding 3 207409 a LECT2 eukocyte cell-derived chemotaxin 2 207092 a LEP eptin 236761 a LHFPL3 ipoma HMGIC fusion partner-like 3 206140 a LHX2 LIM homeobox2 225571 a LIFR eukemia inhibitory factor receptor alpha 212328 a LIMCH1 LIM and calponin homology domains 1 212327 a LIMCH1 LIM and calponin homology domains 1 212325 a. LIMCH1 LIM and calponin homology domains 1 232457 a LIMCH1 LIM and calponin homology domains 1, mRNA (cDNA clone MGC: 16598 IMAGE: 4110496) 98.23 a LIN28 in-28 homolog (C. elegans) 29349 a LIN28B in-28 homolog B (C. elegans) 41957 x at LINAB in-7 homolog B (C. elegans) 9181 a LIPG ipase, endothelial 42178 a LIPI ipase, member I 6543 a LOC100093.698 unknown transcript 7655 a. LOC10O127972 hypothetical LOC100127972 24095 a LOC100128175 similar to PRO2591 O7478 a LOC100128329 similar to PRO2958 2.9999 a LOC100128416 Full length insert cDNA clone ZE12A08 5590 X at LOC10012864O PREDICTED: Homo sapiens hypothetical protein LOC100128640 (LOC100128640), mRNA 240395 a LOC100128727 hypothetical LOC100128727 244723 a LOC100129488 hypothetical protein LOC100129488 244518 a LOC10O130452 similar to hCG1777700 1560425 s at LOC10O13O868 hypothetical protein LOC100.130868 215301 a LOC10O130958 hypothetical protein LOC100.130958 1565814 at LOC100131040 hypothetical protein LOC100131040 fit tripartite motif fif TRIM36 containing 36 211341 a LOC100131317 similar to hCG1781.072 POU class 4 homeobox 1 POU4F1 237711 a LOC100131980 similar to zinc finger protein 705A i? zinc finger protein 705G ZNF705G ike 1561170 at LOC10O132O2S transmembrane domain-containing protein ENSP00000320207 2.28603 ike 236181 a LOC10O1321.81 PREDICTED: Homo sapiens hypothetical protein 2.60614 LOC100.132181 (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 LOC100.133283 (LOC100133283), mRNA 224110 a LOC10O133319 PRO1804 18742S 1562974 at LOC10O133899 hypothetical protein LOC100.133899 18921 1556,704 S at LOC10O13392O hypothetical protein LOC100.133920 i? hypothetical protein 2.36676 J. LOC286297 LOC286297 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 LOC1SOOOS hypothetical protein LOC15.0005 186593 239965 at LOC151878 hypothetical protein LOC151878 2.92.204 US 2012/OO 15904 A1 Jan. 19, 2012 52

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 215978 X at LOC152719 hypothetical protein LOC152719 56227 239691 at LOC1964.15 hypothetical protein LOC1964.15 53729 232370 at LOC2S4OS7 hypothetical protein LOC254.057 630S 5625O1 a LOC255.177 hypothetical protein LOC255.177 562527 a LOC283O27 hypothetical protein LOC283027 56385.4 S at LOC283O45 hypothetical protein LOC283045 558195 a LOC2834.04 hypothetical protein LOC2834.04 556425 a. at LOC284219 hypothetical protein LOC284219 214162 at LOC284244 hypothetical protein LOC284244 563009 a LOC284930 Homo sapiens, clone IMAGE: 5538478, mRNA 557267 s at LOC284952 hypothetical protein LOC284952 557570 a. at LOC285084 hypothetical protein LOC285084 558601 a LOC285.194 hypothetical LOC285.194 556528 a LOC285326 hypothetical protein LOC285326 561096 a LOC285419 hypothetical protein LOC285419 557107 a LOC286OO2 hypothetical protein LOC286002 556573 s at LOC2861.78 hypothetical protein LOC286.178 556421 a. LOC286189 hypothetical protein LOC286189 240545 at LOC286.382 hypothetical protein LOC286382 557717 a LOC338862 hypothetical protein LOC338862 557534 a LOC339862 hypothetical protein LOC339862 560823 a LOC34.0017 hypothetical protein LOC34.0017 563589 a LOC340184 hypothetical protein LOC340184 557664 a LOC34O239 PREDICTED: Homo sapiens hypothetical protein LOC340239, transcript variant 2 (LO 559002 a LOC340544 hypothetical protein LOC340544 235606 at LOC344595 hypothetical LOC344595 563022 a. LOC34747S UPF0625 coiled-coil domain-containing protein ENSPOOOOO3S9845 558423 a LOC349114 Homo sapiens, clone IMAGE: 4385460, mRNA 233879 at LOC374491 TPTE and PTEN homologous inositol lipid phosphatase pseudogene 558982 a LOC37SO10 hypothetical LOC375010 558425 X at LOC3883.12 hypothetical LOC388312 // hypothetical LOC728417 /// LOC728417 hypothetical LOC729737 /// LOC729737 LOC73O235 56O773 at LOC388458 hypothetical gene Supported by BC040718 56O119 at LOC389634 hypothetical LOC389634 226582 at LOC4OOO43 hypothetical gene Supported by BC009385 561414 at LOC4O1497 similar to PRO2738 561997 at LOC44OO61 PREDICTED: Homo sapiens misc RNA (LOC440061), miscRNA 240268 at LOC44O117 hypothetical gene Supported by BC037858 214984 at LOC440345 hypothetical protein LOC440345 244766 at LOC44O3S4 PI-3-kinase-related kinase SMG-1 pseudogene if PI-3-kinase LOCS951O1 if related kinase SMG-1 LOC641298 LOC728423 LOC729513 SMG1 216193 at LOC440366 heet domain and RLD 2 pseudogene 181363 1562558 at LOC44O704 hypothetical gene Supported by BC042042 240362 224426 s at LOC44.0888 ARP3 actin-related protein 3 homolog B pseudogene 3.36427 224424 X at LOC44.0888 ARP3 actin-related protein 3 homolog B pseudogene 2.83853 224425 X at LOC44.0888 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 1559459 at LOC613266 hypothetical LOC613266 -2.71264 1561098 at LOC641365 hypothetical protein LOC641365 1.59224 1562223 at LOC642426 hypothetical LOC642426 2.36874 1554996 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 1566145 S. at LOC644,450 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 US 2012/OO 15904 A1 Jan. 19, 2012 53

