BIOMARKERS OF LATENT TUBERCULOSIS INFECTION

Title:

BIOMARKERS OF LATENT TUBERCULOSIS INFECTION

Document Type and Number:

WIPO Patent Application WO/2018/013883

Kind Code:

A1

Abstract:

The present invention provides biomarkers, methods and kits for diagnosing latent tuberculosis (TB) in a subject exposed to TB, and methods and kits for monitoring the effectiveness of treatment for latent TB.

Inventors:

PARAMITHIOTIS EUSTACHE (CA)
BOOM W HENRY (US)
BARK CHARLES (US)

Application Number:

PCT/US2017/042039

Publication Date:

January 18, 2018

Filing Date:

July 14, 2017

Export Citation:

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Assignee:

CAPRION PROTEOMICS INC (CA)
UNIV CASE WESTERN RESERVE (US)

International Classes:

G01N33/569

Domestic Patent References:

WO2015006515A1	2015-01-15
WO2015025281A1	2015-02-26
WO2010045714A1	2010-04-29
WO2009143519A2	2009-11-26
WO2011086161A2	2011-07-21

Foreign References:

CN105588944A	2016-05-18
CN104792894A	2015-07-22
KR20110137766A	2011-12-23
US20070054407A1	2007-03-08
US20160154005A1	2016-06-02
US4683202A	1987-07-28
US5854033A	1998-12-29
US5770722A	1998-06-23
US5874219A	1999-02-23
US5744305A	1998-04-28
US5677195A	1997-10-14
US5445934A	1995-08-29
US6040138A	2000-03-21
US5800992A	1998-09-01
US6020135A	2000-02-01
US6033860A	2000-03-07
US6344316B1	2002-02-05

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Attorney, Agent or Firm:

SPARKS, Jonathan, M. et al. (US)

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Claims:

We claim:

1. A method for determining whether a subject exposed to tuberculosis (TB) will develop latent TB, the method comprising

determining the level of one or more markers listed in Table 1 in a sample(s) from the subject;

comparing the level of the one or more markers in the subject sample(s) with a level of the one or more markers in a control sample(s), wherein a difference in the level of the one or more markers in the subject sample(s) as compared to the level of the one or more markers in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

2. The method of any one of claim 1, wherein the level in the subject sample(s) is determined by mass spectrometry.

3. The method of claim 2, wherein the mass spectrometry is matrix assisted laser desorption/time of flight (MALDI/TOF) mass spectrometry, liquid chromatography quadruple ion trap electrospray (LCQ-MS), or surface enhanced laser desorption

ionization/time of flight (SELDI/TOF) mass spectrometry.

4. The method of claim 1, wherein the level in the subject sample(s) is determined by immunoassay.

5. The method of any of the preceding claims, wherein the sample(s) from the subject is a fluid sample(s).

6. The method of any of the preceding claims, wherein the sample(s) from the subject is a tissue sample(s). 7. The method of any one of the preceding claims, wherein the level of the marker is an expression level and/or activity of the marker.

8. The method of any of claims 1-7, further comprising determining the level of one or more markers selected from the group consisting of CLEC3B, ECMl, PONl, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1.

9. A method for determining whether a subject exposed to tuberculosis (TB) will develop latent TB, the method comprising determining the level of CLEC3B and the level of ECM1 in a sample(s) from the subject;

comparing the level of CLEC3B and the level of ECM1 in the subject sample(s) with a level of CLEC3B and a level of ECM1 in a control sample(s),

wherein a difference in the level of CLEC3B and a difference in the level of ECM1 in the subject sample(s) as compared to the level of CLEC3B and the level of ECM1 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. 10. The method of claim 9, further comprising

determining the level of one or more additional markers selected from the group consisting of PONl, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLN1 in a sample(s) from the subject. 11. The method of claim 9, further comprising

determining the level of PONl in a sample(s) from the subject.

12. The method of claim 9, further comprising

determining the level of VTN in a sample(s) from the subject.

13. The method of claim 9, further comprising

determining the level of PONl and the level of VTN in a sample(s) from the subject.

14. The method of claim 9, further comprising

determining the level of PONl and the level of one or more additional markers selected from the group consisting of, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLN1 in a sample(s) from the subject.

15. The method of claim 9, further comprising

determining the level of VTN and the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLN1 in a sample(s) from the subject.

16. The method of claim 9, further comprising

determining the level of PONl, the level of VTN, and the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLN1 in a sample(s) from the subject.

17. The method of any of claims 9-16, further comprising determining the level of one or more markers listed in Table 1 in a sample(s) from the subject.

18. A method for determining whether a subject exposed to tuberculosis (TB) will develop latent TB, the method comprising

determining the level of CLEC3B, the level of ECMl, and the level of PON1 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, and the level of PON1 in the subject sample(s) with a level of CLEC3B, the level of ECMl, and the level of PON1 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, and a difference in the level of PON1 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of PON1 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

19. A method for determining whether a subject exposed to tuberculosis (TB) will develop latent TB, the method comprising

determining the level of CLEC3B, the level of ECMl, and the level of VTN in a sample(s) from the subject;

comparing the level of CLEC3B , the level of ECM 1 , and the level of VTN in the subject sample(s) with a level of CLEC3B, the level of ECMl, and the level of VTN in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, and a difference in the level of VTN in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of VTN in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

20. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of IGFALS in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFALS in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFALS in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of IGFALS in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFALS in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

21. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFBP3 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFBP3 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFBP3 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of IGFBP3 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of IGFBP3 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

22. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of CLU in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of CLU in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of CLU in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of CLU in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of CLU in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. 23. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of VWF in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of VWF in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of VWF in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of VWF in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of VWF in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. 24. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of SPP2 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of SPP2 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of SPP2 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of SPP2 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of SPP2 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

25. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of SELL in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of SELL in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of SELL in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of SELL in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of SELL in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

26. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of LUM in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of LUM in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of LUM in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of LUM in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of LUM in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

27. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of NCAMl in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of NCAMl in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of NCAMl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of NCAMl in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of NCAM 1 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

28. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of PON1, and the level of TLN1 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PON1, and the level of TLN1 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PON1, and the level of TLN1 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PON1, and a difference in the level of TLN1 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PON1, and the level of TLN1 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

29. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of IGFALS in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

30. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of IGFBP3 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. 31. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of CLU in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

32. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of VWF in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of VWF in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of VWF in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of VWF in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of VWF in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

33. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of SPP2 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of SPP2 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of SPP2 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of SPP2 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of SPP2 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

34. A method for determining whether a subject will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of SELL in a sample(s) from the subject;

comparing the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of SELL in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of SELL in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of SELL in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of SELL in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

35. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of LUM in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of LUM in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of LUM in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of LUM in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of LUM in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. 36. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of NCAMl in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

37. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising

determining the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of TLN1 in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLN1 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLN1 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of TLN1 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLN1 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

38. A method for determining whether a subject exposed to TB will develop latent tuberculosis (TB), the method comprising determining the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a sample(s) from the subject;

comparing the level of CLEC3B, the level of ECMl, the level of PONl, the level of

VTN, and the level of VTN, and the level of the one or more additional markers in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of the one or more additional markers in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, a difference in the level of VTN, and a difference in the level of one additional marker in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of the one or more additional markers in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

39. The method of any one of claims 9-38, wherein the level of the marker is an expression level and/or activity of the marker.

40. The method of any one of claims 9-38, wherein the level in the subject sample(s) is determined by mass spectrometry.

41. The method of claim 40, wherein the mass spectrometry is matrix assisted laser desorption/time of flight (MALDI/TOF) mass spectrometry, liquid chromatography quadruple ion trap electrospray (LCQ-MS), or surface enhanced laser desorption

ionization/time of flight (SELDI/TOF) mass spectrometry.

42. The method of any one of claims 9-38, wherein the level in the subject sample(s) is determined by immunoassay. 43. The method of any one of claims 9-38, wherein the sample(s) from the subject is a fluid sample(s).

44. The method of any one of claims 9-38, wherein the sample(s) from the subject is a tissue sample(s).

45. The method of any one of claims 9-38, wherein the combination of markers has an area under the curve of abou 0.85 to about 1.00.

46. A method of detecting the level of one or more markers listed in Table 1 in a subject, comprising

obtaining subject sample(s) from a human subject; and

detecting whether one or more markers listed in Table 1 is present in the subject sample(s).

47. The method of claim 46, further comprising detecting the level of one or more additional markers selected from the group consisting of CLEC3B, ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1.

48. A method for detecting the level of one or more markers in a subject, the method comprising

obtaining subject sample(s) from a human subject; and

detecting the level of CLEC3B and the level of ECM1 in said subject sample(s).

49. The method of claim 48, further comprising detecting the level of one or more additional markers selected from the group consisting of PON 1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in said subject sample(s). 50. The method of claim 48, further comprising detecting the level of PON1 in said subject sample(s).

51. The method of claim 48, further comprising detecting the level of VTN in said subject sample(s).

52. The method of claim 48, further comprising detecting the level of PON1 and the level of VTN in said subject sample(s).

53. The method of claim 48, further comprising detecting the level of PON1 and the level of one or more additional markers selected from the group consisting of IGFALS,

IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in said subject sample(s).

54. The method of claim 48, further comprising detecting the level of VTN and the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in said subject sample(s).

55. The method of claim 48, further comprising detecting the level of PON1, the level of VTN, and the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in said subject sample.

56. The method of any of claims 46-55, further comprising detecting the level of one or more markers listed in Table 1 in a sample(s) from the subject.

57. The method of any of claims 46-56, wherein the level of the marker is an expression level and/or activity of the marker. 58. The method of any one of claims 46-56, wherein the level in the subject sample(s) is determined by mass spectrometry.

59. The method of claim 58, wherein the mass spectrometry is matrix assisted laser desorption/time of flight (MALDI/TOF) mass spectrometry, liquid chromatography quadruple ion trap electrospray (LCQ-MS), or surface enhanced laser desorption

ionization/time of flight (SELDI/TOF) mass spectrometry.

60. The method of any one of claims 46-56, wherein the level in the subject sample(s) is determined by immunoassay.

61. The method of any of claims 46-56, wherein the sample(s) from the subject is a fluid sample(s).

62. The method of any of claims 46-56, wherein the sample(s) from the subject is a tissue sample(s).

63. The method of any of claims 1-62, further comprising administering to the subject an effective amount of a therapeutic agent for treating TB, thereby treating latent TB in the subject.

64. The method of claim 63, wherein the therapeutic agent modulates the level and/or activity of any one or more of the markers listed in Table 1.

65. A kit for determining whether a subject exposed to tuberculosis (TB) will develop latent TB, the kit comprising reagents for determining the level of one or more markers listed in Table 1 in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB.

Description:

BIOMARKERS OF LATENT TUBERCULOSIS INFECTION

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/362,225, filed on July 14, 2016, the entire contents of which are hereby incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant number

HHSN272200800047C, awarded by National Institute of Health (NIH)/ National Institute of Allergy and Infectious Diseases (NIAID), grant numbers N01-AI95383 and

HHSN266200700022C/ N01-AI70022 awarded by National Institutes of Health National Institute of Allergy and Infectious Diseases, and grant number CTSA KL2TR000440 awarded by the National Institutes of Health/National Center for Research Resources (NIH/NCRR). The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Tuberculosis (TB) remains a major global public health problem. About a third of the world's population is latently infected with Mycobacterium tuberculosis, and an estimated 8.7 million new TB cases were diagnosed in 2011 (World Health Organization, Global tuberculosis control: WHO report 2011, 2011: Geneva, Switzerland). In addition, in 2011 almost one million TB-associated deaths occurred among HIV uninfected (HIV-) individuals and about 0.43 million deaths among HIV-infected (HIV+) individuals.

In addition to prevention, the cornerstones of TB control are reduction of

transmission, morbidity, and mortality all of which require early treatment initiation. This in turn necessitates timely TB diagnosis, underlining the need for new rapid diagnostic tests. Rapid identification of active TB is the key unmet need in TB disease management.

Currently, TB diagnostic tests depend on the detection of M. tuberculosis which, thus, require a specimen from the site of disease which is not always easy to obtain. Furthermore, the current tests for TB are limited by lack of sensitivity (microscopy of sputum smears) or require amplification of M. tuberculosis which takes weeks (culture) and/or is expensive (molecular detection). Moreover, these gold standard tests (culture and molecular detection) require laboratory infrastructure which is not accessible in many endemic regions.

In addition, diagnosis of latent TB infection (LTBI) is based on host immunological activity measured by either the tuberculin skin test (TST) or the interferon gamma release assay (IGRA). Risk of developing active TB is highest after recent infection, but neither TST not IGRA tests can distinguish between a recent infection and a cleared infection. Accordingly, there is a need in the art for novel TB biomarkers that are easily detectable, and neither require a specimen from the site of infection, nor laboratory infrastructure to provide rapid TB diagnosis and limit the spread of the disease. Furthermore, developing new tests that identify recent infection would allow for targeted treatment for those most likely to progress to active TB, and is a priority among international TB agencies.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery of markers that are associated with the presence of latent tuberculosis (TB) in a subject exposed to TB, e.g., in order to target treatment to those likely to develop active TB and/or spread the disease.

Accordingly, the present invention provides sensitive and facile methods and kits for determining whether a subject exposed to TB has latent TB, as well as methods for monitoring the effectiveness of a therapy for treating TB in a subject by measuring and identifying particular markers, or particular combinations of markers.

Accordingly, in one aspect the present invention provides methods for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The methods include determining the level of one or more markers listed in Table 1 in a sample(s) from the subject; comparing the level of the one or more markers in the subject sample(s) with a level of the one or more markers in a control sample(s), wherein a difference in the level of the one or more markers in the subject sample(s) as compared to the level of the one or more markers in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of one or more markers listed in Table 1 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of one or more markers listed in Table 1 in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of the one or more markers in the first sample(s) with a level of the one or more markers in the second sample(s), wherein a difference in the level of the one or more markers in the first sample(s) as compared to the level of the one or more markers in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of CLEC3B, ECMl, PONl, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1.

In one embodiment, the level of the marker is an expression level and/or activity of the marker. In one embodiment, the level in the subject sample(s) is determined by mass spectrometry. In one embodiment, the mass spectrometry is matrix assisted laser

desorption/time of flight (MALDI/TOF) mass spectrometry, liquid chromatography quadruple ion trap electrospray (LCQ-MS), or surface enhanced laser desorption

ionization/time of flight (SELDI/TOF) mass spectrometry. In another embodiment, the level in the subject sample(s) is determined by immunoassay.

In one embodiment, the sample(s) from the subject is a fluid sample(s). In another embodiment, the sample(s) from the subject is a tissue sample(s).

In one embodiment, the one or more markers is selected from the group consisting of CLEC3B, ECMl, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1.

In another embodiment, the methods further comprise determining the level of one or more of PRG4, CA1, SHBG, CPN1, CPN2, QSOX1, PRDX2, APOA1, CA2, LPA,

TAGLN2, GPX3, MST1, CNDP1, ATRN, PFN1, PEPD, VASN, BTD, CPB2, GPLD1, DBH, HGFAC, CDH5, LRGl, MASPl, PGLYRP2, TNXB, CD14, CKM, APOE, MANlAl, PROS 1, S 100A8, S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1, LGALS3BP, PTGDS, APOC3, MINPP1, SEPP1, APOA4, MASP2, HYOU1, IGF2, GP1BA, CACNA2D1, CNTN1, NIDI, COMP, PCSK9, LCP1 and APOC1.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B and the level of ECMl in a sample(s) from the subject; comparing the level of CLEC3B and the level of ECMl in the subject sample(s) with a level of CLEC3B and a level of ECMl in a control sample(s), wherein a difference in the level of CLEC3B and a difference in the level of ECMl in the subject sample(s) as compared to the level of CLEC3B and the level of ECMl in the control sample(s) indicates that the subject will develop latent tuberculosis (TB). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in a sample(s) from the subject, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B and the level of ECMl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B and the level of ECMl in a second sample(s) from the subject after at least a portion of the treatment has been

administered; comparing the level of CLEC3B and the level of ECMl in the first sample(s) with a level of CLEC3B and the level of ECMl in the second sample(s), wherein a difference in the level of CLEC3B and a difference in the level of ECMl in the first sample(s) as compared to the level of the CLEC3B and the level of ECMl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, and the level of PONl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, and the level of PONl in the subject sample(s) with a level of CLEC3B, the level of ECMl, and the level of PONl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, and a difference in the level of PONl in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of PONl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, and the level of PONl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, and the level of PONl in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, and the level of PONl in the first sample(s) with a level of CLEC3B, the level of ECMl, and the level of PONl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, and the level of PONl in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of PONl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, and the level of VTN in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, and the level of VTN in the subject sample(s) with a level of CLEC3B, the level of ECMl, and the level of VTN in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, and a difference in the level of VTN in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of VTN in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, and the level of VTN in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, and the level of VTN in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, and the level of VTN in the first sample(s) with a level of CLEC3B , the level of ECM 1 , and the level of VTN in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, and the level of VTN in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, and the level of VTN in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level ofVTN in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, and a difference in the level of VTN in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of

CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in the second sample(s), wherein a difference in the level of CLEC3B, the level of

ECMl, the level of PONl, and the levl of VTN in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VTN in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of IGFALS in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PON1, and a difference in the level of IGFALS in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of

PON1, and the level of IGFALS in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PON1, and a difference in the level of IGFBP3 in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of PONl, and the level of IGFBP3 in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of PONl, and the level of IGFBP3 in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PONl, and the level of IGFBP3 in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PONl, and a difference in the level of CLU in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of CLU in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of CLU in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PONl, and the level of CLU in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of PONl, and the level of VWF in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PONl, and the level of VWF in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PONl, and the level of VWF in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PONl, and a difference in the level of VWF in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of VWF in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, and a difference in the level of SPP2 in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of SPP2 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of SPP2 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SPP2 in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of SELL in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, and a difference in the level of SELL in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of SELL in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, and a difference in the level of LUM in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of LUM in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of PONl, and a difference in the level of NCAMl in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, and the level of NCAMl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB. In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PON1, and a difference in the level of TLNl in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLNl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in the subject sample(s) with a level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of IGFALS in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of IGFALS in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in the first sample(s) with a level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of IGFALS in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFALS in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of IGFBP3 in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the second sample(s), wherein a difference in the level of

CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of IGFBP3 in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of CLU in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of CLU in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of CLU in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of VWF in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of SPP2 in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of SPP2 in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of SPP2 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of SELL in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of VTN, and a difference in the level of LUM in the subject sample(s) as compared to the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of LUM in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of LUM in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of NCAMl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of NCAMl in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of

NCAMl in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of NCAMl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLNl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLNl in the subject sample(s) with a level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLNl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECMl, a difference in the level of VTN, and a difference in the level of TLNl in the subject sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of VTN, and the level of TLNl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB. In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in the first sample(s) with a level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in the first sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLNl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one aspect the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include

determining the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a sample(s) from the subject; comparing the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s) with a level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a control sample(s), wherein a difference in the level of CLEC3B, a difference in the level of ECM1, a difference in the level of PON1, a difference in the level of VTN, and a difference in the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s) as compared to the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the control sample(s) indicates that the subject will develop latent TB, thereby determining whether the subject exposed to TB will develop latent TB.

