Diagnostic markers of cardiovascular illness and methods of use thereof

• US 20050181386A1
• Filed: 09/22/2004
• Published: 08/18/2005
• Est. Priority Date: 09/23/2003
• Status: Abandoned Application

• Current Assignee: Albert Man, Cornelius Diamond, Troy Bremer
• Original Assignee: Albert Man, Cornelius Diamond, Troy Bremer
• Inventors: Man, Albert, Diamond, Cornelius, Bremer, Troy
• Application Number:
  US10/948,834
• Publication Number:
  US 20050181386A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 2800/2871 Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 33/48 Biological material, e.g. blood, urine G01N33/02, G01N33/26, G01N33/44, G01N33/46 take precedence; Haemocytometers counting blood corpuscules distributed over a surface by scanning the surface G06M11/02
• CPC Class Codes: G01N 33/50 Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q
• CPC Class Codes: G01N 33/5082 Supracellular entities, e.g. tissue, organisms
• CPC Class Codes: G01N 33/6848 Methods of protein analysis involving mass spectrometry
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention relates to methods for the diagnosis and evaluation of cardiovascular illness, particularly stroke, myocardial and other cardiovascular damage damage, hypertension treatment. In particular, patient test samples are analyzed for the presence and amount of members of a panel of markers comprising one or more specific markers for cardiovascular illness or hypertension treatment and one or more non-specific markers for cardiovascular illness or hypertension treatment. A variety of markers are disclosed for assembling a panel of markers for such diagnosis and evaluation. Algorithms for determining proper treatment are disclosed. A diagnostic kit for a panel of said markers is disclosed. In various aspects, the invention provides methods for the early detection and differentiation of cardiovascular illness or hypertension treatment. Invention methods provide rapid, sensitive and specific assays that can greatly increase the number of patients that can receive beneficial treatment and therapy, reduce the costs associated with incorrect diagnosis, and provide important information about the prognosis of the patient.

Claims

1. A method of determining response to the pharmaceutical agent for hypertension, the method comprising:

correlating (i) a mutational burden at one or more nucleotide positions in the AGT, ACE, AGTR1, GPB, EDN1, EDN2, alpha-adducin, haptoglobin, CYP2C9, RGS2, ADRA1a, 11betaHSD2, ADRA1b, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, or ENOS gene(s) in a sample from the subject with (ii) the mutational burden at one or more corresponding nucleotide positions in a control sample with known response outcome, and therefrom identifying the probability of response to said pharmaceutical agent.

2. A method according to claim 1 wherein the mutational burden relates to a mutation in the AGT gene at nucleotide position given by the RS # 2071405, 2071406, 5046, 5047, 5049, 5050, 5051, 4762 or at the genetic position and mutation descriptor T395A, A49G, C1015T, C1198T, or G1072A;

in the ACE gene at nucleotide position given by the genetic position and mutation descriptor T5496C, C582T, A731 G, G1060A, C1215T, A12257G, A2328G, or G3906A;

in the AGTR1 gene at nucleotide position given by the RS# 275650, 275651, 1492078, 422858, 387967, 5182, 5183, 5186 or 5443;

in the EDN1 gene at nucleotide position given by the RS# 5370;

in the alpha-adducin gene at nucleotide position given by the RS# 4961;

the haptoglobin gene mutation called haptoglobin 1-2;

in the CYP2C9 gene at nucleotide position given by the genetic position and mutation descriptor A1075C, T1076C, or C1080G;

in the 11 betaHSD2 gene at nucleotide position given by G534A;

in the beta(1)-adrenergic receptor gene at nucleotide position given by the genetic position and mutation descriptor A145G;

in the ADRA2A gene at nucleotide position given by the genetic position and mutation descriptor G278T;

in the ADRAB1 gene at nucleotide position given by the RS# 1801253;

in the ADRAB2 gene at nucleotide position given by the genetic position and mutation descriptor G1342C;

in the APOA gene at nucleotide position given by genetic position and mutation descriptor A1449G;

in the LIPC gene at nucleotide position given by the genetic position and mutation descriptor A110G;

in the EDNRB gene at nucleotide position given by the genetic position and mutation descriptor G40A;

in the ENOS gene at nucleotide position given by the genetic position and mutation descriptor G498A or A2996G;

or combinations thereof.