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1561760 S at LOC64SS13 CDNA clone IMAGE: 5276804 -1.54359 1564200 at LOC646.324 hypothetical LOC646324 944.25 1568933 at LOC646627 phospholipase inhibitor 90895 215467 x at LOC647070 hypothetical LOC647070 1561492 at LOC647107 hypothetical protein LOC647107 232696 at LOC648SS6 uncharacterized gastric protein ZA43P 217998 at LOC652993 hypothetical LOC652993 ff, pleckstrin homology-like domain, PHILDA1 amily A, member 1 1557094 at LOC653110 hypothetical LOC653110 243124 at LOC653390 RRN3 RNA polymerase I transcription factor homolog (S. cerevisiae) pseudogene 216469 at LOC727867 similar to PRED65 // zinc finger protein ENSPOOOOO344568-like LOC7295O1 if if similar to PR LOC7298.63 ZNF834 1559322 at LOC727916 hypothetical protein LOC727916 1564856 S at LOC727924 if hypothetical LOC727924 fit olfactory receptor, family 4, OR4N4 Subfamily N, member 4 1558828 S. at LOC728.264 CDNA FLJ36638 fis, clone TRACH2O18950 231434 at LOC728460 similar to FLJ32921 protein 1559276 at LOC728606 hypothetical LOC728606 234562 x at LOC728678 PREDICTED: Homo sapiens misc RNA (LOC728678), miscRNA 15664.65 at LOC728.987 MRNA, cDNA DKFZp686I1934 (from clone DKFZp686I1934) 2.74.786 214375 at LOC729.222 similar to mKIAA1230 protein i? 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 1562939 at LRRC16A eucine rich repeat containing 1.6A 216149 a LRRC37B2 eucine rich repeat containing 37, member B2 232226 a LRRC4C eucine rich repeat containing 4C 1556427 s at LRRN4CL LRRN4 C-terminal like 206144 a MAGI1 membrane associated guanylate kinase, WW and PDZ domain containing 1 225465 a MAGI1 membrane associated guanylate kinase, WW and PDZ domain containing 1 226084 a MAP1B microtubule-associated protein 1B 1562440 at MAP3K13 Leucine Zipper bearing kinase 1565131 X at MAP3K2 mitogen-activated protein kinase kinase kinase 2 1552928 S. at MAP3K7IP3 mitogen-activated protein kinase kinase kinase 7 interacting protein 3 235066 at MAP4 microtubule-associated protein 4 235141 at MARVELD2 MARVEL domain containing 2 233634 at MARVELD3 MARVEL domain containing 3 205018 s at MBNL2 muscleblind-like 2 (Drosophila) 1554.604 at MBTPS2 membrane-bound transcription factor peptidase, site 2 214884 at MCF2 DBL mRNA for DBL proto-oncogene splicing variant 1 1559.427 at MCF2L KIAA0362 gene 229797 at MCOLN3 mucolipin 3 212732 at MEG3 maternally expressed 3 (non-protein coding) 235.077 at MEG3 maternally expressed 3 (non-protein coding) 207480 s at MEIS2 Meis homeobox2 214077 x at MEIS3P1 Meis homeobox 3 pseudogene 1 211424 X at METTL7A methyltransferase like 7A 240814 at MGC39584 hypothetical gene Supported by BCO29568 238.481 at MGP matrix Gla protein US 2012/OO 15904 A1 Jan. 19, 2012 54

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 203637 S at MID1 midline 1 (Opitz/BBB syndrome) 2.07411 1552572 a at MIPOL1 mirror-image polydactyly 1 .96747 2394.68 at MKX mohawk homeobox 2.02738 238.257 at MLLT10 Zinc fingerfleucine zipper protein (AF10) .6337 1569998 at MMD2 monocyte to macrophage differentiation-associated 2 60681 207012 at MMP16 matrix metallopeptidase 16 (membrane-inserted) 87224 208166 at MMP16 matrix metallopeptidase 16 (membrane-inserted) 2.SS4O2 204575 s at MMP19 matrix metallopeptidase 19 -1.70549 220541 at MMP26 matrix metallopeptidase 26 7046 221636 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 aat 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 237917 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 neurofascinhomolog (chicken) S1334 214799 a NEASC neurofascinhomolog (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 1.5816 215228 at NHLH2 nescient helix loop helix 2 186841 1554601 at NKAIN2 Na+/K+ transporting ATPase interacting 2 1.76903 211024 S at NKX2-1 NK2 homeobox 1 1.7883 205893 at NLGN1 neuroligin 2.23.077 221933 at NLGN4X neuroligin 4, X-linked 1.7674 234762 X at NLN CDNA FLJ39097 fis, clone NTONG2000977, highly similar to 162853 Neurolysin, mitochondri 1552712 a. at NMNAT2 nicotinamide nucleotide adenylyltransferase 2 1.52782 206045. S. at NOL4 nucleolar protein 4 2.539 1560974 S at NOS1 nitric oxide synthase 1 (neuronal) 1.582S 232158 x at NPAL1 NIPA-like domain containing 1 1.9677 US 2012/OO 15904 A1 Jan. 19, 2012 55

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 22O128 S. at NPAL2 NIPA-like domain containing 2 -15032 220316 a NPAS3 neuronal PAS domain protein 3 .69165 229281 a NPAS3 neuronal PAS domain protein 3 8588 230412 a NPAS3 neuronal PAS domain protein 3 2.2537 211585 a NPAT nuclear protein, ataxia-telangiectasia locus 94524 23884.4 S at NPHP1 nephronophthisis 1 (juvenile) 2.41213 225911 a NPNT nephronectin 90656 219789 a NPR3 natriuretic peptide receptor Ciguanylate cyclase C 73795 (atrionatriuretic peptide rec 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 2294.63 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 OCIAD1 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 (6M1-16 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 156O770 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 224940 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 if protocadherin 11 Y-linked 2.SS484 PCDH11 Y 205656 at PCDH17 protocadherin 17 SO888 227 289 at PCDH17 protocadherin 17 2.04806 225975 at PCDH18 protocadherin 18 2.301.13 232054 at PCDH2O protocadherin 20 S9426 210273 at PCDHT protocadherin 7 72605 208.205 at PCDHA9 protocadherin alpha 9 54772 232415 at PCDHB13 protocadherin beta 13 .76909 231726 at PCDHB14 protocadherin beta 14 621.33 232099 at PCDHB16 protocadherin beta 16 2.13788 223927 at PCDHB9 protocadherin beta 9 7009 234515 at PCGEM1 prostate-specific transcript 1 (non-protein coding) 50251 210650 S at PCLO piccolo (presynaptic cytomatrix protein) 69469 US 2012/OO 15904 A1 Jan. 19, 2012 56