In one aspect the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a second sample(s) from the subject after at least a portion of the treatment has been

administered; comparing the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the first sample(s) with a level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the second sample(s), wherein a difference in the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one additional marker selected from the group consisting of

IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the first sample(s) as compared to the level of CLEC3B, the level of ECMl, the level of PONl, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the second sample(s) indicates that the treatment is effective, thereby monitoring the effectiveness of a treatment in the subject having latent TB.

In one embodiment, the methods further comprise determining the level of one or more additional markers selected from the group consisting of CLEC3B, ECMl, PONl,

VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl, PRG4, CAl, SHBG, CPN1, CPN2, QSOX1, PRDX2, APOA1, CA2, LPA, TAGLN2, GPX3, MST1, CNDP1, ATRN, PFN1, PEPD, VASN, BTD, CPB2, GPLD1, DBH, HGFAC, CDH5, LRG1, MASP1, PGLYRP2, TNXB, CD14, CKM, APOE, MAN1A1, PROS 1, S 100A8, S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1, LGALS3BP, PTGDS, APOC3, MINPP1, SEPP1, APOA4, MASP2, HYOU1, IGF2, GP1BA, CACNA2D1, CNTN1, NIDI, COMP, PCSK9, LCP1 and APOC1.

In another embodiment, the methods further comprise determining the level of one or more additional markers listed in Table 1.

In one aspect, the present invention provides methods of detecting the level of one or more markers listed in Table 1 in a subject. The methods include obtaining subject sample(s) from a human subject exposed to TB; and detecting whether one or more markers listed in Table 1 is present in the subject sample(s). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of CLEC3B, ECMl, PONl, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl.

In one aspect, the present invention provides methods for detecting the level of one or more markers in a subject excposed to TB. The methods include obtaining subject sample(s) from a human subject; and detecting the level of CLEC3B and the level of ECM1 in said subject sample(s). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s).

In one aspect, the present invention provides methods for detecting the level of one or more markers in a subject exposed to TB. The methods include obtaining subject sample(s) from a human subject; and detecting the level of CLEC3B, the level of ECM1, and the level of PON1 in said subject sample(s). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s).

In one aspect, the present invention provides methods for detecting the level of one or more markers in a subject exposed to TB. The methods include obtaining subject sample(s) from a human subject; and detecting the level of CLEC3B, the level of ECM1, and the level of VTN in said subject sample(s). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s).

In one aspect, the present invention provides methods for detecting the level of one or more markers in a subject exposed to TB. The methods include obtaining subject sample(s) from a human subject; and detecting the level of CLEC3B, the level of ECM1, the level of PON1, and the level of VTN in said subject sample(s). In one embodiment, the methods further comprise determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in the subject sample(s).

In one embodiment, the methods further comprise detecting the level of one or more markers listed in Table 1 in a sample(s) from the subject.

In one embodiment, the methods further comprise administering to the subject an effective amount of a therapeutic agent for treating TB, thereby treating latent TB in the subject. In one embodiment, the therapeutic agent modulates the level and/or activity of any one or more of the markers listed in Table 1.

In one aspect, the present invention provides kits for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The kits include reagents for determining the level of one or more markers listed in Table 1 in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of one or more markers listed in Table 1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of CLEC3B, ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The kits include reagents for determining the level of CLEC3B and the level of ECM1 in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B and the level of ECM1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, and the level of PON1 in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, and the level of PON1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, and the level of VTN in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, and the level of VTN in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits for determining whether a subject exposed to tuberculosis (TB) will develop latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of VTN in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of VTN in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one embodiment, the kits further comprise reagents for determining the level of one or more markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1 in the subject sample(s).

In one embodiment, the kits further comprise reagents for determining the level of one or more markers listed in Table 1 in a sample(s) from the subject.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFALS in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of IGFBP3 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of CLU in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of CLU in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of VWF in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of VWF in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of SPP2 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of SPP2 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of SELL in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB. In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of SELL in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of LUM in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of LUM in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of NCAM1 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of NCAM1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B , the level of ECM 1 , the level of PON 1 , and the level of

TLN1 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, and the level of TLN1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFALS in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM 1 , the level of VTN, and the level of IGFBP3 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of IGFBP3 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of CLU in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of VWF in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SPP2 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment. In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of SELL in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of LUM in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of NCAM1 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of NCAM1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B , the level of ECM 1 , the level of VTN, and the level of

TLN1 in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of VTN, and the level of TLN1 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a sample(s) from the subject and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of CLEC3B, the level of ECM1, the level of PON1, the level of VTN, and the level of one additional marker selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one embodiment, the kits further comprise reagents for determining the level of any one or more of the markers listed in Table 1 in a sample(s) from the subject.

In one embodiment, the kits further comprise reagents for determining the level of one or more additional markers selected from the group consisting of IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, and TLNl, PRG4, CAl, SHBG, CPNl, CPN2, QSOXl, PRDX2, APOA1, CA2, LPA, TAGLN2, GPX3, MST1, CNDP1, ATRN, PFN1, PEPD, VASN, BTD, CPB2, GPLD1, DBH, HGFAC, CDH5, LRG1, MASP1, PGLYRP2, TNXB, CD14, CKM, APOE, MAN1A1, PROS 1, S 100A8, S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1, LGALS3BP, PTGDS, APOC3, MINPP1, SEPP1, APOA4, MASP2, HYOU1, IGF2, GP1BA, CACNA2D1, CNTN1, NIDI, COMP, PCSK9, LCP1 and APOC1 in a sample(s) from the subject.

In one aspect, the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of each marker in any one of the combination of markers set forth in any one of Tables 2, 3, 4, and 5 in a sample(s) from the subject; comparing the level of each of the markers of the combination in the subject sample(s) with a level of each of the markers of the combination in a control sample(s), wherein a difference in the level of all of the markers of the combination in the subject sample(s) as compared to the level of all of the markers of the combination in the control sample(s) indicates that the subject will develop latent TB.

In one aspect, the present invention provides methods for monitoring the effectiveness of a treatment in a subject having latent tuberculosis (TB). The methods include determining the level of any one of the combination of markers set forth in any one of Tables 2, 3, 4, and 5 in a first sample(s) from the subject prior to the initiation of the treatment; determining the level of each of the markers of the combination in a second sample(s) from the subject after at least a portion of the treatment has been administered; comparing the level of each of the markers of the combination in the first sample(s) with a level of each of the markers of the combination in the second sample(s), wherein a difference in the level of all of the markers of the combination in the first sample(s) as compared to the level of all of the markers of the combination in the second sample(s) indicates that the treatment is effective.

In one embodiment, the combination of markers has an area under the curve (AUC) of about 0.85 to about 1.00.

In one aspect, the present invention provides kits for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The kits include reagents for determining the level of each marker in any one of the combination of markers set forth in any one of Tables 2, 3, 4, and 5 in a subject sample(s) and instructions for use of the kit to determine whether the subject will develop latent TB.

In one aspect, the present invention provides kits for monitoring the effectiveness of a treatment in a subject having latent TB. The kits include reagents for determining the level of each marker in any one of the combination of markers set forth in any one of Tables 2, 3, 4, and 5 in a subject sample(s) and instructions for use of the kit to monitor the effectiveness of the treatment.

In one embodiment, the combination of markers has an area under the curve (AUC) of about 0.85 to about 1.00.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a table showing the charcateristics of included subjects by study phase and clinical cohort. Patients for this study were enrolled in the Kawempe Community Health Study (KCHS), a prospective cohort of adult pulmonary TB index cases and their household contacts, conducted in Kampala, Uganda. Plasma or serum was collected at baseline from these subjects and at regular time points thereafter. Index cases were adults (age 18 years and older) with initial episodes of newly diagnosed culturepositive pulmonary TB. Household contacts were a person (age 12 years and older) living in the same building as an index case for at least one week during the three-month period immediately preceding the index case diagnosis. After the initial evaluation, participants were evaluated at 3, 6, 12, and 24 months for active TB and with repeat TST if their first and subsequent TST remained negative. All individuals were monitored clinically and if signs and symptoms of TB developed, evaluated as TB suspects. Tuberculin skin testing was done using 5 TU of purified protein derivative (PPD). All subjects were HIV-.

Figure 2A is a table depicting the cross-sectional comparison of changes in the level of the indicated markers in sera from non-infected (NI), baseline TST-negative future converters (CO), baseline TST-positive (LTBI), and active TB (ATB) groups. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI). The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. Most protein changes associated with inflammation, immune response, tissue repair, cellular migration and proliferation were observed in subjects with active TB. Early in disease smaller changes were observed in these processes, as well as changes in proteins associated with lipid metabolism and the innate immune response. The results are consistent with low level of distinct observable changes early in disease.

Figure 2B is a another table depicting the cross-sectional comparison of changes in the level of the indicated markers in sera from non-infected (NI), baseline TST-negative future converters (CO), baseline TST-positive (LTBI), and active TB (ATB) groups. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI). The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. Most protein changes associated with inflammation, immune response, tissue repair, cellular migration and proliferation were observed in subjects with active TB. Early in disease smaller changes were observed in these processes, as well as changes in proteins associated with lipid metabolism and the innate immune response. The results are consistent with low level of distinct observable changes early in disease.

Figure 2C is a another table depicting the cross-sectional comparison of changes in the level of the indicated markers in sera from non-infected (NI), baseline TST-negative future converters (CO), baseline TST-positive (LTBI), and active TB (ATB) groups. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI). The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. Most protein changes associated with inflammation, immune response, tissue repair, cellular migration and proliferation were observed in subjects with active TB. Early in disease smaller changes were observed in these processes, as well as changes in proteins associated with lipid metabolism and the innate immune response. The results are consistent with low level of distinct observable changes early in disease.

Figure 2D is a another table depicting the cross-sectional comparison of changes in the level of the indicated markers in sera from non-infected (NI), baseline TST-negative future converters (CO), baseline TST-positive (LTBI), and active TB (ATB) groups. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI). The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. Most protein changes associated with inflammation, immune response, tissue repair, cellular migration and proliferation were observed in subjects with active TB. Early in disease smaller changes were observed in these processes, as well as changes in proteins associated with lipid metabolism and the innate immune response. The results are consistent with low level of distinct observable changes early in disease.

Figure 3A is a table depicting the longitudinal comparison of changes in selected* plasma proteins from baseline TST-negative subjects (N=52) that converted to TST-positive (N=37) or remained TST-negative (N=15). Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI) between each individual's baseline TST-negative sample and the TST-positive conversion sample or corresponding TST- negative sample. The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. * 159 proteins from the cross-sectional discovery phase using the following combination of biological and statistical criteria. All of the significantly differentially expressed proteins from the baseline converter vs NI and LTBI vs NI comparisons were selected along with the most differentially expressed proteins from comparisons to active TB. Also included were the significant proteins described in the MRM- MS assay of U.S. Patent Publication No. 2016/0154005 (incorporated herein in its entirety by reference) and Achkar, et al. (2015 EBioMedicine, 2, 1160-8).

Figure 3B is also a table depicting the longitudinal comparison of changes in selected* plasma proteins from baseline TST-negative subjects (N=52) that converted to TST-positive (N=37) or remained TST-negative (N=15). Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI) between each individual's baseline TST-negative sample and the TST-positive conversion sample or corresponding TST-negative sample. The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios. * 159 proteins from the cross-sectional discovery phase using the following combination of biological and statistical criteria. All of the significantly differentially expressed proteins from the baseline converter vs NI and LTBI vs NI comparisons were selected along with the most differentially expressed proteins from comparisons to active TB. Also included were the significant proteins described in the MRM-MS assay of U.S. Patent Publication No.

2016/0154005 (incorporated herein in its entirety by reference) and Achkar, et al. (2015 EBioMedicine, 2, 1160-8).

Figure 4A is a table showing changes in plasma protein expression after TST-positive conversion. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI) in subjects (N=19) with samples at baseline (DI), 3 months (M3), and 6 months (M6) that had converted to TST-positive at M3. The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios.

Figure 4B is also a table showing changes in plasma protein expression after TST- positive conversion. Shown are protein expression change ratios (also referred to herein as differential intensity ratios, or DI) in subjects (N=19) with samples at baseline (Dl), 3 months (M3), and 6 months (M6) that had converted to TST-positive at M3. The significant changes (p<0.05 ) are shaded in dark and medium dark gray for increased expression ratios and the the significant changes (p<0.05) are shaded in light or medium light gray for decreases expression ratios.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, at least in part, on the discovery of markers that are associated with latent tuberculosis (TB). In particular, biomarkers associated with latent TB have been discovered, prioritized, and validated in relevant in vitro experimental systems. The markers were identified as being expressed, e.g., essentially specifically expressed, in samples from subjects exposed to TB and developing latent TB as compared to noninfected subjects, subjects having active TB infection, or subjects who convert to TB infection during the study.

Accordingly, the present invention provides sensitive and facile methods and kits for determining whether a subject exposed to TB will develop latent TB, and methods and kits for monitoring the effectiveness of a therapy for treating a subject having latent TB.

Various aspects of the invention are described in further detail in the following subsections:

I. Definitions

As used herein, each of the following terms has the meaning associated with it in this section.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

A "marker" or "biomarker" is an organic biomolecule which is differentially present in a sample taken from a subject of one phenotypic status (e.g., having a disease) as compared with another phenotypic status (e.g., not having the disease). A biomarker is differentially present between different phenotypic statuses if the mean or median level, e.g., expression level, of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal-Wallis, Wilcoxon, Mann- Whitney and odds ratio. Biomarkers, alone or in combination, provide measures of relative risk that a subject belongs to one phenotypic status or another. As such, they are useful as markers for, e.g., disease (prognostics and

diagnostics), therapeutic effectiveness of a drug (therano sties) and of drug toxicity.

In some embodiments, the accuracy of a marker(s) useful in the compositions and methods of the present invention may be characterized by a Receiver Operating

Characteristic curve ("ROC curve"). An ROC is a plot of the true positive rate against the false positive rate for the different possible cutpoints of a diagnostic marker(s). An ROC curve shows the relationship between sensitivity and specificity. That is, an increase in sensitivity will be accompanied by a decrease in specificity. The closer the curve follows the left axis and then the top edge of the ROC space, the more accurate the marker(s).

Conversely, the closer the curve comes to the 45-degree diagonal of the ROC graph, the less accurate the marker(s). The area under the ROC is a measure of a marker(s) accuracy. The accuracy of the marker(s) depends on how well the marker(s) separates the group being tested into those with and without the disease in question. An area under the curve (referred to as "AUC") of 1 represents a perfect marker(s), while an area of 0.5 represents a less useful marker(s). Thus, in some embodiments, biomarker(s) and methods of the present invention have an AUC greater than about 0.50, an AUC greater than about 0.60, or an AUC greater than about 0.70.

"Tuberculosis" ("TB") is a multisystemic disease with myriad presentations and manifestations, and is the most common cause of infectious disease-related mortality worldwide. Mycobacterium tuberculosis, a tubercle bacillus, is the causative agent of TB.

The lungs are the most common site for the development of TB (pulmonary TB), and about

85% of patients with TB present with pulmonary complaints. Nonetheless, "extrapulmonary

TB", e.g., "disseminated TB", can occur as part of a primary or late, generalized infection. Extrapulmonary TB can affect bones and joints, bronchus, eye, intestines, larynx, peritoneum, meninges, pericardium, lymph node, organs of the male or female urinary and reproductive systems, skin, stomach, and/or urinary systems.

When a person is infected with M tuberculosis, the infection can take one of a variety of paths, most of which do not lead to actual TB. The infection may be cleared by the host immune system or suppressed into an inactive form called "latent tuberculosis infection", with resistant hosts controlling mycobacterial growth at distant foci before the development of active disease.

A subject has "latent tuberculosis ("LTB") (also referred to as "latent tuberculosis infection" ("LTBI")) when the subject is infected with Mycobacterium tuberculosis but does not have active tuberculosis disease. Subjects having latent tuberculosis are not infectious. The main risk is that approximately 10% of these patients (5% in the first two years after infection and 0.1% per year thereafter but higher risk if immunosuppressed) will go on to develop "active tuberculosis" ("active TB") and spread the disease at a later stage of their life if, for example, there is onset of a disease affecting the immune system (such as AIDS) or a disease whose treatment affects the immune system (e.g., chemotherapy in cancer or systemic steroids in asthma or Enbrel, Humira or Orencia in rheumatoid arthritis); malnutrition (which may be the result of illness or injury affecting the digestive system, or of a prolonged period of not eating, or disturbance in food availability such as famine, residence in refugee camp or concentration camp, or civil war; and/or degradation of the immune system due to aging.

"Miliary tuberculosis" (also known as "disseminated tuberculosis", "tuberculosis cutis acuta generalisata", and "Tuberculosis cutis disseminata") is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1-5 mm). Miliary tuberculosis is characterized by a chronic and contagious

Mycobacterium tuberculosis infection that has spread to other organs of the body by the blood or lymph system. Its name comes from a distinctive pattern seen on a chest X-ray of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds— thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including, for example, the lungs, liver, and spleen. Disseminated disease can occur within weeks of the primary infection, or may lie inactive for years before causing illness. Infants, the elderly, those infected with HIV, and those who take immune-suppressing medications are at higher risk for disseminated TB, because of their weaker immune systems.

The symptoms of a subject having TB are similar to the symtoms of a subject having an "other respiratory disease" or "ORD", such a pnemonia, and include, for example, cough (e.g., coughing that lasts three or more weeks, coughing up blood or sputum, chest pain, or pain with breathing or coughing), unintentional weight loss, fatigue, fever, night sweats, chills, and/or loss of appetite.

Methods to diagnose a subject as having active and/or latent TB are known in the art. The primary screening method for TB infection (active or latent) is the Mantoux tuberculin skin test with purified protein derivative (PPD). An in vitro blood test based on interferon- gamma release assay (IGRA) with antigens specific for M. tuberculosis can also be used to screen for latent TB infection. Chest X-rays and culturing of sputum samples may also be used.

A subject having latent TB usually has a skin test or blood test result indicating TB infection; has a normal chest x-ray and a negative sputum test; has TB bacteria in his/her body that are alive, but inactive; does not feel sick (e.g. does not have a cough and/or fever); and cannot spread TB bacteria to others. A subject having active TB ususally has a positive skin test or tuberculosis blood test, may have an abnormal chest x-ray, or positive sputum smear or culture; has overt indications of illness (e.g., cough and/or fever), and can spread the disease to others. A "level of a marker" or "the level of a biomarker" refers to an amount of a marker present in a sample being tested. A level of a marker may be either in absolute level or amount (e.g., μg/ml) or a relative level or amount (e.g., relative intensity of signals).

A "higher level" or an "increase in the level" of marker refers to a level of a marker in a test sample that is greater than the standard error of the assay employed to assess the level of the marker, and is preferably at least twice, and more preferably three, four, five, six, seven, eight, nine, or ten or more times the level of marker in a control sample (e.g. , a sample from a subject who is not infected with TB, a subject who has been exposed to TB but is asymptomatic, a subject having active TB, a subject having an ORD, and/or the average level of the marker in several control samples).

A "lower level" or a "decrease in the level" of a marker refers to a level of the marker in a test sample that is less than the standard error of the assay employed to assess the level of the marker, and preferably at least twice, and more preferably three, four, five, six, seven, eight, nine, or ten or more times less than the level of the marker in a control sample (e.g. , a sample from a subject who is not infected with TB, a subject who has been exposed to TB but is asymptomatic, a subject having active TB, a subject having an ORD, and/or the average level of the marker in several control samples).