3. A method according to claim 1 wherein the mutational burden is comprised of at least one mutation in linkage disequilibrium with the genetic variants according to claim 2.

4. A method according to claim 1 wherein the mutational burden is comprised of one or more of the following combinations in vertical column format:

5. A method according to claim 1, wherein said correlating step comprising:

a) determining the sequence of one or more of the genes AGT, ACE, AGTR1, GPB, EDN1, EDN2, alpha-adducin, haptoglobin, CYP2C9, RGS2, ADRA1a, 11betaHSD2, ADRA1b, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, or ENOS from humans known to be responsive or non-responsive to anti-hypertension medications;

b) comparing said sequence to that of the corresponding wildtype AGT, ACE, AGTR1, GPB, EDN1, EDN2, alpha-adducin, haptoglobin, CYP2C9, RGS2, ADRA1a, 11betaHSD2, ADRA1b, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, or ENOS gene(s); and

c) identifying mutations in said humans which correlate with the response or non-response to anti-hypertensive medications, respectively.

6. The method according to claim 1, wherein said correlating step comprising:

a) determining the sequence of one or more of the genes AGT, ACE, AGTR1, GPB, EDN1, EDN2, alpha-adducin, haptoglobin, CYP2C9, RGS2, ADRA1a, 11betaHSD2, ADRA1b, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, or ENOS from humans known to be responsive or non-responsive to ACE hypertension medications;

b) comparing said sequence to that of the corresponding wildtype AGT, ACE, AGTR1, GPB, EDN1, EDN2, alpha-adducin, haptoglobin, CYP2C9, RGS2, ADRA1a, 11betaHSD2, ADRA1b, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, or ENOS gene(s); and

c) training an algorithm residing on a computer to identify patterns of mutations in said humans which correlate with the response or non-response to anti-hypertensive medications, respectively.

7. The method according to claim 6, where training said algorithm residing on a computer on characteristic mutations according to claim 2 comprises the steps of obtaining numerous examples of (i) said SNP pattern genomic data, and (ii) historical clinical results corresponding to this genomic data;

constructing a algorithm suitable to map (i) said SNP pattern genomic data as inputs to the algorithm to (ii) the historical clinical results as outputs of the algorithm;

exercising the constructed algorithm to so map (i) the said SNP pattern genomic data as inputs to (ii) the historical clinical results as outputs; and

conducting an automated procedure to vary the mapping function, inputs to outputs, of the constructed and exercised algorithm in order that, by minimizing an error measure of the mapping function, a more optimal algorithm mapping architecture is realized;

wherein realization of the more optimal algorithm mapping architecture means that any irrelevant inputs are effectively excised, meaning that the more optimally mapping algorithm will substantially ignore input alleles and/or said SNP pattern genomic data that is irrelevant to output clinical results; and

wherein realization of the more optimal algorithm mapping architecture also means that any relevant inputs are effectively identified, making that the more optimally mapping algorithm will serve to identify, and use, those input alleles and/or SNP pattern genomic data that is relevant, in combination, to output clinical results.

8. The method according to claim 6, where the algorithm is an algorithm using linear or nonlinear regression or classification.

9. The method according to claim 6, where the algorithm is an algorithm using kernel based machines, such as kernel partial least squares, kernel matching pursuit, kernel fisher discriminate analysis, kernel principal components analysis.

10. The method according to claim 6, where the algorithm is an algorithm using neural networks.

11. The method according to claim 6, where the algorithm is an algorithm using genetic algorithms.

12. The method according to claim 6, where the algorithm is an algorithm using support vector machines.

13. The method according to claim 6, where the algorithm is an algorithm using Bayesian probability functions.

14. The method according to claim 6, where the algorithm is a plurality of algorithms arranged in a committee network.

15. The method according to claim 6, wherein a tree algorithm, such as CART, MARS, or others, is trained to reproduce the performance of another machine-learning classifier or regressor by enumerating the input space of said classifier or regressor to form a plurality of training examples sufficient to span the input space of said classifier or regressor and train the tree to emulate the performance of said classifier or regressor.

16. The method according to claim 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 where the anti-hypertensive medication belongs to the class known as angiotensin converting enzyme inhibitors.