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 1554.828 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 238957 a PDXDC2 MRNA, cDNA DKFZp761H1120 (from clone 2.03644 DKFZp761H1120) 212092 a 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 a PFDN6 prefoldin subunit 6 -151654 24.0883 a PFKFB1 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (EC S229 2.7.1.105, EC 3.1.3.46) 244321 a 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 a PMP2 peripheral myelin protein 2 2.22591 219926 a 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 a POU2F3 POU class 2 homeobox 3 72743 207084 a POU3F2 POU class 3 homeobox2 .51578 219195 a PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 2.39587 alpha 232073 a PPFIA2 protein tyrosine phosphatase, receptor type, fpolypeptide 76444 (PTPRF), interacting 204517 a PPIC peptidylprolyl isomerase C (cyclophilin C) 2.51.701 236142 a. PPIH U-SnRNP-associated cyclophilin (USA-CyP) -1.72474 223999 a PPIL2 peptidylprolyl isomerase (cyclophilin)-like 2 SOS 16 1555462 at PPP1R1C protein phosphatase 1, regulatory (inhibitor) subunit 1C 2.33566 240187 a 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 at PRKAA2 protein kinase, AMP-activated, alpha 2 catalytic Subunit 64369 227892 at PRKAA2 protein kinase, AMP-activated, alpha 2 catalytic Subunit 67124 1554910 at PRKD3 protein kinase D3 -1.6967 220696 at PROO478 PROO478 protein 2.36786 220883 at PRO2012 hypothetical protein PRO2012 781 208004 at PROL1 proline rich, lacrimal 1 2.6306S 228656 at PROX1 prospero homeobox. 1 83495 242119 at PROX1 Homeodomain protein (Prox 1) .938OS 229376 at PROX1 prospero homeobox. 1 2.244.15 US 2012/OO 15904 A1 Jan. 19, 2012 57

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1552455 at PRUNE2 prune homolog 2 (Drosophila) 2.21968 2101.95 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 210355 a. PTHLH parathyroid hormone-like hormone 1555.324 at PTK7 PTK7 protein tyrosine kinase 7 209465 x at PTN pleiotrophin 211737 x at PTN pleiotrophin 208011 a PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid) 213362 a PTPRD protein tyrosine phosphatase, receptor type, D 214043 a PTPRD protein tyrosine phosphatase, receptor type, D 204944 a PTPRG protein tyrosine phosphatase, receptor type, G 235634 a URG purine-rich element binding protein G 215517 a C YGO1 pygopus homolog 1 (Drosophila) 239570 a B1A GTP-binding protein (RAB1A) mRNA, 3' untranslated region 24-1977 s at B3C RA B3C, member RAS oncogene family (RAB3C), mRNA 224200 s at D18 RA D18 homolog (S. cerevisiae) 223417 a D18 RA D18 homolog (S. cerevisiae) 234662 a D21L1 RA D21-like 1 (S. pombe) 204146 a DS1AP1 RA D51 associated protein 1 206591 a recombination activating gene 1 242712 X at NBP2 RAN binding protein 2 ft, RANBP2-like and GRIP domain PD1 containing 1 if RANBP2-li PD2 PD3 PD4 RGPD5 RGPD6 RGPD7 RGPD8 2172.01 a RASAL2 RAS protein activator like 2 1557432 at RASAL2 RAS protein activator like 2 217194 a RASAL2 RAS protein activator like 2 1553986 at RASEF RAS and EF-hand domain containing 1553185 at RASEF RAS and EF-hand domain containing 1553186 X at RASEF RAS and EF-hand domain containing 235638 a RASSF6 Ras association (RalGDSAF-6) domain family member 6 225846 a BM3SA RNA binding motif protein 35A 219121 s at BM3SA RNA binding motif protein 35A 242516 x at BM46 RNA binding motif protein 46 1560322 at BMS3 RNA binding motif, single stranded interacting protein 238447 a BMS3 RNA binding motif, single stranded interacting protein 2094.87 a BPMS RNA binding protein with multiple splicing 232359 a DH11 Vesicle soluble NSF attachment protein receptor (VT11) 212398 a D radixin 1561720 at RecQ protein-like 5 205923 a reelin 220276 a RG L RERGRAS-like 203225 s at K riboflavin kinase 223673 a X4 regulatory factor X, 4 (influences HLA class II expression) 1556354 s at ral guanine nucleotide dissociation stimulator-like 3 1568752. S. at regulator of G-protein signaling 13 209071 s at regulator of G-protein signaling 5 237719 X at regulator of G-protein signaling 7 binding protein 233409 at BDL3 rhomboid, veinlet-like 3 (Drosophila) 238906 s at ras homolog gene family, member J 1552922 at MS1 regulating synaptic membrane exocytosis 1 235153 at F183 ring finger protein 183 210931 at ring finger protein (C3H2C3 type) 6 226709 at BO2 roundabout, axon guidance receptor, homolog 2 (Drosophila) 226766 at BO2 roundabout, axon guidance receptor, homolog 2 (Drosophila) 240425 X at BO2 Roundabout 2 (robo2) 242385 at RB RAR-related orphan receptor B 1555990 at s -127L4.6 hypothetical protein LOC150297 1556.222 at 1-291L22.2 similar to cell division cycle 10 235700 at RP13-36C9.6 canceritestis antigen CT45-5 204666 s at RPS-1OOOE10.4 Suppressor of IKK epsilon 235294 at RPS-1OOOE10.4 Suppressor of IKK epsilon 230661 at RPESP RPE-spondin (RPESP), mRNA US 2012/OO 15904 A1 Jan. 19, 2012 58

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 238375 at 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 at RPL3SA ribosomal protein L35a -1.53S49 213459 at 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 at RUNDC3B RUN domain containing 3B 2.53893 205528 S. at RUNX1T1 runt-related transcription factor 1; translocated to, 1 (cyclin D- 2021.37 related) 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 2108.53 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) US 2012/OO 15904 A1 Jan. 19, 2012 59