The term "known standard level" or "control level" refers to an accepted or predetermined level of a marker which is used to compare the level of the marker in a sample derived from a subject. In one embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) who is not infected with TB. In one embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) who has been exposed to TB, but is asymptomatic (does not present any TB symptoms). In one embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) who converted to latent infection 3 months after a sample was collected. In one embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having active TB. In one embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having latent TB. In another embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having an ORD. In one embodiment, the control level of a marker in a sample from a subject is a level of the marker previously determined in a sample(s) from the subject. In yet another embodiment, the control level of a marker is based on the level of the marker in a sample from a subject(s) prior to the administration of a therapy for TB. In another embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having latent TB that is not contacted with a test compound. In another embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having active TB that is not contacted with a test compound. In another embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having latent TB that is contacted with a test compound. In another embodiment, the control level of a marker is based on the level of the marker in a sample(s) from a subject(s) having active TB that is contacted with a test compound. In one embodiment, the control level of a marker is based on the expression level of the marker in a sample(s) from an animal model of TB, a cell, or a cell line derived from the animal model of TB.

Alternatively, and particularly as further information becomes available as a result of routine performance of the methods described herein, population-average values for "control" level of expression of a marker may be used. In other embodiments, the "control" level of a marker may be determined by determining the level of a marker in a subject sample obtained from a subject before the onset of latent TB, from archived subject samples, and the like.

As used herein, the terms "patient" or "subject" refer to human and non-human animals, e.g., veterinary patients. The term "non-human animal" includes all vertebrates, e.g. , mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dog, cat, horse, cow, chickens, amphibians, and reptiles. In one embodiment, the subject is a human, e.g., a pediatric and adult human.

The term "sample" as used herein refers to a collection of similar cells or tissue isolated from a subject, as well as tissues, cells and fluids present within a subject. The term "sample" includes any body fluid (e.g., blood fluids, lymph, gynecological fluids, cystic fluid, urine, ocular fluids and fluids collected by bronchial lavage and/or peritoneal rinsing), or a cell from a subject. In one embodiment, the tissue or cell is removed from the subject. In another embodiment, the tissue or cell is present within the subject. Other subject samples include tear drops, serum, cerebrospinal fluid, feces, sputum and cell extracts. In one embodiment the sample is a blood sample. In another embodiment, the sample is a serum sample. In one embodiment, the biological sample contains protein molecules from the test subject. In another embodiment, the biological sample may contain mRNA molecules from the test subject or genomic DNA molecules from the test subject.

The term "determining" means methods which include detecting the presence or absence of marker(s) in the sample, quantifying the amount of marker(s) in the sample, and/or qualifying the type of biomarker. Measuring can be accomplished by methods known in the art and those further described herein.

As used herein, the various forms of the term "modulate" are intended to include stimulation (e.g. , increasing or upregulating a particular response or activity) and inhibition (e.g. , decreasing or downregulating a particular response or activity).

A kit is any manufacture (e.g. a package or container) comprising at least one reagent, e.g. a probe, a primer, or an antibody, for specifically detecting a marker of the invention, the manufacture being promoted, distributed, or sold as a unit for performing the methods of the present invention. In certain embodiments, a kit may include a substrate, e.g., a substrate comprising a capture reagent for one or more markers of the invention and/or a capture reagent bound to one or more markers of the invention. In some embodiments, such kits comprise instructions for determining the level of a marker(s) using mass spectrometry. II. Markers of the Invention

The present invention is based upon the discovery of markers that are essentially specifically expressed in samples from subjects having latent tuberculosis (TB) (Table 1).

These markers have been shown to be differentially present in samples of subjects exposed to

TB having latent TB and control subjects.

Accordingly, the level of any one marker or any combination of markers listed in

Table 1 and found in a test sample compared to a control, or the presence or absence of one marker or combination of markers listed in Table 1 in the test sample may be used in the methods and kits of the present invention.

The nucleotide and amino acid sequences of the markers are known in the art and may be found in, for example, the GenBank Accession numbers listed in Table 1, the entire contents of which are incorporated herein by reference.

Table 1. Markers of the Invention.

NP_001193976.1

NP_647537.1

NP_647538.1

ATRN Attractin precursor ATRN_HUMAN 075882

NM_001207047.1

NM_139321.2

NM_139322.2

Transforming growth NP_000349.1

TGFBI factor-beta-induced BGH3_HUMAN Q15582

protein ig-h3 precursor NM_000358.2

NP_000051.1

BTD Biotinidase precursor BTD_HUMAN P43251

NM_000060.2

NP_004235.4

Scavenger receptor

C163A_HUMA NP_981961.2

CD 163 cysteine-rich type 1 Q86VB7

N

protein Ml 30 precursor NM_004244.5

NM_203416.3

Voltage-dependent

NP_000713.2

CACNA2D calcium channel subunit CA2D1_HUMA

P54289

1 alpha-2/delta-l N

NM_000722.2 precursor

CADH5_HUMA NP_001786.2

CDH5 Cadherin-5 precursor P33151

N NM_001795.3

NP_001122301.1 NP_001122302.1 NP_001122303.1 NP_001158302.1 NP_001729.1

CA1 Carbonic anhydrase 1 CAH1_HUMAN P00915

NM_001128829.2 NM_001128830.2 NM .001128831.2 NM_001164830.1 NM_001738.3

NP_000058.1

CA2 Carbonic anhydrase 2 CAH2_HUMAN P00918

NM_000067.2

Carboxypeptidase B2 CBPB2_HUMA NP_001863.2

CPB2 Q96IY4

precursor N NM_001872.3

Carboxypeptidase N NP_001299.1

CPN1 CB PN_HUM AN P15169

catalytic chain precursor NM_001308.2

NP_000582.1 NP_001035110.1 NP_001167575.1

Monocyte

NP_001167576.1

CD14 differentiation antigen CD14_HUMAN P08571

CD 14 precursor NM_000591.3

NM_001040021.2 NM_001174104.1 NM_001174105.1 NP_000046.1

BCHE Cholinesterase precursor CHLE_HUMAN P06276

NM_000055.2

NP_001822.3

CLU Clusterin precursor CLUS_HUMAN P10909

NM_001831.3

Beta-Ala-His CNDP1_HUMA NP_116038.4

CNDP1 Q96KN2

dipeptidase precursor N NM_032649.5

NP_001242992.1

NP_001242993.1

NP_001834.2

CNTN1_HUMA NP_778203.1

CNTN1 Contactin-1 precursor Q12860

N NM_001256063.1

NM_001256064.1 NM_001843.3 NM_175038.2

Cartilage oligomeric NP_000086.2

COMP COMP_HUMAN P49747

matrix protein precursor NM_000095.2

Carboxypeptidase N NP_001073982.2

CPN2 CPN2_HUMAN P22792

subunit 2 precursor NM_001080513.2

Dopamine beta- NP_000778.3

DBH DOPO_HUMAN P09172

hydroxylase NM_000787.3

NP_001189787.1

NP_004416.2

Extracellular matrix NP_073155.2

ECM1 ECM1_HUMAN Q16610

protein 1 precursor NM_001202858.1

NM_004425.3 NM_022664.2

NP_003656.2

NP_775628.1

FCN3 Ficolin-3 precursor FCN3_HUMAN 075636

NM_003665.2

NM_173452.1

Platelet glycoprotein lb GP1BA_HUMA NP_000164.5

GP1BA P07359

alpha chain precursor N NM_000173.5

Platelet glycoprotein V NP_004479.1

GP5 GPV_HUMAN P40197

precursor NM_004488.2

Glutathione peroxidase NP_002075.2

GPX3 GPX3_HUMAN P22352

3 precursor NM_002084.3

NP_001171131.1

Hyaluronan-binding HABP2_HUMA NP_004123.1

HABP2 Q14520

protein 2 precursor N NM_001177660.1

NM_004132.3

Hepatocyte growth NP_001519.1

HGFAC factor activator HGFA_HUMAN Q04756

precursor NM_001528.2

Hepatocyte growth NP_066278.3

MST1 factor-like protein HGFL_HUMAN P26927

precursor NM_020998.3 NP_001124463.1

Hypoxia up-regulated HY0U1_HUMA NP_006380.1

HYOU1 Q9Y4L1

protein 1 precursor N NM_001130991.1

NM_006389.3

NP_000589.2

Insulin-like growth NP_001013416.1

IGFBP3 factor-binding protein 3 IBP3_HUMAN P17936

precursor NM_000598.4

NM_001013398.1

Insulin-like growth NP_002169.1

IGFBP6 factor-binding protein 6 IBP6_HUMAN P24592

precursor NM_002178.2

NP_000603.1

Insulin-like growth NP_001007140.2

IGF2 IGF2_HUMAN P01344

factor II precursor NM_000612.4

NM_001007139.4

KCRM_HUMA NP_001815.2

CKM Creatine kinase M-type P06732

N NM_001824.4

Phosphatidylcholine- NP_000220.1

LCAT sterol acyltransferase LCAT_HUMAN P04180

precursor NM_000229.1

Galectin-3 -binding LG3BP_HUMA NP_005558.1

LGALS3BP Q08380

protein precursor N NM_005567.3

NP_002336.1

LUM Lumican precursor LUM_HUMAN P51884

NM_002345.3

L Y AM 1 _HUM A NP_000646.2

SELL L-selectin precursor P14151

N NM_000655.4

Mannosyl- NP_005898.2

MA1A1_HUMA

MAN1A1 oligosaccharide 1,2- P33908

N

alpha-mannosidase IA NM_005907.3

NP_001027019.1 NP_001870.3

Mannan-binding lectin

MASP1_HUMA NP_624302.1

MASP1 serine protease 1 P48740

N

precursor NM_001031849.2

NM_001879.5 NM_139125.3

NP_006601.2

Mannan-binding lectin

MASP2_HUMA NP_631947.1

MASP2 serine protease 2 000187

N

precursor NM_006610.3

NM_139208.2

NP_001171588.1 NP_001171589.1

Multiple inositol

MINP1_HUMA NP_004888.2

MINPP1 polyphosphate Q9UNW1

N

phosphatase 1 precursor NM_001178117.1

NM_001178118.1 NM_004897.4 NP_000606.3

NP_001070150.1 NP_001229537.1

Neural cell adhesion NCAM1_HUMA NP_851996.2

NCAM1 P13591

molecule 1 precursor N NM_000615.6

NM_001076682.3 NM_001242608.1 NM_181351.4

NP_002499.2

NIDI Nidogen-1 precursor NID1_HUMAN P14543

NM_002508.2

Proprotein convertase NP_777596.2

PCSK9_HUMA

PCSK9 subtilisin/kexin type 9 Q8NBP7

N

precursor NM_174936.3

PDZ and LIM domain NP_066272.1

PDLIM1 PDLI 1 _HUM AN 000151

protein 1 NM_020992.3

NP_000276.2 NP_001159528.1 NP_001159529.1

PEPD Xaa-Pro dipeptidase PEPD_HUMAN P12955

NM_000285.3 NM_001166056.1 NM_001166057.1

N-acetylmuramoyl-L-

PGRP2_HUMA NP_443122.3

PGLYRP2 alanine amidase Q96PD5

N

precursor NM_052890.3

Phosphatidylinositol- NP_001494.2 glycan-specific

GPLD1 PHLD_HUMAN P80108

phospholipase D NM_001503.3 precursor

NP_002289.2

LCP1 Plastin-2 PLSL_HUMAN P13796

NM_002298.4

Serum NP_000437.3

PON1 paraoxonase/arylesterase P0N1_HUMAN P27169

1 NM_000446.5

NP_005800.3

PRDX2_HUMA NP_859428.1

PRDX2 Peroxiredoxin-2 P32119

N NM_005809.4

NM_181738.1

NP_001121180.1 NP_001121181.1 NP_001121182.1

Proteoglycan 4 NP_005798.2

PRG4 PRG4_HUMAN Q92954

precursor NM_001127708.1

NM_001127709.1 NM_001127710.1 NM_005807.3

PR0F1_HUMA NP_005013.1

PFN1 Profilin-1 P07737

N NM_005022.3 Vitamin K-dependent NP_000304.2

PROS1 PROS_HUMAN P07225

protein S precursor NM_000313.3

Prostaglandin-H2 D- PTGDS_HUMA NP_000945.3

PTGDS P41222

isomerase precursor N NM_000954.5

Receptor-type tyrosine-

PTPRG_HUMA NP_002832.3

PTPRG protein phosphatase P23470

N

gamma precursor NM_002841.3

NP_001004128.1

Sulfhydryl oxidase 1 QSOXl_HUMA NP_002817.2

QSOX1 000391

precursor N NM_001004128.2

NM_002826.4

NP_002955.2

S100A8 Protein S100-A8 S10A8_HUMAN P05109

NM_002964.4

NP_002956.1

S100A9 Protein S 100- A9 S10A9_HUMAN P06702

NM_002965.3

NP_001078955.1

Selenoprotein P NP_005401.3

SEPP1 SEPP1_HUMAN P49908

precursor NM_001085486.1

NM_005410.2

NP_001031.2

NP_001139752.1

Sex hormone-binding NP_001139753.1

SHBG SHBG_HUMAN P04278

globulin precursor NM_001040.3

NM_001146280.1 NM_001146281.1

Secreted phosphoprotein NP_008875.1

SPP2 SPP24_HUMAN Q13103

24 precursor NM_006944.2

TAGL2_HUMA NP_003555.1

TAGLN2 Transgelin-2 P37802

N NM_003564.1

NP_061978.6

NP_115859.2

TNXB Tenascin-X precursor TENX_HUMAN P22105

NM_019105.6

NM_032470.3

NP_003269.2

CLEC3B Tetranectin precursor TETN_HUMAN P05452

NM_003278.2

NP_006280.3

TLN1 Talin-1 TLN1_HUMAN Q9Y490

NM_006289.3

Thrombospondin- 1 NP_003237.2

THBS1 TSP1_HUMAN P07996

precursor NM_003246.2

NP_612449.2

VASN Vasorin precursor VASN_HUMAN Q6EMK4

NM_138440.2 NP_001069.1

NP_001186763.1

Vascular cell adhesion VCAM1_HUMA NP_542413.1

VCAM1 P19320

protein 1 precursor N NM_001078.3

NM_001199834.1 NM_080682.2

NP_000629.3

VTN Vitronectin precursor VTNC_HUMAN P04004

NM_000638.3 von Willebrand factor NP_000543.2

VWF VWF_HUMAN P04275

precursor NM_000552.3

In one embodiment, the one or more additional markers is selected from the group consisting of CLEC3B, ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1.

In certain aspects of the invention, a single marker (e.g., any one of the markers listed in Table 1) may be used in the methods and compositions of the invention. In one

embodiment, the one or more markers is selected from the group consisting of CLEC3B, ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, TLN1, PRG4, CAl, SHBG, CPNl, CPN2, QSOXl, PRDX2, APOAl, CA2, LPA, TAGLN2, GPX3, MSTl, CNDPl, ATRN, PFNl, PEPD, VASN, BTD, CPB2, GPLDl, DBH, HGFAC, CDH5, LRG1, MASP1, PGLYRP2, TNXB, CD14, CKM, APOE, MAN1A1, PROS 1, S 100A8,

S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1, LGALS3BP, PTGDS, APOC3, MINPPl, SEPPl, APOA4, MASP2, HYOUl,

IGF2, GPIBA, CACNA2D1, CNTN1, NIDI, COMP, PCSK9, LCP1 and APOC1.

In one embodiment, the marker is selected from the group consisting of CLEC3B,

ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and

TLN1.

In some embodiments, the methods may further comprise determining the level of a marker selected from the group consisting of the markers listed in Table 1. In other

embodiments, the methods may further comprise determining the level of one or more markers selected from the group consisting of CLEC3B, ECM1, PON1, VTN, IGFALS,

IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, TLN1, PRG4, CAl, SHBG, CPNl, CPN2, QSOXl, PRDX2, APOAl, CA2, LPA, TAGLN2, GPX3, MSTl, CNDPl, ATRN, PFNl, PEPD, VASN, BTD, CPB2, GPLDl, DBH, HGFAC, CDH5, LRG1, MASP1,

PGLYRP2, TNXB, CD14, CKM, APOE, MAN1A1, PROS 1, S 100A8, S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1,

LGALS3BP, PTGDS, APOC3, MINPPl, SEPPl, APOA4, MASP2, HYOUl, IGF2, GPIBA, CACNA2D1, CNTN1, NID I, COMP, PCSK9, LCP1 and APOC1

In other aspects of the invention, more than one marker, e.g., a plurality of markers, e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or more markers, may be used in the methods and compositions of the invention. In one embodiment, the combination of the plurality of the markers has an area under the curve (AUC) of about 0.85 to about 1.0. For example, in one embodiment, the combination of markers suitable for use in the methods and compositions of the invention include one of the combination of markers set forth in Table 2. In another embodiment, the combination of markers suitable for use in the methods and compositions of the invention include one of the combination of markers set forth in Table 3. In another embodiment, the combination of markers suitable for use in the methods and compositions of the invention include one of the combination of markers set forth in Table 4. In another embodiment, the combination of markers suitable for use in the methods and compositions of the invention include one of the combination of markers set forth in Table 5.

In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B and ECMl. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl and PON1. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and IGFALS. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and IGFBP3. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and CLU. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and VWF. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and SPP2. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and SELL. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and LUM. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and NCAM1. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and TLN1. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl and VTN. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and IGFALS. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and IGFBP3. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and CLU. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and VWF. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and SPP2. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and SELL. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and LUM. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and NCAMl . In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, VTN, and TLNl . In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, PON1, and VTN. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and IGFALS. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and IGFB3. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and CLU. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and VWF. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and SPP2. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and SELL. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and LUM. In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and NCAMl . In one embodiment, the markers for use in the methods and compositions of the invention include CLEC3B, ECMl, and TLNl . In one embodiment, the combination of the markers has an area under the curve (AUC) of about 0.85 to about 1.0.

In some embodiments, the methods may further comprise determining the level of a marker selected from the group consisting of the markers listed in Table 1. In other embodiments, the methods may further comprise determining the level of one or more markers selected from the group consisting of CLEC3B, ECMl, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAMl, TLNl, PRG4, CA1, SHBG, CPN1, CPN2, QSOX1, PRDX2, APOA1, CA2, LPA, TAGLN2, GPX3, MST1, CNDP1, ATRN, PFN1, PEPD, VASN, BTD, CPB2, GPLD1, DBH, HGFAC, CDH5, LRG1, MASP1, PGLYRP2, TNXB, CD14, CKM, APOE, MAN1A1, PROS 1, S 100A8, S 100A9, HABP2, BCHE, LCAT, PDLIM1, FCN3, ORM1, TGFBI, THBS 1, GP5, CD163, VCAM1,

LGALS3BP, PTGDS, APOC3, MINPPl, SEPPl, APOA4, MASP2, HYOUl, IGF2, GPIBA, CACNA2D1, CNTN1, NID I, COMP, PCSK9, LCP1 and APOC1.

III. Methods of the Invention

A. Diagnostic Methods

In certain aspects, the present invention provides diagnostic methods. For example, in one aspect, the present invention provides methods for determining whether a subject exposed to TB will develop latent tuberculosis (TB). The methods include determining the level of one or more markers of the invention in a sample(s) from the subject with a level of the one or more markers in a control sample(s). A difference in the level (e.g., higher or lower) of the one or more markers in the sample(s) from the subject as compared to the level of the one or more markers in the control sample indicates that the subject will develop latent TB.