17. The method according to claim 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 where the anti-hypertensive medication is the molecule monopril or lisinopril.

18. The method of claim 2 wherein at least one mutation is a silent mutation, missense mutation, or combination thereof.

19. A method according to claim 1, wherein said sample is selected from the group consisting of a blood sample, a serum sample, and a plasma sample.

20. A method according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 wherein the presence of said mutation is detected by a technique that is selected from the group of techniques consisting of hybridization with oligonucleotide probes, a ligation reaction, a polymerase chain reaction and single nucleotide primer-guided extension assays, and variations thereof.

21. A method according to claim 1, wherein said correlating step comprises comparing said mutational burden to a second mutational burden measured in a second sample obtained from said patient, whereby, when said second mutational burden is of the type correlated by one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 than said second mutational burden, said patient is diagnosed as being responsive or resistant to ACE anti-hypertensive therapy.

22. A method according to claim 20, wherein said second sample is obtained prior to treatment with an anti-hypertensive medication.

23. A method for detecting the presence or risk of developing hypertension in a human, said method comprising:

determining the presence in a biological sample from a human of a nucleic acid sequence having a mutational burden according to claim 2 at one or more nucleotide positions in a sequence region corresponding to a wildtype genomic DNA sequence, wherein the mutational burden correlates with the presence of or risk of developing hypertension.

24. A method for evaluating a compound for use in diagnosis or treatment of hypertension, said method comprising:

a) contacting a predetermined quantity of said compound with cultured cybrid cells or animal model having genomic DNA originating from a neuronal rho or human embryonic immortal kidney cell line and from tissue of a human having a disorder that is associated with severe hypertension and the mutational burden according to claim 2;

b) measuring a phenotypic trait in said cybrid cells or animal model that correlates with the presence of said mutational burden and that is not present in cultured cybrid cells or animal model having genomic DNA originating from a neuronal rho cell line and genomic DNA originating from tissue of a human free of a disorder that is associated with severe hypertension; and

c) correlating a change in the phenotypic trait with effectiveness of the compound.

25. A method according to claim 23 where the phenotypic trait is blockade of of at least one cascade in the renin-angiotensin-aldosterone biochemical pathway.

26. A method according to claim 23 where the correlating step is according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

27. A method for diagnosing treatment-resistant hypertension, said method comprising:

determining the presence in a biological sample from a human of a nucleic acid sequence having a mutational burden according to claim 2 at one or more nucleotide positions in a sequence region corresponding to a wildtype genomic DNA sequence, wherein the mutational burden correlates with the lack of response to ACE hypertension medication.

28. A method according to claim 27 where the correlating step is according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

29. A method according to claim 27, wherein said specific marker for treatment-resistant hypertension is selected from the group of genes consisting of AGT, ACE, AGTR1, GPB, EDN1, EDN2, ALPHA-ADDUCIN, HAPTOGLOBIN, CYP2C9, RGS2, ADRA1A, 11BETAHSD2, ADRA1B, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, OR ENOS.

30. A therapeutic composition comprising antisense or small interfering RNA sequences which are specific to mutant genes according to claim 2 or mutant messenger RNA transcribed therefrom, said antisense or small interfering RNA sequences adapted to bind to and inhibit transcription or translation of said target genes according to claim 2 without preventing transcription or translation of wild-type genes of the same type.

31. The therapeutic composition of claim 30, wherein Hypertension is treated and wherein said mutant genes are selected from the group:

AGT, ACE, AGTR1, GPB, EDN1, EDN2, ALPHA-ADDUCIN, HAPTOGLOBIN, CYP2C9, RGS2, ADRA1A, 11 BETAHSD2, ADRA1B, ADRA2A, ADRAB1, ADRAB2, REN, APOA, APOB, CETP, LIPC, EDNRB, OR ENOS.

33. The method of claim 32 when the mutational burden is that of claim 2 or claim 3.

34. The method of claim 32 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

36. The method of claim 35 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

38. The method of claim 37 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

40. The method of claim 39 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

42. The method of claim 41 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

32. A kit comprising devices and reagents and a computer algorithm for measuring one or more mutational burdens of a patient and determining the diagnosis or prognosis in that patient for cardiovascular illness.