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 220551 at 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 at SLC2A13 Solute carrier family 2 (facilitated glucose transporter), member 1.52225 13 239596 at SLC30A7 solute carrier family 30 (zinc transporter), member 7 1.91435 220796 X at SLC3SE1 solute carrier family 35, member E1 167755 228060 at 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 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 a 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 sparefosteonectin, cwcv and kazal-like domains proteglycan 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 1799.21 215885 a. SSX2 synovial sarcoma, X breakpoint 2 180412 208586 s at SSX4 SSX4B synovial sarcoma, X breakpoint 4 synovial sarcoma, X 1.7382 breakpoint 4B 206835 a. STATH statherin 186909 204595 s at STC1 Stanniocalcin 1 167438 204597 X at STC1 Stanniocalcin 1 3.94696 202695 S at STK17A serine/threonine kinase 17a -153066 223883 s at STK31 serine/threonine kinase 31 1.59045 US 2012/OO 15904 A1 Jan. 19, 2012 60

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 a SYNE spectrin repeat containing, nuclear envelope 1 844O6 202796 a SYNPO synaptopodin -1.54SS3 225720 a SYNPO2 synaptopodin 2 2.47627 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), 65116 mRNA 214413 a TAT Tyrosine aminotransferase 56842 221858 a TBC1D12 TBC1 domain family, member 12 -1.898.33 1563272 at TBC1D8B TBC1 domain family, member 8B (with GRAM domain) 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 iteratocarcinoma- 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 at TMEM136 transmembrane protein 136 66054 239593 at TMEM213 transmembrane protein 213 53796 20965.5 S at TMEM47 transmembrane protein 47 52814 204807 at TMEMS transmembrane protein 5 -1.53392 US 2012/OO 15904 A1 Jan. 19, 2012 61

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 156377 a 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 fit transmembrane protease, serine 11E i? 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 1557278 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 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 UGT1A7 . . UGT1A8 221305 S at UGT1A6 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 1 C (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 US 2012/OO 15904 A1 Jan. 19, 2012 62

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 237656 at 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 a ZNF132 Zinc finger protein 132 -158945 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 1566645 at S476 1562341 at 52441 242952 a. 55967 1559807 at .70594 23815S a -15566 1566550 at S4738 242797 X at — -1862O1 242170 a -1.89134 1570.098 at .82945 1559524 at -1.71546 US 2012/OO 15904 A1 Jan. 19, 2012 63

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 239.606 at -1.53539 566544 at 61104 242133 s at — S6343 556760 a. at — 2.0O828 563461 at 53995 570645 at SS841 240730 a. 61181 236602 a 52722 24.2122 a. -150641 559410 at .7089 234100 a -1.52272 239856 a -223215 229243 a -1.73048 231465 a. 62758 562208 a. at — .87O64 561149 at S2S62 24O642 a. -1.71584 557658 at -161047 230503 a 6OO16 242494 a 6.192 561956 at S9298 242495 a 57521 222320 a 61706 237886 a S3331 565788 at 65726 24O133 X at — .88894 242074 a -1.54665 215029 a -161964 568785 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 559709 at 69535 242296 X at — 56148 562456 at 661.78 556518 at 537 233579 a 232946 563531 at 91.261 216757 a 75028 234612 a S48O1 562835 at 7128 234224 a S186 242115 a. 5505 569527 at -154022 238415 a. S3.194 226231 a -1.79439 240506 a 6OOO3 240469 a 62514 557885 at 52753 237356 a 93218 242202 a 573.35 236778 a 6O299 240355 a. -1668.21 242142 a 80096 US 2012/OO 15904 A1 Jan. 19, 2012 64

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 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 1561328 at 62167 237231 a -150546 1558869 at 75081 1554043 a at — -165188 241030 a. 893.93 233306 a 8777 1565874 at 63SS8 US 2012/OO 15904 A1 Jan. 19, 2012 65

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 230874 a -2O6833 569661 at S966S 237742 a. 61044 227985 a -1.82784 566867 at .94122 564773 x at — S4988 562053 at -2.064O2 235.188 a 84682 557512 at -1627 242007 a -1.69897 243455 a. 61.96S 2398.68 a S129 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 234588 a 61426 566995 at 2.12757 566096 X at — 2.08387 233.187 s at — -154128 227745 a. -1.73S47 557443 s at — 608O1 561161 at 8118S 24O997 a 65329 561689 at 65238 241163 a 59299 234248 a 55099 562065 at 74757 2394.37 a -1.80734 569208 a. at — 93479 559737 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 US 2012/OO 15904 A1 Jan. 19, 2012 66

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 233293 at S1923 242811 X at — .70854 1556439 at 69729 1560453 at 8201S 1569779 at 61263 237525 a. S1511 240989 a 61747 234606 a 54255 234692 a 61537 216756 a 653O4 241637 a 2.17642 1556656 at 68.075 235.017 s at — 7341 233130 a. 82787 233779 X at - S1862 237355 a. S4889 232850 a 55.839 23.0020 a -1.8275 243454 a 2.15818 237573 a 82449 234036 x at — 8288S 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 1557861 at .75142 240858 a S4478 1559695 a. at - 822O2 244891 X at — 6181 240297 a 62.096 15584.44 at 2.92859 1570482 at 2.572O1 1563.055 at S8052 US 2012/OO 15904 A1 Jan. 19, 2012 67

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 241173 at 86436 562760 a 72579 562588 a 94416 566763 a 2.04467 569740 a 64645 240290 a 67943 237496 a 2.0686S 567379 a 62299 244125 a. 2.575.99 235445 a. 91.795 555.174 a S8019 216643 a 8921S 569983 a 2.39576 560429 a 2.04382 563386 a 76382 244511 a 62772 570350 a 61993 241487 a .66578 567913 a 5.71757 562686 a 74.144 565860 a 2.969.18 244510 a 2.46633 237622 a. -2.61939 557780 a 71847 239520 a 53506 243034 a S628 238,571 a 80516 232113 a 2.22875 242641 a 61615 234579 a SS619 566842 at 75893 21558.7 x at — 53373 236740 a 828S 224.549 X at — 68422 233276 a .62961 56.1256 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 233958 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 US 2012/OO 15904 A1 Jan. 19, 2012 68