The methods of the present invention can be practiced in conjunction with any other method(s) used by the skilled practitioner to diagnose, prognose, and/or monitor TB. For example, the methods of the invention may be performed in conjunction with any clinical measurement of TB known in the art including serological, cytological and/or detection (and quantification, if appropriate) of other molecular markers.

In any of the methods (and kits) of the invention, the level of a marker(s) of the invention in a sample obtained from a subject may be determined by any of a wide variety of well-known techniques and methods, which transform a marker of the invention within the sample into a moiety that can be detected and quantified. Non-limiting examples of such methods include analyzing the sample using immunological methods for detection of proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods, immunoblotting, Western blotting, Northern blotting, electron microscopy, mass spectrometry, e.g., MALDI-TOF and SELDI-TOF, immunoprecipitations, immunofluorescence, immunohistochemistry, enzyme linked immunosorbent assays

(ELISAs), e.g., amplified ELISA, quantitative blood based assays, e.g., serum ELISA, quantitative urine based assays, flow cytometry, Southern hybridizations, array analysis, and the like, and combinations or sub-combinations thereof.

For example, an mRNA sample may be obtained from the sample from the subject (e.g., blood, serum, bronchial lavage, mouth swab, biopsy, or peripheral blood mononuclear cells, by standard methods) and expression of mRNA(s) encoding a marker of the invention in the sample may be detected and/or determined using standard molecular biology techniques, such as PCR analysis. A preferred method of PCR analysis is reverse

transcriptase-polymerase chain reaction (RT-PCR). Other suitable systems for mRNA sample analysis include microarray analysis (e.g., using Affymetrix's microarray system or Illumina's BeadArray Technology).

It will be readily understood by the ordinarily skilled artisan that essentially any technical means established in the art for detecting the level a marker of the invention at either the nucleic acid or protein level, can be used to determine the level a marker of the invention as discussed herein.

In one embodiment, the level of a marker of the invention in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g., mRNA, or cDNA, of a marker of the invention gene. RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays (Melton et al., Nuc. Acids Res. 12:7035), Northern blotting, in situ hybridization, and microarray analysis.

In one embodiment, the level of a marker of the invention is determined using a nucleic acid probe. The term "probe", as used herein, refers to any molecule that is capable of selectively binding to a specific marker of the invention. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules.

Isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction (PCR) analyses and probe arrays. One method for the determination of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to a marker mRNA. The nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 250 or about 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to marker genomic DNA.

In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in determining the level of a marker of the invention mRNA.

An alternative method for determining the level of a marker of the invention in a sample involves the process of nucleic acid amplification and/or reverse transcriptase (to prepare cDNA) of for example mRNA in the sample, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189-193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio/Technology 6: 1197), rolling circle replication (Lizardi et al., U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the invention, the level of expression of a marker of the invention is determined by quantitative fluorogenic RT-PCR (i.e., the TaqMan™ System). Such methods typically utilize pairs of oligonucleotide primers that are specific for a marker of the invention. Methods for designing oligonucleotide primers specific for a known sequence are well known in the art.

The level of a marker of the invention mRNA may be monitored using a membrane blot (such as used in hybridization analysis such as Northern, Southern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677, 195 and 5,445,934, which are incorporated herein by reference. The determination of a level of a marker of the invention may also comprise using nucleic acid probes in solution.

In one embodiment of the invention, microarrays are used to detect the level of a marker of the invention. Microarrays are particularly well suited for this purpose because of the reproducibility between different experiments. DNA microarrays provide one method for the simultaneous measurement of the levels of large numbers of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning.

Hybridization intensities for each probe on the array are determined and converted to a quantitative value representing relative gene expression levels. See, e.g., U.S. Pat. Nos.

6,040, 138, 5,800,992 and 6,020, 135, 6,033,860, and 6,344,316, which are incorporated herein by reference. High-density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of RNA's in a sample.

In certain situations it may be possible to assay for the level of a marker of the invention at the protein level, using a detection reagent that detects the protein product encoded by the mRNA of a marker of the invention. For example, if an antibody reagent is available that binds specifically to a marker of the invention protein product to be detected, and not to other proteins, then such an antibody reagent can be used to detect the expression of a marker of the invention in a cellular sample from the subject, or a preparation derived from the cellular sample, using standard antibody-based techniques known in the art, such as FACS analysis, and the like.

Other known methods for detecting a marker of the invention at the protein level include methods such as electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitin reactions, immunodiffusion (single or double), Immunoelectrophoresis, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, and Western blotting.

Proteins from samples can be isolated using techniques that are well known to those of skill in the art. The protein isolation methods employed can, for example, be those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York). In one embodiment, antibodies, or antibody fragments, are used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins.

Antibodies for determining the expression of a marker of the invention are commercially available and one of ordinary skill in the art can readily identify appropriate antibodies for use in the methods of the invention.

It is generally preferable to immobilize either the antibody or proteins on a solid support for Western blots and immunofluorescence techniques. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

One skilled in the art will know many other suitable carriers for binding antibody or antigen, and will be able to adapt such support for use with the present invention. For example, protein isolated from cells can be run on a polyacrylamide gel electrophoresis and immobilized onto a solid phase support such as nitrocellulose. The support can then be washed with suitable buffers followed by treatment with the detectably labeled antibody. The solid phase support can then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on the solid support can then be detected by

conventional means. Means of detecting proteins using electrophoretic techniques are well known to those of skill in the art (see generally, R. Scopes (1982) Protein Purification, Springer- Verlag, N.Y.; Deutscher, (1990) Methods in Enzymology Vol. 182: Guide to Protein Purification, Academic Press, Inc., N.Y.).

Other standard methods include immunoassay techniques which are well known to one of ordinary skill in the art and may be found in Principles And Practice Of Immunoassay, 2nd Edition, Price and Newman, eds., MacMillan (1997) and Antibodies, A Laboratory Manual, Harlow and Lane, eds., Cold Spring Harbor Laboratory, Ch. 9 (1988), each of which is incorporated herein by reference in its entirety.

Antibodies used in immunoassays to determine the level of a marker of the invention, may be labeled with a detectable label. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling {i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.

In one embodiment, the antibody is labeled, e.g. a radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody. In another embodiment, an antibody derivative {e.g. an antibody conjugated with a substrate or with the protein or ligand of a protein-ligand pair { e.g. biotin- streptavidin}), or an antibody fragment {e.g. a single- chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically with a marker of the invention.

In one embodiment of the invention, proteomic methods, e.g., mass spectrometry, are used to determine the level of a marker of the invention. Mass spectrometry is an analytical technique that consists of ionizing chemical compounds to generate charged molecules (or fragments thereof) and measuring their mass-to-charge ratios. In a typical mass spectrometry procedure, a sample is obtained from a subject, loaded onto the mass spectrometry, and its components (e.g., a marker of the invention) are ionized by different methods (e.g., by impacting them with an electron beam), resulting in the formation of charged particles (ions). The mass-to-charge ratio of the particles is then calculated from the motion of the ions as they transit through electromagnetic fields.

For example, matrix-associated laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or surface-enhanced laser desorption/ionization time-of- flight mass spectrometry (SELDI-TOF MS) which involves the application of a biological sample, such as serum, to a protein-binding chip (Wright, G.L., Jr., et al. (2002) Expert Rev Mol Diagn 2:549; Li, J., et al. (2002) Clin Chem 48: 1296; Laronga, C, et al. (2003) Dis Markers 19:229; Petricoin, E.F., et al. (2002) 359:572; Adam, B.L., et al. (2002) Cancer Res 62:3609; Tolson, J., et al. (2004) Lab Invest 84:845; Xiao, Z., et al. (2001) Cancer Res 61:6029) can be used to determine the level of a marker of the invention.

Furthermore, in vivo techniques for determination of the level of a marker of the invention include introducing into a subject a labeled antibody directed against a marker of the invention, which binds to and transforms a marker of the invention into a detectable molecule. As discussed above, the presence, level, or even location of the detectable marker of the invention in a subject may be detected determined by standard imaging techniques.

In general, it is preferable that the difference between the level of a marker of the invention in a sample from a subject and the amount of a marker of the invention in a control sample, is as great as possible. Although this difference can be as small as the limit of detection of the method for determining the level of a marker it is preferred that the difference be at least greater than the standard error of the assessment method, and preferably a difference of at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 100-, 500-, 1000-fold or greater than the standard error of the assessment method.

B. Methods for Monitoring the Effectiveness of a Treatment

The present invention also provides methods for monitoring the effectiveness of a therapy or treatment regimen or any other therapeutic approach useful for treating a subject having latent TB and/or inhibiting the progression of TB to disseminated TB (or a

complication associated with disseminated TB (e.g., spinal and kidney meningitis, peritonitis, pericarditis, bone and joint complications, fallopian tube infection, bowel infection, Adult respiratory distress syndrome (ARDS), liver inflammation, lung failure, and/or relapse of the disease) in a subject having TB.

In these methods the level of one or more markers of the invention in a pair of samples (a first sample not subjected to the treatment regimen and a second sample subjected to at least a portion of the treatment regimen) is assessed. A modulation in the level of expression of the one or more markers in the first sample, relative to the second sample, is an indication that the therapy is effective for treating a subject having latent TB and/or inhibiting the progression of TB to disseminated TB (or a complication associated with disseminated TB (e.g., spinal and kidney meningitis, peritonitis, pericarditis, bone and joint complications, fallopian tube infection, bowel infection, Adult respiratory distress syndrome (ARDS), liver inflammation, lung failure, and/or relapse of the disease) in a subject having TB.

C. Treatment Methods

The present invention also provides methods for treating a subject having latent TB and methods for reducing or inhibiting the development of complications associated with the disease in a subject

The methods of "inhibiting", "slowing", and/or "treating" include administration of a therapeutic agent to a subject in order to cure or to prolong the health or survival of a subject beyond that expected in the absence of such treatment.

The terms "patient" or "subject" as used herein is intended to include human and veterinary patients. In a particular embodiment, the subject is a human. The term "non- human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non- human primates, mice, rabbits, sheep, dog, cow, chickens, amphibians, and reptiles.

The methods of the invention include administering to the subject one or more "standard" therapies. For example, the therapeutic agents include cytotoxins,

immunosuppressive agents, radiotoxic agents, and/or therapeutic antibodies. Particular co- therapeutics contemplated by the present invention include, but are not limited to, Isoniazid, Rifampin (Rifadin, Rimactane), Ethambutol (Myambutol), Pyrazinamide, streptomycin, vitamin D, Clarithromycin, Dapsone, Ofloxacin, Rifabutin, Non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., efavirenz (Sustiva), etravirine (Intelence) and nevirapine (Viramune, Nucleoside reverse transcriptase inhibitors (NRTIs; e.g., Abacavir (Ziagen), and the combination drugs emtricitabine and tenofovir (Truvada), and lamivudine and zidovudine (Combivir), Protease inhibitors (Pis; e.g., atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva) and ritonavir (Norvir), Entry or fusion inhibitors, e.g., enfuvirtide (Fuzeon) and maraviroc (Selzentry), and Integrase inhibitors, e.g., Raltegravir (Isentress), or combinations thereof.

The methods of the invention also contemplate the use of therapeutic agents in combination with other therapies, including life- style changes. In some embodiments, two or more therapeutic agents are applied to a subject. Two or more therapeutic agents can be administered in the same formulation or separately. In the case of separate administration, the therapeutic agents can be administered before, after or concurrently with the co-therapeutic or co-therapy. One agent may precede or follow administration of the other agent by intervals ranging from minutes to weeks. In

embodiments where two or more different kinds of therapeutic agents are applied separately to a subject, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that these different kinds of agents would still be able to exert an advantageously combined effect on the target tissues or cells.

The term "effective amount" as used herein, refers to that amount of therapeutic agent(s) which is sufficient to treat and/or inhibit the progression of latent TB and/or a complication of TB in a subject when administered to a subject. An effective amount will vary depending upon the subject and the severity of the disease and age of the subject, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (i.e., side effects) of a therapeutic agent(s) are minimized and/or outweighed by the beneficial effects.

IV. Kits of the Invention

The invention also provides kits for determining whether a subject exposed to TB will develop latent TB. Kits for monitoring the effectiveness of a treatment for latent TB are also provided.

These kits include means for determining the level of one or more markers of the invention and instructions for use of the kit.

The kits of the invention may optionally comprise additional components useful for performing the methods of the invention. By way of example, the kits may comprise reagents for obtaining a biological sample from a subject, a control sample, one or more sample compartments, a diabetic therapeutic, an instructional material which describes performance of a method of the invention and tissue specific controls/standards.

The reagents for determining the level of one or more marker(s) can include, for example, buffers or other reagents for use in an assay for evaluating the level of one or more markers, e.g., expression level (e.g., at either the mRNA or protein level). The instructions can be, for example, printed instructions for performing the assay for evaluating the level of one or more marker(s) of the invention.

The reagents for isolating a biological sample from a subject can comprise one or more reagents that can be used to obtain a fluid or tissue from a subject, such as means for obtaining a saliva or blood. The kits of the invention may further comprise reagents for culturing a sample obtained from a subject.

Preferably, the kits are designed for use with a human subject.

The present invention is further illustrated by the following examples which should not be construed as further limiting. The contents of all references, patents and published patent applications cited throughout this application, as well as the Figures, are expressly incorporated herein by reference in their entirety.

EXAMPLES

EXAMPLE I. Biomarker Identification

Introduction

Approximately one-third of the world's population is latently infected with

Mycobacterium tuberculosis, meaning they do not have symptoms, chest radiographic abnormalities, or other findings of active tuberculosis (TB). People with latent Mtb infection (LTBI) are the primary source of future TB cases, and their identification is important for TB control. Diagnosis of LTBI is based on immunological activity suggesting current or previous infection, commonly measured by either the tuberculin skin test (TST) or interferon gamma release assay (IGRA). Neither test is able to differentiate between LTBI and active TB, nor distinguish recent from remote infection. This is an important distinction since recent infection is a strong risk factor for progression to active TB, and in some high incidence areas, the majority of TB cases are likely due to recent infections from ongoing TB transmission (Chin et al., 1998, Am J Respir Crit Care Med, 158, 1797-803, Verver et al., 2004 Int J Epidemiol, 33, 351-7). Developing a diagnostic assay that identifies recent Mtb infection (LTBI) would allow for targeted treatment of those persons most likely to progress to active TB and is a priority among international TB agencies (Pai and Schito, 2015 J Infect Dis, 211 Suppl 2, S21-8).

Mass spectrometry (MS) coupled with multiple reaction monitoring (MRM-MS) allows for rapid detection and quantification of proteins with high sensitivity and precision (Hunter and Paramithiotis, 2010 Expert Opin Med Diagn, 4, 11-20). Previous studies have used MRM-MS proteomic assays to identify new biomarkers of LTBI by detecting both Mtb (Kruh-Garcia et al., 2014 PLoS One, 9, el03811) and human host proteins in peripheral blood (Sandhu et al., 2012, PLoS One, 7, e38080, Zhang et al., 2014 Diagn Microbiol Infect Dis, 79, 432-7). In these previous cross-sectional studies, LTBI was diagnosed by TST or IGRA, but it was not known when the subject was infected with Mtb (recent vs remote infection). In this study, blood samples from a prospective TB household contact cohort were analyzed using MRM-MS to assess the host-protein proteomic profiles in blood from household contacts who converted from TST-negative to TST-positive. Changes in circulating host- proteins as a person develops LTBI are reported.

Materials and Methods

Study Design and Subjects

The studies described below was designed to identify protein biomarkers associated with early stage TB infection. The studies entailed two parts, a discovery and a verification phase. For both parts, independent serum and plasma samples were collected and evaluated from a household exposure study in Kampala, Uganda. Patients in this study were enrolled in the Kawempe Community Health Study (KCHS), a prospective cohort of adult pulmonary TB index cases and their household contacts, conducted in Kampala, Uganda. Individuals diagnosed with TB and their household members were recruited and followed for a period of 2 years. In this study, index cases were adults (age 18 and older) with initial episodes of newly diagnosed culture-positive pulmonary TB. Household contacts included persons (age 12 years and older) living in the same building as an index case for at least one week during the three-month period immediately preceding the index case diagnosis. After the initial evaluation, participants were evaluated at 3, 6, 12, and 24 months for active TB and with repeat TST if their first and subsequent TST remained negative. All individuals were monitored clinically and if signs and symptoms of TB developed, evaluated as TB suspects. Tuberculin skin testing was done using 5 TU of purified protein derivative (PPD). All subjects were HIV-. A subset of the household members developed TB infection, and a portion of these progressed to active TB. The study was approved by the responsible institutional review boards in Uganda and the U.S. Converters were defined as household contacts, with an initial TST < 10 mm at baseline visit, who subsequently converted their skin test to positive (TST > 10 mm and an increment of 6 mm) during follow-up testing. Subjects that remained TST-negative and did not convert their TST were considered to be persistently not infected (NI) (Ma et al., 2014 BMC Infect Dis, 14, 352). All subjects with a positive TST (at baseline or conversion during follow-up) were offered treatment with isoniazid preventive therapy (IPT) (10 - 20 mg/kg or a maximum dose of 300 mg/day) for 9 months.

TB cases were compared to various controls groups in a case-control design. In the discovery phase, cross-sectional comparisons of biomarker expression were made between individuals that were either non-infected for the period of the study (NI), or had been exposed and will convert to latent infection 3 months after the sample was collected (CO), or had a latent infection at the time of sample collection (LTBI), or had an active infection (ATB) at the time of sample collection. The clinical data of the subjects for the discovery phase is provided in Figure 1.

In the verification phase, two sets of independent cross-sectional and longitudinal samples from the same household exposure study were used to confirm performace of candidate biomarkers identified in the discovery phase in predicting the establishment of latent TB infection. The clinical data of the subjects for the verification phases is also provided in the Figure 1.

Sample processing.

To avoid introducing bias in the sample preparation, the samples were grouped into blocks containing one of each of the groups (if possible). The order of the groups within each block was then randomized.

For the discovery samples, all sera samples were depleted of abundant proteins using affinity chromatography ((an antibody column (IgY14 and Supermix, Sigma)). The remaining lower abundance proteins were digested with trypsin (Promega) prior to analysis by LC-MS. Plasma from the longitudinal verification phase was also depleted of abundant proteins using affinity chromatography and trypsin digestion prior to LC-MS analysis.

Following freeze-drying of the digested samples, they were resolubilized and treated with TCEP (tris(2-carboxyethyl)phosphine) to reduce disulfide bonds. The samples were then desalted by solid phase extraction using a 3M Empore C18 desalting plate and distributed into 96-well plates and vacuum evaporated. Peptides were stored at - 20°C until use.

Tandem mass spectrometry analysis

Freeze dried peptides were resuspended in 92.5/7.5 water/acn +0.2 % formic acid and analyzed using a nanoAcquity pump (Waters) coupled to a Q-TOF mass spectrometer

(Waters). Peptide separation was achieved using a Waters nanoAcquity Symmetry UPLC Trap column (180 μιη x 20 mm, 5 μιη particle size) and a Waters nanoAcquity UPLC BEH300 analytical column (150 μιη x 100 mm, 1.7 μιη particle size). Each sample was loaded on the trapping column for 3 min at a flow rate of 10 μί/ηιίη, and then the gradient was started at a flow rate at 1.8 μΕ/ηιίη. The total run time per sample was 105 min.