35. The method of claim 32 when the prognostic outcome is that of response to ACE anti-hypertension medication.

37. The method of claim 32 when the diagnostic outcome is that of treatment-resistant hypertension.

39. The method of claim 32 when the prognostic outcome is that of response to the molecule monopril or lisinopril.

41. The method of claim 32 when the diagnostic outcome is that of determining risk of hypertension.

43. A kit comprising devices and reagents and a computer algorithm residing on a computer for measuring one or more proteomic or non-proteomic markers of a patient and determining the diagnosis or prognosis in that patient for cardiovascular illness by using the computer algorithm to correlate levels of said proteomic or non-proteomic markers.

44. The method according to claim 43, wherein said correlating step comprising:

a) determining the expression levels or mass spectrometry peak levels of one or more proteomic marker(s) or mass-to-charge ratio(s) and the numerical quantity of one or more non-proteomic marker(s) or mass-to-charge ratio(s) from humans suspected or known to have some form of cardiovascular illness;

b) comparing said levels and numerical values to humans known to have said matched type of cardiovascular illness; and

c) training an algorithm to identify patterns of differences in said humans which correlate with the prescience or absence of said matched type of cardiovascular illness, respectively.

45. The method according to claim 44, where training said algorithm on characteristic protein patterns comprises the steps of obtaining numerous examples of (i) said proteomic and non-proteomic data, and (ii) historical clinical results corresponding to this proteomic and non-proteomic data;

constructing a algorithm suitable to map (i) said protein expression levels or mass spectrometry peak mass-to-charge ratio(s) and said non-proteomic values as inputs to the algorithm to (ii) the historical clinical results as outputs of the algorithm;

exercising the constructed algorithm to so map (i) the said protein expression levels or mass spectrometry peak mass-to-charge ratio(s) and said non-proteomic values as inputs to (ii) the historical clinical results as outputs; and

conducting an automated procedure to vary the mapping function, inputs to outputs, of the constructed and exercised algorithm in order that, by minimizing an error measure of the mapping function, a more optimal algorithm mapping architecture is realized;

wherein realization of the more optimal algorithm mapping architecture, also known as feature selection, means that any irrelevant inputs are effectively excised, meaning that the more optimally mapping algorithm will substantially ignore said protein expression levels or mass spectrometry peak mass-to-charge ratio(s) and said non-proteomic values that are irrelevant to output clinical results; and

wherein realization of the more optimal algorithm mapping architecture, also known as feature selection, also means that any relevant inputs are effectively identified, making that the more optimally mapping algorithm will serve to identify, and use, those input protein expression levels or mass spectrometry peak mass-to-charge ratio(s) and said non-proteomic values that is relevant, in combination, to output clinical results.

46. The method according to claim 45, where the algorithm is an algorithm using linear or nonlinear regression.

47. The method according to claim 45, where the algorithm is an algorithm using linear or nonlinear classification.

48. The method according to claim 45, where the algorithm is an algorithm using ANOVA.

49. The method according to claim 45, where the algorithm is an algorithm using neural networks.

50. The method according to claim 45, where the algorithm is an algorithm using genetic algorithms.

51. The method according to claim 45, where the algorithm is an algorithm using support vector machines.

52. The method according to claim 45, where the algorithm is an algorithm using kernel based machines, such as kernel partial least squares, kernel matching pursuit, kernel fisher discriminate analysis, kernel principal components analysis.

53. The method according to claim 45, where the algorithm is an algorithm using Bayesian probability functions.

54. The method according to claim 45, where the Bayesian probability functions algorithm is an algorithm using Markov Blanket technique.

55. The method according to claim 45, where the algorithm is an algorithm using forward or backward selection methods such as forward floating search or backward floating search.

56. The method according to claim 45, where the feature selection algorithm is an algorithm according to one or more of claims 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55.

57. The method according to claim 45, where the feature selection algorithm is an algorithm using recursive feature elimination or entropy-based recursive feature elimination.

58. The method according to claim 45, where the algorithm is a plurality of algorithms arranged in a committee network.

59. The method according to claim 45, wherein a tree algorithm, such as CART, MARS, or others, is trained to reproduce the performance of another machine-learning classifier or regressor by enumerating the input space of said classifier or regressor to form a plurality of training examples sufficient to span the input space of said classifier or regressor and train the tree to emulate the performance of said classifier or regressor.