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 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 237.491 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 240152 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 US 2012/OO 15904 A1 Jan. 19, 2012 69

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 a 2.098.78 235629 a S2947 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 234083 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 2396.04 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 US 2012/OO 15904 A1 Jan. 19, 2012 70

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 1561305 at 1.51196 233502 at 3.43598 244588 at 186108 240783 at 28921 235.739 at 188882 233273 at 2.07697 1565873 at 175922 242881 X at — 2.91.173 1563568 at 1894.45 1569755 at 186666 242391 a 2.54095 1565637 at 244.504 241657 a 1.653O4 232957 x at — 2.28244 233683 a 2.15259 237065 s at — -2.23415 1566,597 at 2.38873 239849 a 249616 1564358 at 3.57914 233152 x at — S398 243473 a 8121 216094 a 22O104 1568589 at 2.83131 1555925 at 3.SO923 243572 a .7936 241.186 a 2.07335 239340 a 3.10534 243192 a .79294 1569230 at 89893 215062 a. 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 2.26SOS 234.433 a 2.2O167 240067 a 94901 562263 a 83224 237850 a 60944 222299 X at — 80516 557215 a. 8.2993 23.9985 a 67697 243877 a 65948 569656 a 83943 239344 a S3249 561631 a 67024 237365 a. 70238 243936 x at — 2.23539 216337 a S6682 570423 a 2.37274 558672 a. 65888 564580 a 2.5145 562923 a 52114 237951 at 6943 242890 at .885.08 234.805 at .76687 239311 at 55589 US 2012/OO 15904 A1 Jan. 19, 2012 71

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 565861 at 2.3658 562409 s at

561268 at 563331 at 224254 x at 561,346 at

561478 at 239706 X at 240877 x at 232925 at 558497 a. at 555014 X at 216101 at 240077 at 234550 at 242845 at 1561778 at 242401 X at 1566695 at 1561123 at 1556491 at 233626 a 1562166 at 2424.83 a 23074.6 s at 1561437 at 238,512 a 237486 a 215768 a 1561112 at 243566 a 242733 a 242171 a 239962 a 1568931 at 239.066 a 1558226 a. at 241549 a 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 at 2.28069 244736 at 1.63S28 232795 at 18848S 235938 at 2.53577 AFFX 3.11913 M27830 3 at 233365 at 2.76277 234282 at 2.01659 241667 x at 17844 243211 at 1.95149 1557029 at 1.88354 1564878 at 1.97934 242419 at 1546O1 1560049 at 3.57O66 243401 at 2.22064 1561012 at 3.09703 1564451 at 2.88901 1563.077 at 2.08269 US 2012/OO 15904 A1 Jan. 19, 2012 72

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 244637 a 83073 243694 a 56713 237,422 a. 60881 557348 at 3.30543 564097 at 2.32219 24O157 a 802.17 241.222 a. 724O7 216104 a 72674 570506 at 2.2933S 561418 at 2.52035 561658 at 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 234593 a 86.662 23.3606 a 3.32752 233668 a 2.298.68 558O19 a 76057 233593 a 64392 561777 a 2.1.2493 241536 a 2.91919 236962 a SO896 564654 a S8649 244821 a 2.3S422 231597 X at — 3.28195 564807 a 2.09646 562137 a 8O249 243781 a 69708 244762 a 2.22632 236276 a 2.OO169 238408 a 244824 56O189 a 70373 561703 a 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 1570.125 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 1562613 at 2.67097 1566.846 at 2.74769 231239 a 181363 1562311 at 1521.18 216496 s at — 1.69818 1562853 x at — 1.6179 215801 a 2.67753 1569809 at 1.54798 1566469 at 2.73721 1569858 at 2.28984 1563561 at 195979 US 2012/OO 15904 A1 Jan. 19, 2012 73

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 562828 at 559.434 at 240738 a 555.498 at 561309 X at 566658 at

556834 at

566633 at 231598 x at 566969 at 562420 at

562820 at

561453 at 568611 at 566716 at 562076 at

561087 at 239303 a 24O788 a 234578 a 241633 x at 24.1509 a 566938 at 241636 X at 562169 at 242715 a. 568872 at 556021 at 24.1254 a 564083 at 564547 X at 2.681.96 .70862 .82247 55938 561450 at .708O2 234104 a 61476 563190 at

233448 s at 561351 at 23997O a 559149 at 569944 at 216745 X at 561199 at 241583 x at 234228 at 241287 X at US 2012/OO 15904 A1 Jan. 19, 2012 74

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 23.3853 at 155509 566970 a 2.31372 224.546 at 2.91364 57.0191 a 2.76356 215.810 X at — 1.56175 231284 at 194763 239025 at 1.66351 566748 a 2.34934 56.9577 X at - 181271 562083 a 3.40841 234279 at 1.7SO62 236576 at 1.7866S 562677 a 1.8276 56O131 a 2.6117 216858 x at — 15146 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. 79518 234558 at 82691 216764 at 78566 57O155 a. 2.22005 561411 a 51791 564070 s at — 64228 233449 at .76305 216286 at 2.06666 240431 at 86816 244613 at 93862 241628 at 2O1118 564134 a 2.32579 555.187 a S2436 566863 a 4.56348 237898 at S1413 563138 a .72121 238358 x at — 3.14686 243533 x at — 2.2352 55817O a 2.47388 56.4107 a 2.4479 234773 x at — 185715 556936 a 2.OO32 561143 a 1.531.23 242420 a 2.36834 222325 a. 3.02684 568878 a 2.17186 220874 a 2.17222 222300 a 2.40438 243262 a 186741 570176 a 2.79226 562111 a S.11742 555364 a 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 US 2012/OO 15904 A1 Jan. 19, 2012 75