Components were detected and matched across all samples using the Elucidator software (Rosetta Biosoftware) and compared for relative peak intensity. All intensity values were log (base e) transformed with values < 0 replaced by 0. Peak intensity was normalized to account for small differences in protein concentration between samples: a subset of the samples was used to create an average sample {i.e. the Reference sample) against which all samples were then normalized. The normalization factors were chosen so that the median of log ratios between each sample and the Reference sample over all the peptides was adjusted to zero. For batch-effect correction, a one-way ANOVA model ¾ = M + Di +8jj (I: intensity, M: overall interception, and D: batch-factor) was solved and parameters Di (i=l,2) under the constraint of∑i ₌₁ (Ni*Di)=0 were obtained; the Di's were then subtracted from the normalized intensities to form the "batch-effect corrected" intensities. Intensities below the limit of detection (LOD=30) were transformed to avoid spurious large fold changes:

intensities in the range of (0, LOD) were linearly mapped to the range of (LOD/2, LOD). A one-way ANOVA analysis was then applied to identify peptides that were differentially expressed between the groups of interest. High stringency thresholds were used to ensure the statistical significance of the identified peptides. Each group was analyzed using the same one-way ANOVA model [=(Montgomery, D. C, Design and Analysis of Experiments, Wiley, 2001 ; Keeping, E.S., Introduction to Statistical Inference, Dover Publication, Inc. 1995): ¾ = M + Ci +8ij where I is the peptide intensity, M is the overall average intensity, C is the 'clinical group' factor, and ε is random error. FDR (false detection rate) and q-value were calculated, based on the p-values obtained from the ANOVA, using Storey' s method (Storey, J.D. (2002) Journal of the Royal Statistical Society 64(3):479-498) to make multiple testing adjustments (implemented in MATLAB)

(mathworks.com/access/helpdesk/help/helpdesk.html; MATLAB for Math Works Inc.).

'Post hoc' contrast analyses were conducted using Tukey' s hsd (Hochberg, Y., and A. C. Tamhane. Multiple Comparison Procedures. John Wiley & Sons, 1987) method to calculate p-values associated with each pair wise comparison. Protein identification was done by analysis of replicate samples by tandem mass spectrometry (LC-MS/MS). A protein level analysis was then applied using an extension of the one-way ANOVA used above in the peptide level analysis, which takes into consideration that one protein may have several peptides, by introducing a 'peptide factor' in the model: Ij _jk = M + Ci + P _j +8ijk where I is the protein intensity, M an overall constant, C the 'clinical group', and P the peptide factor. The number of the levels for P is protein-dependent, equal to the number of children peptides for the protein. These calculations were implemented in MATLAB

(mathworks.com/access/helpdesk/help/helpdesk.html; MATLAB for Math Works Inc.).

Proteins were considered to be differentially expressed if they met the following thresholds: p- and q-values<0.05, and Differential Intensity (DI) superior at 1.1-fold change.

Multiple reaction monitoring mass spectrometry

A multiplex MRM assay was developed for the selected biomarker candidates. The assay contained 392 peptides representing 162 host proteins. Peptides were synthesized by JPT Peptide Technologies (Berlin, Germany). The synthesized peptides were resolubilized in 72/25 water/DMSO, pooled and diluted with water + 0.2 % formic acid to a final

concentration of 2 nmol/mL. Five iL of this solution was analyzed on a QTRAP 5500 mass spectrometer (ABSciex, Canada) using a 320 μιη x 150 mm, 5μιη particle size, Thermo Biobasic C18 column. A linear gradient of 10-40% acetonitrile (0.2% formic acid) in 30 minutes was used for peptide separation. MS/MS spectra of the synthetic peptides were acquired using selected reaction monitoring (SRM) -triggered MS/MS allowing the identification of peptide and peptide fragments (transitions). The two most intense fragment ions (b or y fragment ions only) in the MS/MS spectrum and its elution time were determined for each acquired peptide. The collision energy (CE) was then optimized for each of the chosen transitions. The CE values evaluated were the empirical calculated CE value and the empirical CE value -6, +3 and +6. Independent plasma samples from those used for the discovery study by tandem mass spectrometry were processed as described and the resulting peptides were analyzed by the MRM assay.

Expression analysis of MRM data was performed using R version 2.14.0, platform x86_64-pc-mingw32/x64 (64-bit). The calculation of q-values was done using function "qvalue" from Storey's package "qvalue" version 1.24.0. A limit of quantification (LOQ), defined as an intensity value below which the measure is deemed unreliable, was determined empirically according to the QTRAP 5500 and was set to 10000, pre-normalization. The detection rate (DR), defined for each group that needed to be compared, was defined as the proportion of samples with a raw intensity (i.e. pre normalization) value greater or equal to the LOQ. Transitions for which the DR was below 50% for one of the two groups were excluded from expression analysis. Prior to expression analysis, an outlier and pattern detection analysis was performed. The distribution of sample detection was investigated and a sample was rejected from analysis because of a poor detection rate. The sample intensity average distribution by depletion day was also investigated and three samples were rejected for being too weak. A standard Principal Component Analysis (PCA) was applied to the In intensities in order to visually assess any pattern in the data that are likely to be unrelated to sample condition. Differential intensity ratios (DI) were then calculated for each transition, for two-group comparisons (e.g., Active TB vs Latent TB), as the ratio of the median normalized intensities of each group. Prior to calculating the differential intensity ratios, all intensity values that were below the LOQ quantity in the raw data prior to normalization were replaced by the half-LOQ value. Student' s t-test were applied for the expression analysis Protein-level statistics were also computed by first linearly combining the transitions of a given protein into a single variable and then applying a t-test on it.

Panel definition

Area Under the Curve (AUC) values were computed from bootstrap. Select n samples with replacement (i.e. take a sample at random, then a second - with the first selected sample being possibly selected again, and so on). By design, some samples were left out, called out- of-bag. The selected samples (some more than once) are called the bootstrap samples. Build panel on the bootstrap samples and evaluate on the out-of-bag sample by calculating AUC. This was done 100 times. Reported AUC is the average of the 100 AUC. Each protein was represented by a single transition. Transitions with a DR lower than 80% were filtered-out. Among the remaining transitions, proteins for which the transitions were not trending the same way, based on DI, were filtered-out. The selected transition of a protein was the one with the highest DR. In situation of ties, this transition was selected randomly. Logistic Regression models were built with the proteins (i.e. represented by its selected transition) as explanatory variables. All combinations of proteins from 1 to 4 were systematically fitted into such logistic models. Proteins were then ranked by their propensity to be a good team player. For k from 1 to 4, combinations were ranked by their AUC and for each protein, the mean rank of the combinations they appear in, for a given k, was calculated. Within each k, the protein rank was calculated as the rank of the average rank. The final rank was taken as the weighted average over k of the ranks. The highest ranking of the 4 protein panels were then used as the base for extending panel size to 8 proteins, and the larger panels were evaluated in the same manner as decribed. Results

Peripheral blood specimens previously collected from 172 TB patients and household contacts were used for this study. The clinical characteristics of the subjects are shown in Table 1. The discovery phase was conducted by a cross-sectional analysis of proteomic expressions among baseline samples from 37 index cases with active TB, 8 TST-negative contacts who remained TST-negative and non-infected (NI), 21 TST-negative contacts who later converted their TST at either 3 or 6 months (converters), and 38 TST-positive contacts with LTBI at baseline.

Peptide expression data acquired were log-transformed and normalized for injection order and depletion day. ANOVA analysis was then applied to identify differentially expressed peptides. The average peptide intensity was used to create an intensity value per protein which was z-scored and differential intensity ratios (DI) were calculated.

Two humdred eight-nine proteins were identified to be significantly differentially expressed in any of these comparisons using mass spectrometry (LC-MS)((p <0.05)).

Figures 2A-2D show cross-sectional comparisons of changes in blood protein expression ratios from the baseline samples. The significant changes in Differntial Intensity (DI) (p < 0.05) are shaded in gray as described above. If the DI value is above 1 the level of the protein is upregulated. If the DI value is less than 1, the level of the marker is downregulated.

It was found that when compared to the NI group, the number of differentially expressed proteins increased by the following group order: converters, LTBI, and active TB. The largest absolute differences in protein expression were observed between NI participants and patients with active TB. It was also found differences in protein expression when looking at changes grouped by biological processes. Most protein changes associated with

inflammation, immune response, tissue repair, cellular migration and proliferation were observed in subjects with active TB. Among the LTBI and converter groups, smaller changes were observed in these processes, as well as changes in proteins associated with lipid metabolism and the innate immune response (Figures 2A-2D). The results are consistent with a low level of distinct observable changes in Mtb infection, including very recent infection, exhibited by the baseline TST-negative future converters who were in the process of developing LTBI.

A targeted MRM-MS assay was developed for 159 proteins selected from each comparison in the cross-sectional discovery phase using the following combination of biological and statistical criteria. All of the significantly differentially expressed proteins from the baseline converter vs NI and LTBI vs NI comparisons were selected along with the most differentially expressed proteins from comparisons to active TB. Also included were the significant proteins identified previously in an active TB biomarker study, as provided in U.S. Patent Publication No. 2016/0154005 (incorporated herein in its entirety by reference) and Achkar, et al. (2015 EBioMedicine, 2, 1160-8)). Re-analysis of the discovery samples with the MRM-MS assay confirmed the differential expression observed in the discovery phase. Next, an independent set of 161 longitudinal samples collected from 52 subjects who were initially all TST-negative and either converted to TST-positive (N=37) or remained TST- negative (N=15) were tested with the prioritized candidate biomarkers. The changes in plasma proteins at baseline and at a minimum of 2 additional time points over a 6 month period were calculated.

Figures 3 A and 3B show protein expression change ratios between each individual's baseline TST-negative sample and the longitudinal TST-positive conversion sample or corresponding TST-negative sample. The significant changes (p < 0.05) are shded in gray as described above. As expected, subjects who became TST-positive had a more extensive host response than the subjects that remained TST-negative.

In an analysis of subjects that converted by 3 months, most of the proteins associated with inflammatory, innate and adaptive immune responses were elevated at month 3, when TST conversion was recorded, but returned to baseline levels by month 6. In contrast, most of the proteins associated with cellular movement and tissue repair remained elevated through month 6 (Figures 4 A and 4B). Converters were treated with isoniazid preventive therapy for 9 months after TST conversion, and this may have had an effect on protein expression measured at month 6.

This data was used to define combinations of up to 4 candidate biomarker proteins able to distinguish latent TB from the other clinical groups. 131 proteins from the MRM assay were detected in this second study. A subset of 76 proteins were used to derive panel combinations in order to identify proteins that predict the establishment of latent TB infection (see Tables 2-5).

In verification phase 2, the panel combinations of the 76 proteins were evaluated further using another set of longitudinal samples, collected from subjects from the same household exposure study who had not participated in prior phases of the project. A total of 43 longitudinal samples from 16 subjects were used in this sample set. As demonstrated in Tables 3-5, the data demonstrate that small panel combinations of 13 proteins (CLEC3B, ECM1, PON1, VTN, IGFALS, IGFBP3, CLU, VWF, SPP2, SELL, LUM, NCAM1, and TLN1) predict the establishment of latent infection consistently. Combining the biomarker candidates into panels was a more effective strategy to derive high performing discriminators (see Tables 3-5). A small number of combinations of the biomarkers identified in this study were found to be predictive of latent and active TB infection (Table 7).

Biomarkers predictive of active TB infection (as provided in U.S. Patent Publication No. 2016/0154005 (incorporated herein in its entirety by reference) were evaluated for their ability to predict latent TB infection as well. As provided in Table 6, combinations of two or three of the previously identified active TB biomarkers showed significantly lower AUC values than high performing panel combinations of latent TB biomarkers (see Tables 3-5).

The performance of the candidate biomarkers for latent TB is presented in Tables 8-9 which provide the Differential Intensity (DI) value for each marker comparison. If the DI value is above 1, the level of the protein is upregulated for that particular comparison. If the DI value is less than 1, the level of the marker is downregulated for that particular comparison. Table 8 provides a cross-sectional comparison of DI values for 13 markers in sera from non-infected (NI), TST+ converter (CO), latent TB (LTBI) and active TB groups. Table 9 provides a longitudinal comparison of DI values for 13 markers in plasma from TST- subjects that converted to TST+ during the sampling time course, or TST- subjects that remained TST- during the sampling time course.

These results demonstrate that small panels of biomarkers are able to predict 3-6 months ahead of time the conversion from a TST-negative to a TST-positive state and thus predict the establishment of LTBI.

Table 2. Panel protein.1 protein.2 AUC protein.1 protein.2 AUC Combinations of Two ECM1 LPA 0.79 ECM1 TAGLN2 0.78 Candidate Latent TB PDLIM1 TAGLN2 0.79 CDH5 ECM1 0.78 Biomarkers HABP2 THBS1 0.79 CD14 PON1 0.78