60. The method of claim 43 when the diagnostic outcome is that of determining risk of myocardial ischemia.

61. The method of claim 60 when said proteomic markers are selected from the group consisting of two or more of an MMP-9 level, a TpP level, an MCP-1 level, an H-FABP level, a CRP level, a creatine kinase level, an MB isoenzyme level, a cardiac troponin I level, a cardiac troponin T level, and a level of complexes comprising cardiac troponin I and cardiac troponin T.

62. The method of claim 60 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

63. The method of claim 43 when the diagnostic outcome is that of determining risk of atherosclerotic plaque rupture.

64. The method of claim 63 when said proteomic markers are selected from two or more of the group consisting of human neutrophil elastase, inducible nitric oxide synthase, lysophosphatidic acid, malondialdehyde-modified low density lipoprotein, matrix metalloproteinase-1, matrix metalloproteinase-2, matrix metalloproteinase-3, and matrix metalloproteinase-9.

65. The method of claim 63 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

66. The method of claim 43 when the diagnostic outcome is that of determining risk of coagulation.

67. The method of claim 66 when said proteomic markers are selected from two or more of the group consisting of .beta.thromboglobulin, D-dimer, fibrinopeptide A, platelet-derived growth factor, plasmin-.alpha.-2-antip-lasmin complex, platelet factor 4, prothrombin fragment 1+2, P-selectin, thrombin-antithrombin III complex, thrombus precursor protein, tissue factor, and von Willebrand factor.

68. The method of claim 66 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

69. The method of claim 43 when the diagnostic outcome is that of determining risk of acute coronary syndrome.

70. The method of claim 69 when said proteomic markers are selected from two or more of the group consisting of matrix metalloprotease-9 (MMP-9), an MMP-9-related marker, TpP, MCP-1, H-FABP, C-reactive protein, creatine kinase, MB isoenzyme, cardiac troponin I, cardiac troponin T, complexes comprising cardiac troponin I and cardiac troponin T, and B-type natriuretic protein.

71. The method of claim 69 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

72. The method of claim 43 when the diagnostic outcome is that of determining risk of myocardial injury.

73. The method of claim 72 when said proteomic markers are selected from two or more of the group consisting of annexin V, B-type natriuretic peptide, .beta.-enolase, cardiac troponin I, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein, phosphoglyceric acid mutase-MB, S-100ao, a marker of atherosclerotic plaque rupture, a marker of coagulation, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1.beta., interleukin-1 receptor antagonist, interleukin-6, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-9, TpP, and tumor necrosis factor alpha.

74. The method of claim 72 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

75. The method of claim 43 when the diagnostic outcome is that of determining risk of myocardial necrosis.

76. The method of claim 75 when said proteomic markers are selected from both BNP and NT pro-BNP.

77. The method of claim 75 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

78. The method of claim 43 when the diagnostic outcome is that of determining risk or occurrence of stroke.

79. The method of claim 78 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SM), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

80. The method of claim 78 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

81. The method of claim 78 when said proteomic markers are comprised of a panel of five or six markers.

82. The method of claim 81 when said five or six proteomic markers are comprised of a panel of MMP-9 or TAT;

TAT;

IL-8 or IL1b;

D-Dimer or VCAM;

VCAM;

BNP, vWF, IL-6 or Caspase 3, and NCAM or IL-1

83. The method of claim 78 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

84. The method of claim 78 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

85. The method of claim 78 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

86. The method of claim 43 when the diagnostic outcome is that of determining risk or occurrence of ischemic stroke.

87. The method of claim 86 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin II, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

88. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

89. The method of claim 86 when said proteomic markers are comprised of a panel of three or four or five markers.

90. The method of claim 89 when said three, four or five proteomic markers are comprised of a panel of MMP-9, TAT, S100b or Tissue Factor;

IL-8 or IL1b;

IL-8 or IL1b;

Myelin Basic Protein, TAT, Calbindin-D, or MMP-9;