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 561953 at 2.391.51 215849 X at 1.72743 56.6887 x at 2.41216 560517 s at 2.16789 2.14141 184284 566609 at 2.486.79 564610 at 198581 215811 at 2.30524 563396 x at 1.65546 190797 2.37OO1 2.461.46 2.58.393 1.7321 3.04.026 4.14875 566637 at 2.58398 566967 at 2.6.1969 2363.89 x at 1.73264 563941 at 3.17348 3.52279 1.65994 563115 at 2.22091 562642 at 3.39927 561473 at 2.4745 238362 a 3.295.08 564767 at 262248 241200 x at 1.72239 4.O3908 2.10442 570300 at 2.38986 562678 at 2.4369 237700 a 2.31864 561212 at 2.10873 240208 a 73797 238755 a. 241883 x at 243183 a 1559780 at 237454 a 233.133 a 237608 a 215643 a 237399 a 1560144 at 220859 a 237049 a 216463 a 1555373 at 1561657 at 24O921 a 1569409 x at 237552 a. 238390 a 3496.33 220878 a 2.63943 244420 a 2.17474 1561895 at 2.59003 233373 a 2.31025 232712 a 3.31619 244282 a 164142 215473 a 173547 238.274 a 1.7.1931 243.04.1 s at 3.902 215448 a S.O.9122 241542 a. 2.64253 237480 a 197714 242769 a 2.65101 240956 a 2.82294 242840 a 181443 1558048 x at 4.43301 US 2012/OO 15904 A1 Jan. 19, 2012 76

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 241094 at 94O22 241945 at 75756 56.1242 at 3.36844 216319 at 2.21853 569927 at 2.86702 234096 at 898.63 242645 at 2.01823 234653 at .92OOS 557778 a .77943 563494 a 61383 215962 at 3.6O791 242652 at 9361 561795 a .78961 566498 a 2.74467 563963 a 2.14216 23838.6 X at — 99773 232817 a 2.194O6 569759 a 2.46257 244885 a .90316 242310 a 91359 569596 a 3.39789 241.183 a 2.94.372 230791 a 3.79676 570268 a 2.16933 557832 a. 2.09744 570177 a 2.4673 234655 a. 189067 561065 a. 1.64279 562480 a 3.83981 557644 a 2.59969 234690 a 169061 216518 a 1.90215 234794 a 2.89785 240186 a 3.29381 240714 a 2.18363 217 132 a 1.72792 1561881 at 2.3596S 1562992 at 2.46132 1568794 at 2.94.OOS 1568936 a. at — 2.0225 1557665 at 2.99.179 233944 a 4.72O23 240160 X at — 65013 231212 X at — 289146 243756 a 2.11775 232944 a 2.10953 243177 a 3.23332 243442 X at — 9452 243897 a 82779 240825 a. 2.47627 1569664 at 4.4506S 228936 a 2.51633 1562353 x at — 69798 224237 a 2.90306 2441.69 X at — 3.29.173 241632 X at — 59752 228934 x at — 2.47447 220877 a 2.67012 228218 a 2.19026 1561340 at 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 1562997 a. at — 2.34S47 2298.23 a 1.67524 US 2012/OO 15904 A1 Jan. 19, 2012 77

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 244866 at 2.04538 563546 at 6.23891 233906 at 3.09354 242266 X at — 2.86831 2434.66 at 2.071.49 570623 a 2.34232 243632 at 2.62996 240864 at 3.791.35 569539 a 5.27322 243489 at 6.03255 2O7744 at 2.86433 237684 at 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 563026 a 2.232 210893 at 2.14379 563316 a 410042 554225 a. at — 3.18715 56.2071 a 173705 561754 a 5.09305 232453 at 2.65615 243273 at 2.91.387 244300 at 1.81931 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 US 2012/OO 15904 A1 Jan. 19, 2012 78

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 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 2.11436 1.SS456 562797 a 3.02768 563.032 a 6.9936S 242232 at 3.47935 563189 a 4.43695 3.37897 6.71681 556983 a at 3.928.04 558496 a 5.841.22 566600 a 199013 557645 a. 2.36718 190383 238384 x at 3.07283 6.6OOO3 569818 a 2.5437 562084 a 4.883O8 238103 at 2.96539 561448 a 2.8O876 240992 at 170856 568812 a 2.82372 562276 a 4.36824 564964 a S.68325 233330 s at 4.92758 233282 a 3.534O2 233331 a 2.994.13 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 1563881 at 2.97996 237937 X at 7.10043 1561856 at 8.77012 1561529 at 193256 230.064 at 2.99589 1564676 a. at 3.7315 1562755 at 4.87812 235494 at 26S509 1568871 at 1.71949 1562873 at 1.93S11 1561214 at 4.07318 242718 at 2.S6091 US 2012/OO 15904 A1 Jan. 19, 2012 79

TABLE 8-continued Table 8 - Significant genes between TIAl and TIA2 (FDR s 0.05, absolute fold change 2 1.5. TIAl vs TIA2 Fold AFFY ID Gene Symbol Gene Title Change 562811 a 2.21403 241457 a 2.64311 564851 a 2.15494 2.04989 4.90225 562916 at – 4.O1294 564306 at — 3.50683 4.93S21 2.4O905 561213 at – 2.01136 569810 at - 3.1075 566,622 at — 3.07274 3.10323 2.31223 560905 a 5.46696 560086 a 3.09926 556263 s at — 2.85.076 244612 a 5.78514 560296 a 3.17524 3.63922 2.8616 566638 at – 190699 561926 at — 3.80796 563.087 at - 242998 168879 3.901.74 562610 a 1.96876 2345.02 a 3.82276 242198 a 2.81983 234235 a. 5.71387 241675 s at — 6.66189 1555,263 at 2.30475 1566862 at 3.92941 207 731 a 7.5.127 231074 a 5.19962 237233 a 4.19082 233279 a 2.6O1 237479 a 6.74O27 2428O2 X at — 4621.83 234800 a 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 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, 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, Stem Cell 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 11 FGF18, MMP26, MMP16, FGF14, FGF12, FGF20, Signaling FGF7, PGF, EGFR, MMP19, FGF5 Amyotrophic Lateral 10 NOS1, CACNA1E, IGF1, HECW1, PIK3C2G, US 2012/OO 15904 A1 Jan. 19, 2012

TABLE 9-continued TIA subtype specific genes: pathways Ingenuity Canonical i Pathways p-value Molecules Molecules 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