BTD ECM1 0.79 LCP1 PON1 0.78

IGFALS THBS1 0.79 IGFBP3 THBS1 0.78

ECM1 LGALS3BP 0.79 DBH ECM1 0.78

ECM1 VCAM1 0.79 ECM1 HYOU1 0.78

CA2 ECM1 0.79 ECM1 S100A9 0.78

ECM1 IGF2 0.79 ECM1 TLN1 0.78

ECM1 GP1BA 0.79 PON1 TLN1 0.78

ECM1 MASP1 0.79 ECM1 PCSK9 0.78

ECM1 TNXB 0.79 PON1 PRDX2 0.78

ECM1 IGFBP3 0.79 CPN2 ECM1 0.78

ECM1 HABP2 0.79 APOC1 PON1 0.78

CPB2 ECM1 0.79 BTD THBS1 0.78

ECM1 IGFALS 0.79 ORM1 PON1 0.78

ECM1 PGLYRP2 0.79 PON1 NA 0.77

ECM1 SELL 0.79 GP5 PON1 0.77

ECM1 LCP1 0.79 CLEC3B SELL 0.77

APOA4 ECM1 0.79 LCP1 PDLIM1 0.77

ECM1 HGFAC 0.79 PON1 SELL 0.77

ECM1 PFN1 0.79 CA2 PON1 0.77

ECM1 VTN 0.79 ORM1 SELL 0.77

ECM1 LRG1 0.79 LPA PON1 0.77

ECM1 LUM 0.79 PTGDS THBS1 0.77

LCP1 THBS1 0.79 COMP SELL 0.77

CD 163 ECM1 0.79 MASP1 PON1 0.77

APOA1 ECM1 0.79 IGFALS VWF 0.77

APOC3 ECM1 0.79 SELL VWF 0.77

PDLIM1 SELL 0.79 NIDI PON1 0.77

ECM1 VASN 0.79 MAN1A1 PON1 0.77

ECM1 FCN3 0.79 HABP2 PON1 0.77

ECM1 SHBG 0.79 CDH5 PON1 0.77

ECM1 NIDI 0.79 ORM1 THBS1 0.77

ATRN ECM1 0.78 LCP1 NA 0.77

ECM1 PRG4 0.78 PON1 S100A8 0.77

ECM1 PTGDS 0.78 PDLIM1 PFN1 0.77

ECM1 PROS1 0.78 GPX3 PON1 0.77

CD14 ECM1 0.78 PON1 PTGDS 0.77 ECM1 S100A8 0.78 IGFALS PON1 0.77 COMP PON1 0.77 LCAT PON1 0.76 CPN1 SELL 0.75

CD 163 PON1 0.77 ORMl TNXB 0.76 LCP1 PRDX2 0.75

LCP1 VWF 0.77 HABP2 MST1 0.76 CLEC3B HABP2 0.75

PON1 TAGLN2 0.77 APOA1 PON1 0.76 CD14 THBS1 0.75

PFN1 PON1 0.77 CPB2 PON1 0.76 IGFALS SELL 0.75

HABP2 PDLIM1 0.77 HABP2 NA 0.76 BTD ORMl 0.75

CA1 PON1 0.77 PON1 TNXB 0.75 BTD LCP1 0.75

IGFALS NA 0.76 ATRN PON1 0.75 CD14 SELL 0.75

CLEC3B PON1 0.76 ORMl VWF 0.75 BTD CLEC3B 0.75

S100A8 SELL 0.76 LCP1 SELL 0.75 LRG1 THBS1 0.75

PON1 SEPP1 0.76 COMP HABP2 0.75 CA2 LCP1 0.74

PON1 SPP2 0.76 BTD COMP 0.75 IGFALS PDLIM1 0.74

IGF2 PON1 0.76 PGLYRP2 PON1 0.75 PRDX2 SELL 0.74

IGFBP3 PON1 0.76 IGFALS ORMl 0.75 PCSK9 PON1 0.74

CNDP1 PON1 0.76 BTD PON1 0.75 CDH5 THBS1 0.74

NCAM1 PON1 0.76 CACNA2D1 ECM1 0.75 PON1 PROS1 0.74

LGALS3BP PON1 0.76 IGFBP3 ORMl 0.75 IGFBP3 VWF 0.74

APOC3 PON1 0.76 BTD PDLIM1 0.75 ORMl NA 0.74

GP1BA PON1 0.76 LCP1 QSOX1 0.75 CD14 VWF 0.74

PON1 TGFBI 0.76 PON1 S100A9 0.75 LCAT SELL 0.74

SELL NA 0.76 QSOX1 SELL 0.75 HABP2 LCP1 0.74

PEPD PON1 0.76 CLEC3B LCP1 0.75 CD14 PDLIM1 0.74

GPLD1 PON1 0.76 CKM PON1 0.75 APOA4 THBS1 0.74

LRG1 PON1 0.76 THBS1 VTN 0.75 CPN1 LCP1 0.74

APOE PON1 0.76 HGFAC PON1 0.75 MAN1A1 SELL 0.74

BCHE PON1 0.76 MST1 SELL 0.75 CNDPl LCP1 0.74

S100A8 THBS1 0.76 S100A9 SELL 0.75 BTD VWF 0.74

ORM1 PDLIM1 0.76 HABP2 SELL 0.75 LCP1 TGFBI 0.74

PON1 VCAM1 0.76 MINPP1 THBS1 0.75 MASP1 SELL 0.74

PON1 PRG4 0.76 MST1 PON1 0.75 GP1BA SELL 0.74

PON1 QSOX1 0.76 PON1 VASN 0.75 IGFBP3 LCP1 0.74

MASP2 PON1 0.76 LUM PON1 0.75 CKM SELL 0.74

CPN1 PON1 0.76 DBH PON1 0.75 IGFALS LCP1 0.74

FCN3 PON1 0.76 PDLIM1 S100A8 0.75 GPX3 SELL 0.74

APOA4 PON1 0.76 CNDP1 HABP2 0.75 BCHE SELL 0.74

HYOU1 PON1 0.76 LRG1 PDLIM1 0.75 IGFBP3 PDLIM1 0.74

MINPP1 PON1 0.76 HABP2 VWF 0.75 CPN1 PDLIM1 0.74

CLU PON1 0.76 LCAT LCP1 0.75 CD 163 SELL 0.74

CPN2 PON1 0.76 LRG1 SELL 0.75 LCP1 LGALS3BP 0.74

CLU THBS1 0.76 ATRN THBS1 0.75 CPN2 SELL 0.74

PON1 SHBG 0.76 PON1 VTN 0.75 SELL TGFBI 0.74 SELL SPP2 0.74 VTN VWF 0.73 BTD SELL 0.73

LCP1 MASP2 0.74 GPLD1 SELL 0.73 MASP1 VWF 0.73

LCP1 ORMl 0.74 HABP2 TNXB 0.73 IGFBP3 PROS1 0.73

APOC1 LCP1 0.74 CPN1 THBS1 0.73 TNXB VWF 0.73

NIDI SELL 0.74 GPX3 LCP1 0.73 APOC3 HABP2 0.73

CNTN1 ECM1 0.74 ORMl PTGDS 0.73 PDLIM1 VWF 0.73

LRG1 VWF 0.74 APOE LCP1 0.73 HABP2 IGFBP3 0.73

SELL TLN1 0.74 CD14 COMP 0.73 HGFAC LCP1 0.73

BCHE LCP1 0.74 CPB2 LCP1 0.73 LCP1 MASP1 0.73

CA1 SELL 0.73 HABP2 MASP2 0.73 HGFAC SELL 0.73

NCAM1 SELL 0.73 LCP1 LPA 0.73 CA1 IGFALS 0.73

CLU SELL 0.73 CD14 NA 0.73 APOC3 LCP1 0.73

SELL SEPP1 0.73 PRG4 SELL 0.73 LCP1 LUM 0.73

THBS1 TNXB 0.73 CDH5 LCP1 0.73 COMP LCP1 0.73

FCN3 LCP1 0.73 LCP1 NIDI 0.73 HABP2 PCSK9 0.73

CNDP1 SELL 0.73 HABP2 TGFBI 0.73 PGLYRP2 SELL 0.73

HABP2 SEPP1 0.73 LCP1 NCAM1 0.73 GP1BA LCP1 0.73

HABP2 ORMl 0.73 CD14 IGFALS 0.73 ATRN LCP1 0.73

MASP2 SELL 0.73 CD14 LCP1 0.73 LCP1 PTGDS 0.73

CPN2 THBS1 0.73 CLEC3B IGFALS 0.73 HABP2 S100A8 0.73

NCAM1 THBS1 0.73 APOA4 ORMl 0.73 CLU VWF 0.72

LPA SELL 0.73 APOC1 SELL 0.73 APOA4 SELL 0.72

CDH5 SELL 0.73 CLU PDLIM1 0.73 APOE HABP2 0.72

IGFBP3 SELL 0.73 APOC3 SELL 0.73 LUM ORMl 0.72

PEPD SELL 0.73 HABP2 IGFALS 0.73 LCP1 MST1 0.72

HABP2 PRDX2 0.73 IGFALS S100A8 0.73 BTD NA 0.72

CA2 SELL 0.73 IGF2 SELL 0.73 MINPP1 SELL 0.72

SELL VCAM1 0.73 LCP1 PEPD 0.73 CD14 VCAM1 0.72

LCP1 TNXB 0.73 LCP1 SPP2 0.73 HABP2 MAN1A1 0.72

APOE SELL 0.73 CPB2 SELL 0.73 ORMl VTN 0.72

PDLIM1 VTN 0.73 LCP1 S100A8 0.73 MASP1 THBS1 0.72

LPA ORMl 0.73 SELL SHBG 0.73 LCP1 SHBG 0.72

THBS1 VWF 0.73 GP5 SELL 0.73 BTD HABP2 0.72

APOA4 COMP 0.73 CA1 LCP1 0.73 S100A8 VWF 0.72

FCN3 SELL 0.73 CA2 HABP2 0.73 SELL TNXB 0.72

HABP2 QSOX1 0.73 HABP2 LCAT 0.73 APOA4 CLEC3B 0.72

LGALS3BP SELL 0.73 APOA4 VWF 0.73 CPN1 IGFALS 0.72

CD 163 LCP1 0.73 LCP1 PCSK9 0.73 PROS1 SELL 0.72

MASP1 PDLIM1 0.73 IGFALS PRDX2 0.73 IGFALS LRG1 0.72

PDLIM1 PTGDS 0.73 VWF NA 0.73 LCP1 SEPP1 0.72

LCP1 TLN1 0.73 LCP1 MINPP1 0.73 CDH5 ORMl 0.72 CD 163 VWF 0.72 CD 163 IGFALS 0.72 CPN2 VWF 0.71

PTGDS SELL 0.72 HABP2 LRG1 0.72 NCAM1 VWF 0.71

APOA4 PDLIM1 0.72 SELL VASN 0.72 CD 163 THBS1 0.71

COMP TNXB 0.72 HYOU1 SELL 0.72 CPN2 PDLIM1 0.71

SELL VTN 0.72 LCP1 PROS1 0.72 ORM1 S100A8 0.71

DBH SELL 0.72 HABP2 SPP2 0.72 APOA4 S100A8 0.71

PCSK9 SELL 0.72 S100A8 TNXB 0.72 FCN3 IGFALS 0.71

GP5 HABP2 0.72 CD14 TNXB 0.72 PDLIM1 PRG4 0.71

CD 14 HABP2 0.72 MASP1 ORM1 0.72 HYOU1 LCP1 0.71

BTD LRG1 0.72 IGFALS S100A9 0.72 LCP1 TAGLN2 0.71

APOA1 SELL 0.72 HABP2 SHBG 0.72 BTD GP5 0.71

BTD S100A8 0.72 LUM VWF 0.72 GP1BA HABP2 0.71

IGF2 LCP1 0.72 LCP1 VASN 0.72 HABP2 HGFAC 0.71

BCHE THBS1 0.72 CA2 IGFALS 0.72 CD14 MST1 0.71

LUM SELL 0.72 CA1 HABP2 0.72 CD14 LPA 0.71

ATRN ORM1 0.72 CPN1 HABP2 0.72 CA2 ORM1 0.71

CD 14 IGFBP3 0.72 IGF2 ORM1 0.72 DBH LCP1 0.71

GP5 LCP1 0.72 LCP1 PGLYRP2 0.72 APOA4 LCP1 0.71

GPLD1 LCP1 0.72 HABP2 PRG4 0.72 APOE IGFALS 0.71

MASP2 ORM1 0.72 LCP1 MANlAl 0.72 LCP1 LRG1 0.71

APOC1 HABP2 0.72 CD14 LCAT 0.72 IGFALS LPA 0.71

SELL TAGLN2 0.72 CNDP1 ORM1 0.72 ORM1 SPP2 0.71

HYOU1 THBS1 0.72 LCP1 S100A9 0.72 IGFALS PCSK9 0.71

ATRN SELL 0.72 IGFALS LGALS3BP 0.71 IGFALS MASP1 0.71

LCAT ORM1 0.72 HABP2 NCAM1 0.71 COMP ORM1 0.71

BTD PRDX2 0.72 GPX3 HABP2 0.71 BTD S100A9 0.71

CLU LCP1 0.72 CD14 QSOX1 0.71 NCAM1 ORM1 0.71

LCP1 PFN1 0.72 CD 163 HABP2 0.71 FCN3 ORM1 0.71

LCP1 VCAM1 0.72 APOA1 LCP1 0.71 HABP2 VCAM1 0.71

BTD IGFALS 0.72 CDH5 HABP2 0.71 BTD CD14 0.71

ORM1 QSOX1 0.72 S100A9 THBS1 0.71 HABP2 LPA 0.71

PFN1 SELL 0.72 HABP2 TLN1 0.71 LCP1 VTN 0.71

CPB2 HABP2 0.72 FCN3 HABP2 0.71 ORM1 TLN1 0.71

ORM1 PRDX2 0.72 COMP IGFALS 0.71 APOC1 IGFALS 0.71

LCP1 PRG4 0.72 HABP2 MASP1 0.71 APOE ORM1 0.71

MST1 ORM1 0.72 CKM LCP1 0.71 CD14 VTN 0.71

CNTN1 PON1 0.72 CPN1 IGFBP3 0.71 CACNA2D1 PON1 0.71

HABP2 LUM 0.72 IGFBP3 LRG1 0.71 PGLYRP2 VWF 0.71

HABP2 PTGDS 0.72 PTGDS VWF 0.71 PDLIM1 TNXB 0.71

IGFBP3 S100A8 0.72 GP5 IGFALS 0.71 IGFALS TGFBI 0.71

APOA1 HABP2 0.72 LRG1 TNXB 0.71 CPN1 VWF 0.71 HABP2 VASN 0.71 BCHE ORMl 0.70 HABP2 VTN 0.70

IGFALS TNXB 0.71 ATRN IGFALS 0.70 TLN1 VTN 0.70

ORM1 SHBG 0.71 APOC1 ORMl 0.70 PCSK9 VWF 0.70

CNDP1 IGFALS 0.71 LRG1 NA 0.70 APOA1 IGFALS 0.70

ORM1 VCAM1 0.71 CLU ORMl 0.70 APOE CD14 0.70

GPLD1 ORM1 0.71 APOA1 PDLIM1 0.70 CD14 CLEC3B 0.70

HABP2 S100A9 0.71 PTGDS NA 0.70 QSOX1 THBS1 0.70

ORM1 PGLYRP2 0.71 CD14 MASP2 0.70 CDH5 IGFALS 0.70

HABP2 PEPD 0.71 NIDI ORMl 0.70 ORMl PROS1 0.70

APOE VWF 0.71 BTD CA1 0.70 CD14 FCN3 0.70

CA1 ORM1 0.71 IGFALS PROS1 0.70 ORMl S100A9 0.70

CKM ORM1 0.71 ATRN HABP2 0.70 CKM HABP2 0.70

BCHE HABP2 0.71 BTD IGFBP3 0.70 HABP2 PROS1 0.70

IGFALS PTGDS 0.71 CACNA2D1 ORMl 0.70 CPB2 THBS1 0.70

IGFALS SPP2 0.71 VTN NA 0.70 APOC3 IGFALS 0.70

APOA4 PRDX2 0.71 CD14 CNDP1 0.70 LPA LRG1 0.70

MASP1 PTGDS 0.71 BTD FCN3 0.70 BCHE VWF 0.70

APOC3 ORMl 0.71 HABP2 PFN1 0.70 PDLIM1 S100A9 0.70

IGFALS MASP2 0.71 IGFBP3 S100A9 0.70 GPX3 ORMl 0.70

HABP2 LGALS3BP 0.71 IGFALS LUM 0.70 CPN2 ORMl 0.70

LPA MASP1 0.71 ORMl PRG4 0.70 APOC3 VWF 0.70

CPB2 IGFALS 0.71 PROS1 VWF 0.70 IGFALS NIDI 0.70

S100A8 NA 0.71 PRG4 VWF 0.70 APOA1 THBS1 0.70

COMP LUM 0.71 LGALS3BP ORMl 0.70 MAN1A1 ORMl 0.70

HGFAC ORMl 0.71 CD 163 PDLIM1 0.70 APOC3 THBS1 0.70

CPN1 ORMl 0.71 GPLD1 HABP2 0.70 S100A8 VTN 0.70

GP1BA THBS1 0.71 HABP2 NIDI 0.70 BTD CA2 0.70

CLU HABP2 0.71 GP1BA ORMl 0.70 LPA VWF 0.70

HYOU1 VWF 0.71 NIDI THBS1 0.70 MINPP1 ORMl 0.70

CD 14 ORMl 0.71 ORMl PCSK9 0.70 BTD LPA 0.70

BCHE IGFALS 0.71 CDH5 MASP1 0.70 CPB2 ORMl 0.70

IGFALS PEPD 0.71 HABP2 TAGLN2 0.70 APOA4 NA 0.70

HABP2 PGLYRP2 0.71 HABP2 IGF2 0.70 IGFALS SHBG 0.70

CD 163 ORMl 0.71 S100A9 VWF 0.70 APOA4 HABP2 0.70

DBH HABP2 0.71 CPN2 LCP1 0.70 BTD TNXB 0.70

S100A9 TNXB 0.71 GPX3 IGFALS 0.70 IGFALS PRG4 0.70

LUM THBS1 0.71 CDH5 PDLIM1 0.70 DBH ORMl 0.70

CD 14 PTGDS 0.71 ORMl SEPP1 0.70 IGFBP3 NA 0.70

HYOU1 PDLIM1 0.71 BTD QSOX1 0.70 GPX3 PDLIM1 0.70

CLEC3B ORMl 0.70 IGFALS VTN 0.70 NIDI VWF 0.70

APOA4 CD14 0.70 PDLIM1 PGLYRP2 0.70 CLU IGFALS 0.70 VASN VWF 0.70 IGFALS SEPP1 0.69 GPX3 VWF 0.69

CD 163 PTGDS 0.70 PTGDS S100A8 0.69 CD14 MAN1A1 0.69

ORM1 PEPD 0.70 IGFALS QSOX1 0.69 LRG1 VTN 0.69

QSOX1 VWF 0.70 CD14 CPN1 0.69 CD14 MASP1 0.69

CPN2 IGFALS 0.70 CLU IGFBP3 0.69 BTD GP1BA 0.69

BTD CDH5 0.70 BTD CPN1 0.69 BTD NIDI 0.69

GP1BA IGFALS 0.70 BTD PROS1 0.69 BTD SEPP1 0.69

CD 14 CDH5 0.70 GP1BA VWF 0.69 CACNA2D1 SELL 0.69

CDH5 VWF 0.70 ATRN CD14 0.69 PDLIM1 QSOX1 0.69

HABP2 HYOU1 0.70 LUM S100A8 0.69 CD14 GPLD1 0.69

CD 14 S100A8 0.70 APOA4 LPA 0.69 PEPD VWF 0.69

ORM1 TGFBI 0.70 CD14 TLN1 0.69 BTD SHBG 0.69

IGFALS TLN1 0.70 CPN2 IGFBP3 0.69 IGF2 IGFALS 0.69

NCAM1 PDLIM1 0.70 CD14 PCSK9 0.69 CDH5 NA 0.69

CD 14 NIDI 0.70 HYOU1 IGFALS 0.69 GPLD1 VWF 0.69

GP5 ORM1 0.70 APOC3 BTD 0.69 CKM IGFALS 0.69

APOC1 BTD 0.70 APOA4 S100A9 0.69 CD14 PRDX2 0.69

HYOU1 ORM1 0.70 CD14 CPN2 0.69 MAN1A1 PDLIM1 0.69

ORM1 PFN1 0.70 CD14 SHBG 0.69 APOE THBS1 0.69

ATRN VWF 0.70 LUM PDLIM1 0.69 GPLD1 PDLIM1 0.69

BTD CD 163 0.70 PGLYRP2 VTN 0.69 CD14 IGF2 0.69

BTD PTGDS 0.70 PRDX2 S100A8 0.69 MASP1 S100A8 0.69

ORM1 VASN 0.70 BTD CNDPl 0.69 IGFALS MINPP1 0.69

ATRN S100A8 0.70 TAGLN2 VWF 0.69 MASP2 VWF 0.69