TGF-a, NCAM, IL1ra, or a marker selected from the group comprised of MMP-9, Myelin basic protein, IL-1alpha, IL-8, Tumor necrosis factor alpha, (TGF-alpha) Thrombin-antithrombin III (TAT), brain-derived neurotrophic factor (BDNF), Beta nerve growth factor (alpha NGF), Neuronal cell adhesion molecule, (NCAM, CD56), IL-1 receptor antagonist, D-Dimer, VCAM, Heat shock protein 60, IL-6, Caspase 3, Glial fibrillary acidic protein (GFAP), vWF, S100 beta, Tissue factor, Brain natriuretic peptide, NR2A, cellular fibronectin (c-Fn), heart-type fatty acid binding protein (H-FABP), apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), Intracellular adhesion molecule, ICAM, (CD54), Monocyte chemoattractant protein-1, (MCP-1), Vascular endothelial growth factor, (VEGF), Proteolipid protein, RU Malendialdehyde, Calbindin-D, Creatine kinase (CK-BB), IL-10, neuron-specific enolase (NSE) (gamma gamma isoform), Platelet factor 4 (PF4), C-reactive protein (CRP), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), beta-thromboglobulin (beta TG), or Prothrombin fragment 1+2, PGI2.

91. The method of claim 86 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

92. The method of claim 86 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

93. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

94. The method of claim 43 when the diagnostic outcome is that of determining risk or occurrence of hemorrhagic stroke.

95. The method of claim 94 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

96. The method of claim 94 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

97. The method of claim 94 when said proteomic markers are comprised of a panel of four or five markers.

98. The method of claim 97 when said three, four or five proteomic markers are comprised of a panel of MMP-9 or TAT;

IL-8 or IL1b;

IL-8 or IL1b;

Myelin Basic Protein, TAT, Calbindin-D, or MMP-9;

TGF-a, NCAM, IL1ra, or a marker selected from the group comprised of MMP-9, Myelin basic protein, IL-1 alpha, IL-8, Tumor necrosis factor alpha, (TGF-alpha) Thrombin-antithrombin III (TAT), brain-derived neurotrophic factor (BDNF), Beta nerve growth factor (beta NGF), Neuronal cell adhesion molecule, (NCAM, CD56), IL-1 receptor antagonist, D-Dimer, VCAM, Heat shock protein 60, IL-6, Caspase 3, Glial fibrillary acidic protein (GFAP), vWF, S100beta, Tissue factor, Brain natriuretic peptide, NR2A, cellular fibronectin (c-Fn), heart-type fatty acid binding protein (H-FABP), apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), Intracellular adhesion molecule, ICAM, (CD54), Monocyte chemoattractant protein-1, (MCP-1), Vascular endothelial growth factor, (VEGF), Proteolipid protein, RU Malendialdehyde, Calbindin-D, Creatine kinase (CK-BB), IL-10, neuron-specific enolase (NSE) (gamma gamma isoform), Platelet factor 4 (PF4), C-reactive protein (CRP), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), beta-thromboglobulin (beta TG), or Prothrombin fragment 1+2, PGI2.

99. The method of claim 94 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

100. The method of claim 94 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

101. The method of claim 94 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

102. The method of claim 94 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 95, 96, 99, 100, or 101 and the type of hemorrhagic stroke is intracerebral hemorrhage.

103. The method of claim 94 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 95, 96, 99, 100 or 101 and the type of hemorrhagic stroke is subarachnoid hemorrhage.

104. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 87, 88, 91, 92 or 93 and the type of ischemic stroke is transient ischemic stroke.

105. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 87, 88, 91, 92 or 93 and the type of ischemic stroke is cortical ischemic stroke.

106. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 87, 88, 91, 92 or 93 and the type of ischemic stroke is subcortical ischemic stroke.

107. The method of claim 86 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 87, 88, 91, 92 or 93 and the type of ischemic stroke is global hypoperfusion ischemic stroke.

108. The method of claim 43 when the diagnostic outcome is that of determining the differentiation of ischemic stroke and hemorrhagic stroke.