REFERENCES 0204 10. Castillo J. Alvarez-Sabin J. Martinez-Vila E et al. Inflammation markers and prediction of post-stroke (0195 1. Johnston SC, Nguyen-Huynh MN, Schwarz ME vascular disease recurrence: the MITICO study. J Neurol. et al. National Stroke Association guidelines for the man 2009; 256:217-224 agement of transient ischemic attacks. Ann Neurol. 2006; (0205 11. Nambi V. Hoogeveen RC, Chambless Let al. 60:301-313 Lipoprotein-associated phospholipase A2 and high-sensi 0196. 2. Rothwell PM, Buchan A, Johnston S C. Recent tivity C-reactive protein improve the stratification of advances in management of transient ischaemic attacks ischemic stroke risk in the Atherosclerosis Risk in Com and minorischaemic strokes. Lancet Neurol. 2006; 5:323 munities (ARIC) study. Stroke. 2009:40:376-381 331 0206 12. Cucchiara B L. Messe S R. Sansing L et al. (0197) 3. Easton JD, Saver J. L., Albers GW et al. Definition Lipoprotein-associated phospholipase A2 and C-reactive and Evaluation of Transient Ischemic Attack A Scientific protein for risk-stratification of patients with TIA. Stroke. Statement for Healthcare Professionals From the American 2009; 40:2332-2336 Heart Association/American Stroke Association Stroke 0207 13. Rothwell P M. Howard S. C. Power D A et al. Council; Council on Cardiovascular Surgery and Anesthe Fibrinogen concentration and risk of ischemic stroke and sia; Council on Cardiovascular Radiology and Interven acute coronary events in 5113 patients with transient tion; Council on Cardiovascular Nursing; and the Interdis ischemic attack and minor ischemic stroke. Stroke. 2004; ciplinary Council on Peripheral Vascular Disease The 35:2300-2305 American Academy of Neurology affirms the value of this (0208. 14. Woodward M. Lowe G D, Campbell DJ et al. statement as an educational tool for neurologists. Stroke. Associations of inflammatory and hemostatic variables 2009; 40:2276-2293 with the risk of recurrent stroke. Stroke. 2005; 36:2143 (0198 4. Josephson SA, Sidney S. Pham TNet al. Higher 2147 ABCD2 score predicts patients most likely to have true (0209 15. Kang DW, Yoo SH, Chun Set al. Inflammatory transient ischemic attack. Stroke. 2008; 39:3096-3098 and hemostatic biomarkers associated with early recurrent (0199 5. Zhan X, Ander B P. Jickling Get al. Brief focal ischemic lesions in acute ischemic stroke. Stroke. 2009; cerebral ischemia that simulates transientischemic attacks 40:1653-1658 in humans regulates gene expression in rat peripheral 0210 16. Moore DF, Li H, Jeffries N et al. Using periph blood. J Cereb Blood Flow Metab. 2010: 30:110-118 eral blood mononuclear cells to determine a gene expres (0200. 6. Zhan X, Kim C, Sharp F R. Very brief focal sion profile of acute ischemic stroke: a pilot investigation. ischemia simulating transient ischemic attacks (TIAS) can Circulation. 2005; 111:212-221 injure brain and induce Hsp70 protein. Brain Res. 2008; 0211 17. Tang Y. Xu H, Du X et al. Gene expression in 1234:183-197 blood changes rapidly in neutrophils and monocytes after 0201 7. Arenillas J. F. Alvarez-Sabin J, Molina CA et al. ischemic stroke in humans: a microarray study. J Cereb C-reactive protein predicts further ischemic events in first Blood Flow Metab. 2006; 26:1089-1102 ever transient ischemic attack or stroke patients with 0212 18. Xu H, Tang Y. Liu DZetal. Gene expression in intracranial large-artery occlusive disease. Stroke. 2003; peripheral blood differs after cardioembolic compared 34:2463-2468 with large-vessel atherosclerotic stroke: biomarkers for the 0202) 8. Elneihoum A M, Falke P, Axelsson L et al. Leu etiology of ischemic stroke. J Cereb Blood Flow Metab. kocyte activation detected by increased plasma levels of 2008; 28:1320-1328 inflammatory mediators in patients with ischemic cere 0213 19. Giles MF, Rothwell PM. Systematic review and brovascular diseases. Stroke. 1996; 27:1734-1738 pooled analysis of published and unpublished validations 0203 9. Ross A M, Hurn P. Perrin Netal. Evidence of the of the ABCD and ABCD2 transient ischemic attack risk peripheral inflammatory response inpatients with transient scores. Stroke. 2010:41:667-673 ischemic attack. J Stroke Cerebrovasc Dis. 2007; 16:203 0214 20. Cucchiara B L. Messe S R. Sansing L et al. 2O7 D-dimer, magnetic resonance imaging diffusion-weighted US 2012/OO 15904 A1 Jan. 19, 2012 81