IGFALS IGFBP3 0.70 BTD MST1 0.69 COMP MASP1 0.69

IGFALS NCAM1 0.70 CD14 SPP2 0.69 BTD VTN 0.69

GPLD1 IGFALS 0.70 BTD MASP2 0.69 CPN1 NA 0.69

CACNA2D1 CD14 0.70 PGLYRP2 THBS1 0.69 PTGDS VTN 0.69

CD 14 CLU 0.69 BTD GPX3 0.69 BTD PCSK9 0.69

CPN1 TNXB 0.69 APOA4 APOC1 0.69 IGFBP3 MASP1 0.69

CPN2 HABP2 0.69 CDH5 CPN1 0.69 APOA4 CA1 0.69

APOA4 LRG1 0.69 PROS1 S100A8 0.69 CD14 CD 163 0.69

CPN2 S100A8 0.69 CNDPl VWF 0.69 PGLYRP2 PTGDS 0.69

APOA1 ORM1 0.69 IGFALS LCAT 0.69 BCHE CD14 0.69

CPN1 PTGDS 0.69 CNTNl LCP1 0.69 HABP2 MINPP1 0.69

ORM1 TAGLN2 0.69 TNXB VTN 0.69 BTD CPB2 0.69

APOC3 CD14 0.69 CD14 TGFBI 0.69 APOA4 CD 163 0.69

BTD CLU 0.69 IGFALS MST1 0.69 CPB2 PDLIM1 0.69

LRG1 ORM1 0.69 IGFBP3 VTN 0.69 GPX3 IGFBP3 0.69

APOA4 IGFALS 0.69 CPB2 VWF 0.69 LPA PGLYRP2 0.69

PDLIM1 SEPP1 0.69 LGALS3BP VWF 0.69 CD14 GP1BA 0.69 PRDX2 VWF 0.69 APOE BTD 0.68 LRG1 PTGDS 0.68

COMP IGFBP3 0.69 BTD MANlAl 0.68 LCAT LRG1 0.68

PFN1 VWF 0.69 CD14 HYOU1 0.68 CD14 SEPP1 0.68

ATRN LRG1 0.69 CA2 S100A8 0.68 ATRN BTD 0.68

COMP HYOU1 0.69 CD14 S100A9 0.68 LRG1 S100A8 0.68

ATRN PDLIM1 0.69 CD14 MINPP1 0.68 CACNA2D1 HABP2 0.68

GP5 VWF 0.69 CPN1 PGLYRP2 0.68 GP5 VTN 0.68

IGFALS MAN1A1 0.69 LPA VTN 0.68 PRDX2 PTGDS 0.68

BCHE BTD 0.69 FCN3 VWF 0.68 LRG1 TLN1 0.68

BCHE PDLIM1 0.69 CPN2 PTGDS 0.68 CD14 LUM 0.68

BTD CKM 0.69 MASP1 TNXB 0.68 NIDI VTN 0.68

CNTN1 SELL 0.69 NCAM1 S100A8 0.68 COMP CPN2 0.68

CPN2 TNXB 0.69 GPLD1 S100A8 0.68 LUM NA 0.68

CD 14 LGALS3BP 0.69 APOA1 IGFBP3 0.68 BTD IGF2 0.68

APOA4 BTD 0.69 APOA1 VWF 0.68 CLU TNXB 0.68

CD 14 GP5 0.69 IGFALS VCAM1 0.68 BTD GPLD1 0.68

PRG4 S100A8 0.69 COMP VTN 0.68 BTD TLN1 0.68

DBH IGFALS 0.69 LGALS3BP PTGDS 0.68 LGALS3BP S100A8 0.68

APOA4 CPN1 0.69 PROS1 THBS1 0.68 LGALS3BP PDLIM1 0.68

PROS1 TNXB 0.69 BTD HGFAC 0.68 SPP2 VWF 0.68

BTD LUM 0.69 APOC1 PTGDS 0.68 TGFBI THBS1 0.68

BTD NCAM1 0.69 CDH5 VTN 0.68 TNXB NA 0.68

BTD SPP2 0.69 CD 163 NA 0.68 CPB2 IGFBP3 0.68

CACNA2D1 LCP1 0.69 APOA4 TNXB 0.68 APOA4 APOE 0.68

IGFBP3 PTGDS 0.69 PRDX2 VTN 0.68 CA1 VTN 0.68

PCSK9 PTGDS 0.69 IGFBP3 TLN1 0.68 CPN1 LUM 0.68

LRG1 MASP1 0.69 APOA1 S100A8 0.68 CD14 GPX3 0.68

APOA4 NIDI 0.69 CPN1 MASP1 0.68 IGFBP3 PRDX2 0.68

MST1 VWF 0.69 APOA4 PTGDS 0.68 APOA4 QSOX1 0.68

APOA4 CA2 0.69 CLU S100A8 0.68 MANlAl THBS1 0.68

HGFAC VWF 0.69 CLU PGLYRP2 0.68 CACNA2D1 LRG1 0.68

FCN3 PTGDS 0.68 CD14 PRG4 0.68 CA2 VTN 0.68

CACNA2D1 VWF 0.68 BTD MASP1 0.68 DBH VWF 0.68

CD 14 NCAM1 0.68 LRG1 PROS1 0.68 APOA4 IGFBP3 0.68

CLEC3B VWF 0.68 COMP VWF 0.68 GPLD1 THBS1 0.68

LRG1 QSOX1 0.68 BTD VASN 0.68 CLU MASP1 0.68

MAN1A1 VWF 0.68 BTD TGFBI 0.68 IGFALS PGLYRP2 0.68

SHBG VWF 0.68 LPA S100A8 0.68 IGFALS VASN 0.68

CD 14 CPB2 0.68 CD14 TAGLN2 0.68 CA2 CD14 0.68

CD 14 HGFAC 0.68 MASP1 NA 0.68 SEPP1 VWF 0.68

LRG1 LUM 0.68 LRG1 PGLYRP2 0.68 CPN2 LRG1 0.68 BTD VCAM1 0.68 GPX3 PTGDS 0.68 APOA4 MST1 0.67

IGFALS PFN1 0.68 CA2 VWF 0.68 PCSK9 S100A8 0.67

PRG4 PTGDS 0.68 CNTNl HABP2 0.68 NIDI PTGDS 0.67

BTD DBH 0.68 PGLYRP2 S100A8 0.68 IGFBP3 PRG4 0.67

GPX3 TNXB 0.68 ATRN S100A9 0.68 S100A9 NA 0.67

CD 14 PROS1 0.68 GPLD1 LRG1 0.68 CDH5 LRG1 0.67

APOA4 PCSK9 0.68 PRG4 THBS1 0.68 APOA4 GP5 0.67

QSOX1 VTN 0.68 BTD PFN1 0.68 APOE S100A8 0.67

CD 14 DBH 0.68 BTD CPN2 0.68 PROS1 VTN 0.67

CPN2 NA 0.68 CD 163 CDH5 0.68 CD14 PGLYRP2 0.67

LCAT VWF 0.68 CA1 S100A8 0.68 APOA1 TNXB 0.67

CD 14 CKM 0.68 GPX3 THBS1 0.68 COMP LRG1 0.67

CD 163 VTN 0.68 MINPP1 PDLIM1 0.68 APOE PTGDS 0.67

IGF2 VWF 0.68 BTD LCAT 0.68 LRG1 VCAM1 0.67

HGFAC IGFALS 0.68 CA1 CD14 0.68 CD 163 MASP1 0.67

PTGDS S100A9 0.68 CPN1 VTN 0.68 CD14 VASN 0.67

TLNl VWF 0.68 PFN1 VTN 0.68 COMP CPN1 0.67

CD 14 PEPD 0.68 COMP NCAM1 0.68 CLEC3B PTGDS 0.67

BTD TAGLN2 0.68 APOA1 CD14 0.67 QSOX1 S100A8 0.67

TGFBI VWF 0.68 CDH5 CPN2 0.67 APOA4 FCN3 0.67

CKM VWF 0.68 APOC1 CD14 0.67 NCAM1 VTN 0.67

APOA4 CNDP1 0.68 CDH5 PRG4 0.67 CLEC3B LRG1 0.67

CD 14 PFN1 0.68 LPA TNXB 0.67 CPN1 LPA 0.67

BTD PRG4 0.68 CD 163 CPN1 0.67 PTGDS QSOX1 0.67

LRG1 PRDX2 0.68 IGFALS TAGLN2 0.67 APOA4 CKM 0.67

CD 14 LRG1 0.68 LPA PTGDS 0.67 PGLYRP2 PROS1 0.67

CD 163 PROS1 0.68 IGFBP3 TNXB 0.67 PROS1 PTGDS 0.67

CPN1 S100A8 0.68 FCN3 S100A8 0.67 LUM VTN 0.67

HYOU1 PTGDS 0.68 CPB2 PTGDS 0.67 APOA4 MASP1 0.67

CDH5 S100A8 0.68 BTD LGALS3BP 0.67 CDH5 GPX3 0.67

BTD MINPP1 0.68 APOA4 NCAM1 0.67 APOA4 MASP2 0.67

APOA4 VTN 0.68 BTD HYOU1 0.67 HYOU1 S100A8 0.67

S100A9 VTN 0.68 MASP1 PROS1 0.67 APOC3 LRG1 0.67

FCN3 LRG1 0.68 SEPP1 THBS1 0.67 APOA4 CPB2 0.67

LPA THBS1 0.68 LUM S100A9 0.67 CLU LUM 0.67

VCAM1 VWF 0.68 APOA4 CLU 0.67 CLEC3B VTN 0.67

IGFBP3 LPA 0.68 NIDI PDLIM1 0.67 CA2 PTGDS 0.67

BTD PGLYRP2 0.68 CD 163 LPA 0.67 SPP2 VTN 0.67

MASP1 VTN 0.68 APOA4 LUM 0.67 CLU NA 0.67

APOA4 CDH5 0.68 LRG1 NCAM1 0.67 CNDPl LRG1 0.67

COMP PTGDS 0.68 CA1 VWF 0.67 LGALS3BP LRG1 0.67 GP1BA S100A8 0.67 LRG1 S100A9 0.67 APOA4 MAN1A1 0.67

APOA4 LGALS3BP 0.67 MAN1A1 PTGDS 0.67 APOA4 GPX3 0.66

BTD PEPD 0.67 S100A8 VASN 0.67 GPLD1 IGFBP3 0.66

PRG4 TNXB 0.67 MASP1 S100A9 0.67 APOE TNXB 0.66

APOA4 APOC3 0.67 IGFBP3 PGLYRP2 0.67 CDH5 GPLD1 0.66

APOE VTN 0.67 FCN3 VTN 0.67 APOA1 LRG1 0.66

APOA4 PROS1 0.67 PDLIM1 TGFBI 0.67 SPP2 THBS1 0.66

APOE LRG1 0.67 NCAM1 PTGDS 0.67 CDH5 LPA 0.66

MINPP1 VWF 0.67 APOA4 SEPP1 0.67 APOA4 ATRN 0.66

MASP1 NCAM1 0.67 BCHE PTGDS 0.67 S100A8 TGFBI 0.66

S100A8 S100A9 0.67 CACNA2D1 S100A8 0.67 PDLIM1 PROS1 0.66

GPLD1 PTGDS 0.67 CD 163 LRG1 0.67 SEPP1 VTN 0.66

IGF2 LRG1 0.67 LRG1 PFN1 0.67 CNDPl PTGDS 0.66

S100A8 TLN1 0.67 COMP PGLYRP2 0.67 GP1BA LRG1 0.66

IGFBP3 NCAM1 0.67 APOA4 GP1BA 0.67 FCN3 IGFBP3 0.66

CD 163 IGFBP3 0.67 NCAM1 PRDX2 0.67 TAGLN2 VTN 0.66

CDH5 CLU 0.67 CA2 LRG1 0.67 LRG1 PCSK9 0.66

APOC3 PTGDS 0.67 ATRN IGFBP3 0.67 IGFBP3 LGALS3BP 0.66

APOA4 TGFBI 0.67 GP5 IGFBP3 0.67 CD 163 TNXB 0.66

APOA4 SPP2 0.67 PTGDS SHBG 0.67 CLU VTN 0.66

CPN1 QSOX1 0.67 APOA4 HGFAC 0.67 PROS1 NA 0.66

CKM LRG1 0.67 APOA4 CPN2 0.67 CDH5 PROS1 0.66

CDH5 PGLYRP2 0.67 LUM PRDX2 0.67 CKM S100A8 0.66

IGF2 VTN 0.67 CLU LPA 0.67 IGF2 S100A8 0.66

CNDP1 VTN 0.67 CA1 IGFBP3 0.67 S100A8 SEPP1 0.66

CDH5 HYOU1 0.67 CLU TLN1 0.67 PRG4 VTN 0.66

PEPD THBS1 0.67 CD 163 CPN2 0.67 CA2 IGFBP3 0.66

LPA LUM 0.67 IGFBP3 SPP2 0.67 TGFBI VTN 0.66

APOC3 VTN 0.67 CKM VTN 0.67 CLU PTGDS 0.66

CPN1 LRG1 0.67 HGFAC LRG1 0.67 CACNA2D1 IGFALS 0.66

HGFAC S100A8 0.67 CPN2 S100A9 0.67 LRG1 SHBG 0.66

APOA4 SHBG 0.67 CLEC3B S100A8 0.67 HYOU1 NA 0.66

APOC1 VWF 0.67 S100A8 SPP2 0.67 CNDPl S100A8 0.66

MASP2 PTGDS 0.67 LUM PROS1 0.67 CA1 LRG1 0.66

GP1BA PDLIM1 0.67 APOE PDLIM1 0.67 CA1 PTGDS 0.66

CDH5 PRDX2 0.67 BCHE LRG1 0.67 LRG1 SPP2 0.66

APOC3 S100A8 0.67 PFN1 S100A8 0.67 PTGDS SEPP1 0.66

APOA1 BTD 0.67 CD 163 S100A8 0.67 LRG1 MASP2 0.66

LRG1 NIDI 0.67 CDH5 PTGDS 0.67 VCAM1 VTN 0.66

CPB2 S100A8 0.67 GPX3 VTN 0.67 GP5 S100A8 0.66

LPA PDLIM1 0.67 CPN2 LUM 0.67 CLU LRG1 0.66 PROS1 S100A9 0.66 LRG1 TGFBI 0.66 IGFBP3 PCSK9 0.66

HGFAC VTN 0.66 DBH LRG1 0.66 APOE CDH5 0.66

PTGDS TLN1 0.66 LUM PTGDS 0.66 GP5 PTGDS 0.66

PTGDS TNXB 0.66 GP5 LRG1 0.66 GPX3 S100A8 0.66

LRG1 TAGLN2 0.66 FCN3 LUM 0.66 APOA4 PGLYRP2 0.66

CPB2 LRG1 0.66 MASP1 NIDI 0.66 APOA4 VCAM1 0.66

APOA4 BCHE 0.66 APOA4 PEPD 0.66 HGFAC PTGDS 0.66

CPN2 VTN 0.66 LRG1 MINPP1 0.66 MST1 PTGDS 0.66

IGFBP3 MASP2 0.66 CD 163 CLU 0.66 BCHE S100A8 0.66

PEPD S100A8 0.66 HYOU1 LPA 0.66 APOC1 CPN1 0.66

NCAM1 TNXB 0.66 PGLYRP2 TNXB 0.66 APOA4 GPLD1 0.66

BCHE VTN 0.66 PCSK9 VTN 0.66 MAN1A1 VTN 0.66

APOA1 APOA4 0.66 CD 163 NCAM1 0.66 MST1 S100A8 0.66

NCAM1 PROS1 0.66 MASP2 VTN 0.66 CPN2 NIDI 0.66

LRG1 MST1 0.66 PTGDS TGFBI 0.66 PGLYRP2 NA 0.66

PDLIM1 SPP2 0.66 ATRN VTN 0.66 HYOU1 LRG1 0.66

CPB2 VTN 0.66 MASP1 PCSK9 0.66 COMP S100A8 0.66

CDH5 CPB2 0.66 HYOU1 IGFBP3 0.66 GP1BA IGFBP3 0.66

LRG1 PRG4 0.66 GPX3 LRG1 0.66 CNTNl IGFALS 0.66

DBH PTGDS 0.66 PRDX2 TNXB 0.66 CPN1 PRDX2 0.66

IGF2 PTGDS 0.66 PTGDS SPP2 0.66 CNDPl CPN1 0.66

NIDI S100A8 0.66 IGFBP3 SEPP1 0.66 LCAT VTN 0.66

DBH S100A8 0.66 CNTNl ORM1 0.66 IGFBP3 NIDI 0.66

APOA4 DBH 0.66 IGFBP3 TGFBI 0.66 CKM PTGDS 0.66

CNDP1 CPN2 0.66 APOE IGFBP3 0.66 BCHE CD 163 0.66

CDH5 IGFBP3 0.66 S100A8 TAGLN2 0.66 APOA4 LCAT 0.66

LGALS3BP TNXB 0.66 CDH5 S100A9 0.66 ATRN PTGDS 0.66

LGALS3BP VTN 0.66 LRG1 PEPD 0.66 DBH VTN 0.66

NCAM1 NA 0.66 FCN3 TNXB 0.66 MASP1 QSOX1 0.66

CDH5 FCN3 0.66 GPX3 LUM 0.66 BCHE IGFBP3 0.66

APOA1 PTGDS 0.66 CPB2 TNXB 0.66 NCAM1 S100A9 0.66

CPN1 NCAM1 0.66 SHBG VTN 0.66 CPN1 VASN 0.66

LRG1 VASN 0.66 CLEC3B CPN2 0.66 S100A8 SHBG 0.66

CPN2 LPA 0.66 APOA4 VASN 0.66 CDH5 LGALS3BP 0.66

LPA S100A9 0.66 APOC1 VTN 0.66 MINPP1 PTGDS 0.66

LGALS3BP THBS1 0.66 CPN1 HYOU1 0.66 IGFBP3 MAN1A1 0.66

VASN VTN 0.66 BCHE CDH5 0.66 CDH5 QSOX1 0.66

CPN2 PRDX2 0.66 APOA4 HYOU1 0.66 LUM MASP1 0.66

SEPP1 TNXB 0.66 CNDPl IGFBP3 0.66 APOA1 CDH5 0.66

APOA4 PRG4 0.66 IGFBP3 LUM 0.66 BTD CNTNl 0.66

APOC1 S100A8 0.66 ATRN NA 0.66 CLEC3B CPN1 0.65 CPN1 FCN3 0.65 APOA4 PFN1 0.65 GPX3 MASP1 0.65

APOC1 LRG1 0.65 CA1 CDH5 0.65 CDH5 CNDPl 0.65

IGFBP3 SHBG 0.65 CLEC3B IGFBP3 0.65 CD 163 PGLYRP2 0.65

LUM PRG4 0.65 PEPD PTGDS 0.65 LCAT THBS1 0.65

MASP2 TNXB 0.65 IGFBP3 TAGLN2 0.65 CPN1 PROS1 0.65

PRDX2 S100A9 0.65 CD 163 HGFAC 0.65 LPA NCAM1 0.65

APOA4 TLN1 0.65 APOA1 VTN 0.65 LGALS3BP PROS1 0.65

GP1BA PTGDS 0.65 QSOX1 TNXB 0.65 LCAT PDLIM1 0.65

CD 163 HYOU1 0.65 CD14 CNTN1 0.65 ATRN CDH5 0.65

CLU COMP 0.65 LRG1 SEPP1 0.65 GP1BA VTN 0.65

ATRN CD 163 0.65 IGFBP3 QSOX1 0.65 CPN1 NIDI 0.65

MST1 VTN 0.65 APOA4 IGF2 0.65 CDH5 TNXB 0.65

PTGDS VCAM1 0.65 CA1 CPN2 0.65 BCHE TNXB 0.65

PFN1 THBS1 0.65 CPN1 MINPP1 0.65 CLU NIDI 0.65

PFN1 PTGDS 0.65 CPN1 IGF2 0.65 CPN1 MASP2 0.65

APOA4 MINPP1 0.65 APOC3 IGFBP3 0.65 CPN1 SPP2 0.65

HYOU1 PRDX2 0.65 CPN2 PGLYRP2 0.65 CPN2 TGFBI 0.65

LCAT PTGDS 0.65 ATRN CPN1 0.65 LGALS3BP MASP1 0.65

CLU NCAM1 0.65 CLEC3B TNXB 0.65 IGFBP3 MST1 0.65

FCN3 MASP1 0.65 NCAM1 PGLYRP2 0.65 QSOX1 NA 0.65

CDH5 NCAM1 0.65 PGLYRP2 S100A9 0.65 GP1BA PROS1 0.65

CDH5 PCSK9 0.65 PDLIM1 PEPD 0.65 CA2 CPN1 0.65

PTGDS TAGLN2 0.65 CA2 CPN2 0.65 CNDPl TNXB 0.65

APOE CPN1 0.65 BCHE CPN1 0.65 MASP1 SPP2 0.65

CD 163 GPX3 0.65 HGFAC THBS1 0.65 PCSK9 TNXB 0.65

CPN1 GPX3 0.65 LRG1 MANlAl 0.65 CPN2 MASP1 0.65

NIDI PROS1 0.65 PGLYRP2 SPP2 0.65 CLU CPN1 0.65

CNTN1 MASP1 0.65 CPN1 MST1 0.65 APOC3 PDLIM1 0.65

CLU S100A9 0.65 CPN1 GP1BA 0.65 CPB2 PGLYRP2 0.65