109. The method of claim 108 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

110. The method of claim 108 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

111. The method of claim 108 when said proteomic markers are comprised of a panel of four or five markers.

112. The method of claim 111 when said four or five proteomic markers are comprised of a panel of MMP-9 or TAT;

IL-8 or IL1b;

IL-8 or IL1b;

Myelin Basic Protein, TAT, Calbindin-D, or MMP-9;

TGF-a, NCAM, IL1ra, or a marker selected from the group comprised of MMP-9, Myelin basic protein, IL-1 alpha, IL-8, Tumor necrosis factor alpha, (TGF-alpha) Thrombin-antithrombin III (TAT), brain-derived neurotrophic factor (BDNF), Beta nerve growth factor (betaNGF), Neuronal cell adhesion molecule, (NCAM, CD56), IL-1 receptor antagonist, D-Dimer, VCAM, Heat shock protein 60, IL-6, Caspase 3, Glial fibrillary acidic protein (GFAP), vWF, S100beta, Tissue factor, Brain natriuretic peptide, NR2A, cellular fibronectin (c-Fn), heart-type fatty acid binding protein (H-FABP), apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), Intracellular adhesion molecule, ICAM, (CD54), Monocyte chemoattractant protein-1, (MCP-1), Vascular endothelial growth factor, (VEGF), Proteolipid protein, RU Malendialdehyde, Calbindin-D, Creatine kinase (CK-BB), IL-10, neuron-specific enolase (NSE) (gamma gamma isoform), Platelet factor 4 (PF4), C-reactive protein (CRP), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), beta-thromboglobulin (betã

TG), or Prothrombin fragment 1+2, PGI2.

113. The method of claim 108 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

114. The method of claim 108 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

115. The method of claim 108 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

116. The method of claim 43 when the diagnostic outcome is that of determining the differentiation of stroke and symptoms mimicking stroke, also called stroke mimic.

117. The method of claim 116 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

118. The method of claim 116 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

119. The method of claim 116 when said proteomic markers are comprised of a panel of five or seven markers.

120. The method of claim 119 when said five or seven proteomic markers are comprised of a panel of MBP, TAT, Calbindin-D, or MMP-9;

HSP60;

D-Dimer or VCAM;

IL-6 or Caspase 3;

GFAP or S100b;

VCAM, MMP-9, NCAM, IL1ra, or two markers selected from the group comprised of MMP-9, Myelin basic protein, IL-1 alpha, IL-8, Tumor necrosis factor alpha, (TGF-alpha) Thrombin-antithrombin III (TAT), brain-derived neurotrophic factor (BDNF), Beta nerve growth factor (beta NGF), Neuronal cell adhesion molecule, (NCAM, CD56), IL-1 receptor antagonist, D-Dimer, VCAM, Heat shock protein 60, IL-6, Caspase 3, Glial fibrillary acidic protein (GFAP), vWF, S100 beta, Tissue factor, Brain natriuretic peptide, NR2A, cellular fibronectin (c-Fn), heart-type fatty acid binding protein (H-FABP), apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), Intracellular adhesion molecule, ICAM, (CD54), Monocyte chemoattractant protein-1, (MCP-1), Vascular endothelial growth factor, (VEGF), Proteolipid protein, RU Malendialdehyde, Calbindin-D, Creatine kinase (CK-BB), IL-10, neuron-specific enolase (NSE) (gamma gamma isoform), Platelet factor 4 (PF4), C-reactive protein (CRP), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), beta-thromboglobulin (beta TG), or Prothrombin fragment 1+2, PGI2.

121. The method of claim 116 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

122. The method of claim 116 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

123. The method of claim 116 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

124. The method of claim 43 when the diagnostic outcome is that of determining the differentiation of non-transient ischemic stroke and symptoms mimicking stroke, also called stroke mimic.

125. The method of claim 124 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

126. The method of claim 124 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

127. The method of claim 124 when said proteomic markers are comprised of a panel of five or seven markers.

128. The method of claim 127 when said five or seven proteomic markers are comprised of a panel of MBP, TAT, Calbindin-D, or MMP-9;

HSP60;

D-Dimer or VCAM;

IL-6 or Caspase 3;

GFAP or S100b;