imaging, and ABCD2 score for transient ischemic attack 8. (canceled) risk stratification.J Stroke Cerebrovasc Dis. 2009; 18:367 9. The method of claim 1, wherein a decreased expression 373 level of one or more TIA-associated biomarkers selected 0215 21. Andersohn F. Waring M, Garbe E. Risk of from the group consisting of ATG9B, DIP2C, EDAR, ischemic stroke in patients with Crohn's disease: A popu GSTM1, GUSBL2, SMURF2, ZNF512B indicates that the lation-based nested case-control study. Inflamm Bowel Dis. patient has suffered or is at risk of experiencing TIA. 2009 10. The method of claim 1, wherein a decreased expression 0216 22. Freilinger T. Riedel E. Holtmannspotter Metal. level of one or more TIA-associated biomarkers selected Ischemic stroke and peripheral arterial thromboembolism from the group consisting of NBPF10///RP11-9412.2, in a patient with Crohn's disease: a case presentation. J SFXN1, SPIN3, UNC84A, OLFM2, PPM1 K, P2RY10, Neurol Sci. 2008; 266:177-179 ZNF512B, MORF4L2, GIGYF2, ERAP2, SLFN13, 0217. 23. Karacostas D. Mavromatis J. Artemis K, Milo LOC4.01431, MED6, BAIAP2L1///LOC100128461, nas I. Hemorrhagic cerebral infarct and ulcerative colitis. A LNPEP. MBNL1, NOS3, MCF2L, KIAA1659, SCAMPS, case report. Funct Neurol. 1991; 6:181-184 LOC648921, ANAPC5, SPON1, FUS, GPR22, GAL3ST4, 0218 24. Schneiderman J H, Sharpe JA, Sutton D M. METTL3, LOC100131096, FAAH2, SMURF2, SNRPN, Cerebral and retinal vascular complications of inflamma FBLN7, GLS, G3BP1, RCAN3, EPHX2, DIP2C, CCDC141, tory bowel disease. Ann Neurol. 1979; 5:331-337 CLTC, FOSB, CACNA1I, UNQ6228, ATG9B, AK5, SPIN3, 0219 25. Beck J. D. Offenbacher S. Systemic effects of RBM14, SNRPN, MAN1C1, HELLS, EDAR, SLC3A1, periodontitis: epidemiology of periodontal disease and car ZNF519, LOC10O13OO7O/AFLOC10O130775/77 diovascular disease. J. Periodontol. 2005: 76:2089-2100 LOC10O131787///LOC10O131905//FLOC10O132291/// 0220 26. Beck J. Garcia R, Heiss G et al. Periodontal LOC100132488//RPS27, ZC3H12B, IQGAP2, SOX8, disease and cardiovascular disease. J. Periodontol. 1996; WHDC1L2, TNPO1, TNFRSF21, TSHZ2, DMRTC1/// 67:1123-1137 DMRTC1B, GSTM1, GSTM2, PNMA6A, CAND1, 0221. 27. Elter J. R. Offenbacher S, Toole J F. Beck J. D. CCND3, GSTM1, GUSBL2 indicates that the patient has Relationship of periodontal disease and edentulism to suffered or is at risk of experiencing TIA. stroke/TIA. J Dent Res. 2003; 82:998-1001 11-32. (canceled) 0222 28. Grau A.J. Becher H. Ziegler C Metal. Periodon 33. The method of claim 1, wherein the level of expression tal disease as a risk factor for ischemic stroke. Stroke. 2004; of the biomarker is determined at the transcriptional level. 35:496-5O1 34. The method of claim 1, wherein the level of expression 0223 29. Grau A. J. Infection, inflammation, and cere is determined by detecting hybridization of a TIA-associated brovascular ischemia. Neurology. 1997: 49:547-51 gene probe to gene transcripts of the biomarkers in the bio 0224, 30. Dourado D.F, Fernandes PA, Ramos M.J. Mam logical sample. malian cytosolic glutathione transferases. Curr Protein 35. The method of claim34, wherein the hybridization step Pept Sci. 2008: 9:325-337 is performed on a nucleic acid microarray chip. 0225. It is understood that the examples and embodiments 36. The method of claim34, wherein the hybridization step described herein are for illustrative purposes only and that is performed in a microfluidics assay plate. various modifications or changes in light thereofwill be Sug 37. The method of claim 1, wherein the level of expression gested to persons skilled in the art and are to be included is determined by amplification of gene transcripts of the within the spirit and purview of this application and scope of biomarkers. the appended claims. All publications, sequence accession 38. The method of claim 37, wherein the amplification numbers, patents, and patent applications cited herein are reaction is a polymerase chain reaction (PCR). hereby incorporated by reference in their entirety for all pur 39. (canceled) poses. 40. The method of claim 1, wherein the level of expression 1. A method for diagnosing a transient ischemic attack of at least 15 biomarkers is determined. (TIA) or a predisposition for experiencing TIA, the method 41. The method of claim 1, further comprising the step of comprising: determining a level of expression of a plurality of obtaining a biological sample. TIA-associated biomarkers in a biological sample from a 42. The method of claim 1, wherein the biological sample patient, wherein an increase or decrease of the level of expres is blood, serum or plasma. sion compared to a control indicates that the patient has 43. The method of claim 1, wherein the control is the suffered or is at risk of experiencing TIA, wherein the plural expression level of a plurality of stably expressed endogenous ity of TIA-associated biomarkers is selected from the biom reference biomarkers. arkers set forth in Tables 1, 2, 5A, 5B, 5C, 5D, 7, 8 and 9. 44. The method of claim 43, wherein the one or more 2-5. (canceled) endogenous reference biomarkers is selected from the group 6. The method of claim 1, wherein an increased expression consisting of USP7, MAPRE2, CSNK1G2, SAFB2, level of one or more TIA-associated biomarkers selected PRKAR2A, PI4 KB, CRTC1, HADHA, MAP1LC3B, KAT5, from the group consisting of DKFZP434B061, FAM55D, CDC2L1///CDC2L2, GTSE1, CDC2L1///CDC2L2, TCF25, F 1130375, IGFBP5, LTBR and SCN2A indicates that the CHP, LRRC40, hCG 2003956///LYPLA2///LYPLA2P1, patient has suffered or is at risk of experiencing TIA. DAXX, UBE2NL, EIF1, KCMF1, PRKRIP1, CHMP4A, 7. The method of claim 1, wherein an increased expression TMEM184C, TINF2, PODNL1, FBXO42, LOC441258, level of one or more TIA-associated biomarkers selected RRP1, C10orf104, ZDHHC5, C90rf23, LRRC45, NACC1, from the group consisting of GABRB2, ELAVL3, TWIST1, LOC10O133445/7/LOCI-1511 O and PEX16 DPPA4, DKFZP434P211, DLX6, ZNF479, ASTN2, SNX31, 45. The method of claim 1, wherein the control is the ALS2CR11, LOC440345 indicates that the patient has suf expression level of the same biomarker in a healthy indi fered or is at risk of experiencing TIA. vidual. US 2012/OO 15904 A1 Jan. 19, 2012

46. The method of claim 1, wherein the control is a thresh plurality of nucleic acids that hybridize to a plurality of the old level of expression representative of a population of genes set forth in Table 7, a plurality of nucleic acids that healthy individuals. hybridize to a plurality of the genes set forth in Table 8 and a plurality of nucleic acids that hybridize to a plurality of the 47. The method of claim 1, further comprising the step of genes set forth in Table 9. providing an appropriate treatment or prevention regime for 49. The solid support of claim 48, comprising a plurality of TIA to the patient. nucleic acids that hybridize to a plurality of the genes selected 48. A solid Support comprising a plurality of nucleic acids from the group consisting of GUSBL2, GSTM1, F1130375, that hybridize to a plurality of the genes set forth in Table 2, a SCN2A, DKFZP434B061, EDAR, ATG9B, DIP2C, LTBR, plurality of nucleic acids that hybridize to a plurality of the SMURF2, FAM55D, IGFBP5, and ZNF512B. genes set forth in Table 5A, a plurality of nucleic acids that 50-60. (canceled) hybridize to a plurality of the genes set forth in Table 5B, a 61. The solid support of claim 48, wherein the solid support plurality of nucleic acids that hybridize to a plurality of the is a microarray. genes set forth in Table 5C, a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 5D, a