VCAM, MMP-9, NCAM, IL1ra, or two markers selected from the group comprised of MMP-9, Myelin basic protein, IL-1 alpha, IL-8, Tumor necrosis factor alpha, (TGF-alpha) Thrombin-antithrombin III (TAT), brain-derived neurotrophic factor (BDNF), Beta nerve growth factor (beta NGF), Neuronal cell adhesion molecule, (NCAM, CD56), IL-1 receptor antagonist, D-Dimer, VCAM, Heat shock protein 60, IL-6, Caspase 3, Glial fibrillary acidic protein (GFAP), vWF, S100 beta, Tissue factor, Brain natriuretic peptide, NR2A, cellular fibronectin (c-Fn), heart-type fatty acid binding protein (H-FABP), apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), Intracellular adhesion molecule, ICAM, (CD54), Monocyte chemoattractant protein-1, (MCP-1), Vascular endothelial growth factor, (VEGF), Proteolipid protein, RU Malendialdehyde, Calbindin-D, Creatine kinase (CK-BB), IL-10, neuron-specific enolase (NSE) (gamma gamma isoform), Platelet factor 4 (PF4), C-reactive protein (CRP), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), beta-thromboglobulin (betã

TG), or Prothrombin fragment 1+2, PGI2.

129. The method of claim 124 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

130. The method of claim 124 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

131. The method of claim 124 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.

132. The method of claim 43 when the diagnostic outcome is that of predicting hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke.

133. The method of claim 132 when said proteomic markers are selected from the group consisting of two or more of the following:

Glial fibrillary acidic protein, Cellular-Fibronectin, apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), Platelet factor 4 (PF4), antithrombin-III fragment (AT-III fragment), Creatine kinase (CK-BB), tropinin, BDNF, CPK, LDH Isoenzymes, Thrombin-Antithrombin III, Protein C, Protein S, fibrinogen, Factor VIII, activated Protein C resistance, E-selectin, P-selectin, von Willebrand factor (vWF), platelet-derived microvesicles (PDM), plasminogen activator inhibitor-1 (PAI-1), annexin V, B-type natriuretic peptide (BNP), pro-BNP, N-terminal pro-atrial natriuretic peptide, beta-enolase, cardiac troponin I, cardiac troponin T, creatine kinase-MB, glycogen phosphorylase-BB, heart-type fatty acid binding protein (H-FABP), phosphoglyceric acid mutase-MB, S-100beta, S-100ao, myelin basic protein, a marker of atherosclerotic plaque rupture, a marker of coagulation, NR2A/2B (a subtype of N-methyl-D-aspartate (NMDA) receptors), CD54, CD56, C-reactive protein, caspase-3, hemoglobin .alpha..sub.2, human lipocalin-type prostaglandin D synthase, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin 2, interleukin 2 receptor, interleukin-6, IL-1, IL-8, IL-10, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, MMP-2, MMP-3, MMP-9, tissue factor (TF), fibrin D-dimer (D-dimer), total sialic acid (TSA), TpP, heat shock protein 60, and tumor necrosis factor alpha, and tumor necrosis factor receptors 1 and 2, VEGF, Calbindin-D, Proteolipid protein RU Malendialdehyde neuron-specific enolase (NSE) (γ

γ

isoform), Fibrinopeptide A (FPA), plasmin-.alpha.2AP complex (PAP), also plasmin inhibitory complex (PIC), β

-thromboglobulin ({tilde over (β

)}TG), Prothrombin fragment 1+2, PGI2, Creatinine phosphokinase, brain band, neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurokinin A, neurokinin B, neurotensin, neuropeptide Y, Lactate dehydrogenase (LDH), Insulin-like growth factor-1 (IGF-1), PGE2, 8-epi PGF.sub.2alpha and Transforming growth factor β

(TGFβ

).

134. The method of claim 132 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

135. The method of claim 132 when said non-proteomic markers are selected from a group consisting of Complete blood count (CBC), Coagulation test, Blood chemistry (glucose, serum electrolytes {Na, Ca, K}), Leukocyte and Neutrophil counts, and Blood lipids tests.

136. The method of claim 132 when said non-proteomic markers are selected from a group consisting of age, weight, height, body mass index, gender, time from onset of stroke-like symptoms, ethnicity, heart rate, blood pressure, respiration rate, blood oxygenation, previous personal and/or familial history of cardiac events, recent cranial trauma and unequal eye dilation.

137. The method of claim 132 when the determination of diagnostic or prognostic outcome is made according to one or more of claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 and both proteomic markers and non-proteomic markers are used.