LGALS3BP S100A9 0.65 CPN2 PCSK9 0.65 CPN1 SHBG 0.65

CPN1 S100A9 0.65 MINPP1 S100A8 0.65 HGFAC TNXB 0.65

PTGDS VASN 0.65 CDH5 NIDI 0.65 PRG4 S100A9 0.65

MAN1A1 TNXB 0.65 CPN2 NCAM1 0.65 APOA1 CD 163 0.65

CNTN1 IGFBP3 0.65 GPLD1 VTN 0.65 CD 163 CPB2 0.65

CPB2 MASP1 0.65 GPLD1 S100A9 0.65 CPN1 PCSK9 0.65

HYOU1 TNXB 0.65 CLEC3B HYOU1 0.65 CPN1 TGFBI 0.65

CDH5 COMP 0.65 CA2 CDH5 0.65 APOC3 CPN1 0.65

CLU QSOX1 0.65 CLU FCN3 0.65 CA1 LUM 0.65

APOA4 TAGLN2 0.65 CPN2 FCN3 0.65 CLU PRDX2 0.65

MASP2 S100A8 0.65 NIDI TNXB 0.65 CDH5 LUM 0.65

CD 163 SPP2 0.65 IGFBP3 PFN1 0.65 CD 163 QSOX1 0.65 HYOU1 S100A9 0.65 CPN2 IGF2 0.64 CPN1 TLN1 0.64

IGFBP3 VASN 0.65 CNDPl MASP1 0.64 CPN1 LCAT 0.64

APOC3 CDH5 0.65 S100A8 VCAM1 0.64 APOC1 IGFBP3 0.64

APOA1 LUM 0.65 CLU GP5 0.64 HYOU1 NIDI 0.64

HGFAC IGFBP3 0.64 CD 163 COMP 0.64 PGLYRP2 PRDX2 0.64

CLEC3B CLU 0.64 GP1BA PGLYRP2 0.64 APOC1 NCAM1 0.64

CA2 S100A9 0.64 GP1BA MASP1 0.64 CLU CPN2 0.64

APOA1 S100A9 0.64 CA1 TNXB 0.64 APOE CPN2 0.64

CLU PROS1 0.64 APOA1 COMP 0.64 LPA NA 0.64

QSOX1 S100A9 0.64 HYOU1 NCAM1 0.64 CD 163 MINPP1 0.64

TGFBI TNXB 0.64 APOE MASP1 0.64 GPX3 NCAM1 0.64

BTD CACNA2D1 0.64 APOC3 TNXB 0.64 CDH5 SHBG 0.64

MAN1A1 S100A8 0.64 CDH5 TGFBI 0.64 CLU HYOU1 0.64

CPN2 QSOX1 0.64 MASP1 SEPP1 0.64 LPA PRG4 0.64

CD 163 LUM 0.64 CA2 NCAM1 0.64 CPN1 CPN2 0.64

CD 163 FCN3 0.64 CD 163 S100A9 0.64 GPX3 PGLYRP2 0.64

ATRN TNXB 0.64 CPN1 HGFAC 0.64 SHBG TNXB 0.64

FCN3 NCAM1 0.64 APOC1 CLU 0.64 CPN2 MASP2 0.64

MST1 TNXB 0.64 GPLD1 TNXB 0.64 CA1 CD 163 0.64

CPB2 CPN1 0.64 CDH5 MASP2 0.64 MANlAl MASP1 0.64

CPN1 GP5 0.64 CA1 NCAM1 0.64 APOE S100A9 0.64

MASP1 VASN 0.64 CA1 HYOU1 0.64 APOE PROS1 0.64

CDH5 GP1BA 0.64 MASP1 PRDX2 0.64 GP5 TNXB 0.64

HYOU1 MASP1 0.64 LPA PROS1 0.64 LGALS3BP LUM 0.64

ATRN MASP1 0.64 CPN1 MANlAl 0.64 NCAM1 PRG4 0.64

LGALS3BP NCAM1 0.64 CD 163 CNTN1 0.64 HYOU1 PGLYRP2 0.64

MINPP1 VTN 0.64 CD 163 PRDX2 0.64 TAGLN2 THBS1 0.64

CNTN1 VWF 0.64 CDH5 CLEC3B 0.64 HYOU1 PROS1 0.64

PEPD VTN 0.64 MASP1 TLN1 0.64 CPN1 SEPP1 0.64

CPN1 VCAM1 0.64 ATRN COMP 0.64 CD 163 PRG4 0.64

APOE LUM 0.64 LUM SPP2 0.64 CKM TNXB 0.64

HYOU1 VTN 0.64 CD 163 GPLD1 0.64 CPN2 SPP2 0.64

CD 163 PEPD 0.64 CA2 CLU 0.64 IGF2 PDLIM1 0.64

CA1 CPN1 0.64 APOE CLU 0.64 IGFBP3 MINPP1 0.64

CPN2 HYOU1 0.64 SPP2 TNXB 0.64 CPB2 NCAM1 0.64

IGFBP3 PEPD 0.64 GP5 THBS1 0.64 CKM CLU 0.64

CLU CNDP1 0.64 DBH IGFBP3 0.64 GPLD1 NCAM1 0.64

CD 163 PCSK9 0.64 CPN2 VASN 0.64 CPN1 GPLD1 0.64

MASP1 PGLYRP2 0.64 MASP1 MST1 0.64 CA2 HYOU1 0.64

IGF2 IGFBP3 0.64 LGALS3BP PGLYRP2 0.64 HGFAC PDLIM1 0.64

MASP1 MASP2 0.64 CDH5 SEPP1 0.64 NCAM1 QSOX1 0.64 MASP1 PRG4 0.64 CPN1 PEPD 0.64 MASP1 VCAM1 0.63

CNTN1 LRG1 0.64 APOC3 MASP1 0.64 CD 163 CLEC3B 0.63

IGFBP3 LCAT 0.64 CLU GP1BA 0.64 CD 163 TGFBI 0.63

PRG4 PROS1 0.64 CD 163 LGALS3BP 0.64 DBH TNXB 0.63

CDH5 MST1 0.64 LUM PCSK9 0.64 CD 163 CNDP1 0.63

CPB2 LUM 0.64 FCN3 S100A9 0.64 HGFAC S100A9 0.63

LCAT TNXB 0.64 CACNA2D1 S100A9 0.63 LUM MANlAl 0.63

APOC1 CDH5 0.64 CPB2 NA 0.63 CDH5 MINPP1 0.63

CPN2 GP5 0.64 CDH5 SPP2 0.63 APOA1 MASP1 0.63

BCHE MASP1 0.64 MASP1 TGFBI 0.63 APOC3 LUM 0.63

CPB2 S100A9 0.64 CDH5 MANlAl 0.63 CPN2 PROS1 0.63

APOC1 CPN2 0.64 LPA MANlAl 0.63 ATRN CLU 0.63

CA2 CD 163 0.64 CD 163 GP5 0.63 CPN1 PRG4 0.63

IGF2 TNXB 0.64 CKM IGFBP3 0.63 IGFBP3 VCAM1 0.63

CLU VASN 0.64 CLEC3B MASP1 0.63 CPN2 VCAM1 0.63

CPN2 GP1BA 0.64 LPA PRDX2 0.63 HGFAC LUM 0.63

ATRN FCN3 0.64 CLU SPP2 0.63 MASP2 PDLIM1 0.63

GP5 MASP1 0.64 CD 163 SEPP1 0.63 APOC3 CLU 0.63

PCSK9 S100A9 0.64 GP1BA TNXB 0.63 CLU PCSK9 0.63

CDH5 GP5 0.64 LUM PGLYRP2 0.63 FCN3 PROS1 0.63

ATRN CPN2 0.64 CDH5 DBH 0.63 ATRN CLEC3B 0.63

CA1 S100A9 0.64 CNTNl S100A8 0.63 ATRN NIDI 0.63

CD 163 IGF2 0.64 COMP PROS1 0.63 APOC3 CPN2 0.63

ATRN PGLYRP2 0.64 APOA1 PGLYRP2 0.63 CLU LCAT 0.63

CKM CPN1 0.64 CA2 TNXB 0.63 APOA4 CNTNl 0.63

CA1 CLU 0.64 GP1BA NCAM1 0.63 HYOU1 LGALS3BP 0.63

APOE CD 163 0.64 S100A9 VASN 0.63 LUM QSOX1 0.63

LCAT S100A8 0.64 CPN2 MST1 0.63 LPA NIDI 0.63

APOA1 NA 0.64 CLU LGALS3BP 0.63 PCSK9 PGLYRP2 0.63

CDH5 HGFAC 0.64 CLU GPX3 0.63 CLU VCAM1 0.63

HYOU1 MASP2 0.64 LUM SHBG 0.63 MASP1 SHBG 0.63

CLU CPB2 0.64 CLU TAGLN2 0.63 CPB2 CPN2 0.63

LUM NCAM1 0.64 GPLD1 PGLYRP2 0.63 CPN2 HGFAC 0.63

LUM TNXB 0.64 BCHE CLU 0.63 CPB2 LPA 0.63

LUM SEPP1 0.64 S100A9 SPP2 0.63 CLU MASP2 0.63

GP1BA S100A9 0.64 PROS1 QSOX1 0.63 MINPP1 NA 0.63

IGF2 MASP1 0.64 CPN1 DBH 0.63 APOC3 PROS1 0.63

MINPP1 TNXB 0.64 TNXB VASN 0.63 BCHE CPN2 0.63

APOC1 TNXB 0.64 CLU PFN1 0.63 CD 163 MST1 0.63

ATRN PRDX2 0.64 LUM NIDI 0.63 CDH5 PEPD 0.63

CPN2 TLN1 0.64 CPN1 LGALS3BP 0.63 BCHE S100A9 0.63 CA2 LUM 0.63 CKM S100A9 0.63 CLEC3B PDLIM1 0.63

ATRN LUM 0.63 GPX3 LPA 0.63 CA1 MASP1 0.63

APOC3 S100A9 0.63 NIDI S100A9 0.63 TAGLN2 TNXB 0.63

MASP1 MINPP1 0.63 HYOU1 MINPP1 0.63 CACNA2D1 PTGDS 0.63

CA2 MASP1 0.63 APOC1 MASP1 0.63 CNDPl LUM 0.63

APOA1 NCAM1 0.63 TNXB VCAM1 0.63 CLU DBH 0.63

CPN1 TAGLN2 0.63 HYOU1 LUM 0.63 CACNA2D1 CPN1 0.63

CD 163 GP1BA 0.63 CLU MST1 0.63 APOC3 CD 163 0.63

LUM MASP2 0.63 LUM MST1 0.63 CLU GPLD1 0.63

CLU IGF2 0.63 DBH MASP1 0.63 MST1 PDLIM1 0.63

TLN1 TNXB 0.63 ATRN HYOU1 0.63 CLEC3B NCAM1 0.62

CD 163 NIDI 0.63 CLU PRG4 0.63 CLU HGFAC 0.62

FCN3 PGLYRP2 0.63 CKM LUM 0.63 CLU MANlAl 0.62

PEPD S100A9 0.63 CPN2 SHBG 0.63 PRDX2 PROS1 0.62

GPLD1 MASP1 0.63 APOE HYOU1 0.63 GP5 LUM 0.62

APOA1 LPA 0.63 CPN2 MINPP1 0.63 LCAT MASP1 0.62

PGLYRP2 SEPP1 0.63 BCHE NCAM1 0.63 APOA4 CACNA2D1 0.62

CDH5 LCAT 0.63 CD 163 MANlAl 0.63 PGLYRP2 PRG4 0.62

S100A9 TGFBI 0.63 ATRN PROS1 0.63 BCHE HYOU1 0.62

PEPD TNXB 0.63 PFN1 TNXB 0.63 HYOU1 SPP2 0.62

CDH5 TAGLN2 0.63 CLU TGFBI 0.63 APOA1 CPN1 0.62

APOC1 HYOU1 0.63 PROS1 SPP2 0.63 APOC3 NCAM1 0.62

CD 163 VASN 0.63 CPN1 PFN1 0.63 S100A9 SEPP1 0.62

CLU SEPP1 0.63 LUM TGFBI 0.63 GPX3 HYOU1 0.62

CNTN1 VTN 0.63 CPN2 DBH 0.63 PDLIM1 VASN 0.62

BCHE LUM 0.63 COMP MANlAl 0.63 APOA1 NIDI 0.62

GPLD1 LUM 0.63 HYOU1 MST1 0.63 MST1 S100A9 0.62

S100A9 TLN1 0.63 APOE NA 0.63 CDH5 TLN1 0.62

CPN2 LGALS3BP 0.63 ATRN NCAM1 0.63 FCN3 PDLIM1 0.62

GP1BA LPA 0.63 GP5 PGLYRP2 0.63 GP5 S100A9 0.62

APOE NCAM1 0.63 CDH5 PFN1 0.63 HGFAC MASP1 0.62

APOA1 CLU 0.63 CPN2 LCAT 0.63 IGF2 LUM 0.62

ATRN LPA 0.63 CACNA2D1 VTN 0.63 DBH LUM 0.62

CLU SHBG 0.63 LGALS3BP QSOX1 0.63 BCHE COMP 0.62

CDH5 IGF2 0.63 PRG4 NA 0.63 CKM MASP1 0.62

APOE LPA 0.63 APOC1 LUM 0.63 CLU MINPP1 0.62

PDLIM1 TLN1 0.63 FCN3 HYOU1 0.63 GPX3 S100A9 0.62

CLEC3B LUM 0.63 HYOU1 QSOX1 0.63 CNTNl TNXB 0.62

CLEC3B S100A9 0.63 NCAM1 SPP2 0.63 ATRN PRG4 0.62

CLEC3B THBS1 0.63 APOE ATRN 0.63 CLU PEPD 0.62

CD 163 MASP2 0.63 CNDPl PGLYRP2 0.63 HGFAC NCAM1 0.62 CPN2 PRG4 0.62 CPN2 GPLD1 0.62 APOA1 APOE 0.62

MINPP1 PROS1 0.62 MAN1A1 NA 0.62 COMP S100A9 0.62

NCAM1 TLN1 0.62 CD 163 LCAT 0.62 LCAT LUM 0.62

GPLD1 HYOU1 0.62 HGFAC PROS1 0.62 PCSK9 PROS1 0.62

LPA QSOX1 0.62 MASP2 NCAM1 0.62 MAN1A1 PRDX2 0.62

CPB2 HYOU1 0.62 CPN2 PEPD 0.62 CNDPl NCAM1 0.62

CDH5 VCAM1 0.62 APOA1 TLN1 0.62 ATRN QSOX1 0.62

GP5 PROS1 0.62 APOA1 PRDX2 0.62 CPN2 TAGLN2 0.62

PGLYRP2 SHBG 0.62 IGF2 NCAM1 0.62 NIDI NA 0.62

BCHE NA 0.62 APOC3 HYOU1 0.62 MST1 NCAM1 0.62

GPLD1 PROS1 0.62 MINPP1 S100A9 0.62 HYOU1 SEPP1 0.62

BCHE PROS1 0.62 APOA1 PROS1 0.62 APOC3 ATRN 0.62

GPLD1 LPA 0.62 BCHE PRDX2 0.62 GP1BA HYOU1 0.62

HYOU1 PCSK9 0.62 APOC1 PROS1 0.62 GPX3 NIDI 0.62

CPB2 PROS1 0.62 CNTNl CPN2 0.62 CPN2 MAN1A1 0.62

MINPP1 PRDX2 0.62 CD 163 SHBG 0.62 NCAM1 TGFBI 0.62

CDH5 VASN 0.62 BCHE PGLYRP2 0.62 MAN1A1 NCAM1 0.62

DBH S100A9 0.62 MAN1A1 PGLYRP2 0.62 CD 163 TAGLN2 0.62

PDLIM1 NA 0.62 GPX3 NA 0.62 GP1BA GPX3 0.62

LUM TAGLN2 0.62 CNTNl LGALS3BP 0.62 APOC3 PGLYRP2 0.62

CDH5 CKM 0.62 MST1 PGLYRP2 0.62 CD 163 VCAM1 0.62

CD 163 DBH 0.62 GP5 PDLIM1 0.62 LGALS3BP LPA 0.62

NCAM1 PCSK9 0.62 CACNA2D1 CLU 0.62 THBS1 VASN 0.62

CNDP1 S100A9 0.62 LUM PFN1 0.62 MAN1A1 PROS1 0.62

CD 163 CKM 0.62 CKM CPN2 0.62 NCAM1 PEPD 0.62

CKM HYOU1 0.62 CPN2 SEPP1 0.62 CD 163 PFN1 0.62

PFN1 S100A9 0.62 NIDI PGLYRP2 0.62 PRG4 QSOX1 0.62

LUM TLN1 0.62 LPA VCAM1 0.62 TGFBI NA 0.61

MASP1 TAGLN2 0.62 PGLYRP2 QSOX1 0.62 APOA1 CPN2 0.61

CPB2 QSOX1 0.62 PRG4 VASN 0.62 FCN3 LPA 0.61

CPN2 GPX3 0.62 PDLIM1 VCAM1 0.62 DBH PROS1 0.61

CNTN1 PTGDS 0.62 CNTNl PGLYRP2 0.62 HYOU1 PRG4 0.61

FCN3 QSOX1 0.62 ATRN GPX3 0.62 PGLYRP2 TLN1 0.61

CD 163 TLN1 0.62 PGLYRP2 VASN 0.62 THBS1 VCAM1 0.61

NCAM1 SHBG 0.62 NCAM1 NIDI 0.62 GP5 HYOU1 0.61

MASP1 PFN1 0.62 MASP2 THBS1 0.62 GPLD1 NIDI 0.61

GP1BA LUM 0.62 CA2 PGLYRP2 0.62 APOA1 HYOU1 0.61

IGF2 S100A9 0.62 CPN2 PFN1 0.62 CNTNl LUM 0.61

HGFAC HYOU1 0.62 GP5 LPA 0.62 MASP1 PEPD 0.61

PROS1 VCAM1 0.62 LPA MINPP1 0.62 APOA1 QSOX1 0.61

S100A9 TAGLN2 0.62 CA1 LPA 0.62 GP5 NCAM1 0.61 MASP2 PGLYRP2 0.61 CNTNl CPN1 0.61 CPB2 FCN3 0.61

LPA SEPP1 0.61 NCAM1 VASN 0.61 CLEC3B PROS1 0.61

IGF2 PRG4 0.61 ATRN CA2 0.61 LCAT LPA 0.61

CA1 PGLYRP2 0.61 ATRN MANlAl 0.61 CNDPl PRG4 0.61

CA2 MINPP1 0.61 HYOU1 IGF2 0.61 CNTNl THBS1 0.61

CA1 PROS1 0.61 PROS1 SHBG 0.61 GP1BA PRG4 0.61

HYOU1 PEPD 0.61 COMP QSOX1 0.61 LUM VASN 0.61

CA2 PROS1 0.61 ATRN CPB2 0.61 APOA1 APOC3 0.61

LUM PEPD 0.61 IGF2 PGLYRP2 0.61 PROS1 TAGLN2 0.61

IGF2 THBS1 0.61 LCAT PGLYRP2 0.61 CACNA2D1 IGFBP3 0.61

CNDP1 HYOU1 0.61 GPX3 QSOX1 0.61 APOE PRDX2 0.61

S100A9 SHBG 0.61 MST1 PROS1 0.61 LGALS3BP NA 0.61

CNDP1 PROS1 0.61 HYOU1 VCAM1 0.61 NCAM1 PFN1 0.61

APOA1 ATRN 0.61 ATRN VCAM1 0.61 LPA SHBG 0.61

DBH HYOU1 0.61 MASP2 S100A9 0.61 APOA1 VASN 0.61

MINPP1 NCAM1 0.61 ATRN TGFBI 0.61 ATRN GP5 0.60

APOC1 S100A9 0.61 GPLD1 NA 0.61 ATRN SPP2 0.60

MASP2 PROS1 0.61 APOA1 BCHE 0.61 HGFAC LPA 0.60

LCAT PROS1 0.61 PROS1 TGFBI 0.61 CPB2 PRDX2 0.60

HYOU1 MANlAl 0.61 CPB2 NIDI 0.61 LPA PCSK9 0.60

PGLYRP2 TGFBI 0.61 PFN1 PGLYRP2 0.61 LPA SPP2 0.60

APOA1 FCN3 0.61 CLEC3B PGLYRP2 0.61 HYOU1 VASN 0.60

HYOU1 TGFBI 0.61 CKM NCAM1 0.61 LGALS3BP NIDI 0.60

APOE PGLYRP2 0.61 LPA TGFBI 0.61 PROS1 VASN 0.60

PROS1 SEPP1 0.61 LCAT NCAM1 0.61 DBH PGLYRP2 0.60

PGLYRP2 TAGLN2 0.61 APOC1 CD 163 0.61 APOA1 CNDPl 0.60

LUM MINPP1 0.61 NIDI PRG4 0.61 PFN1 PROS1 0.60

ATRN CA1 0.61 BCHE FCN3 0.61 APOE GP1BA 0.60

GPX3 PROS1 0.61 COMP PRG4 0.61 APOE SPP2 0.60

COMP SEPP1 0.61 CPB2 MINPP1 0.61 PDLIM1 SHBG 0.60

APOC1 PGLYRP2 0.61 APOC3 LPA 0.61 MANlAl QSOX1 0.60

ATRN LGALS3BP 0.61 ATRN PCSK9 0.61 APOA1 CA2 0.60

CA2 LPA 0.61 BCHE LPA 0.61 PROS1 TLN1 0.60

LPA MASP2 0.61 PCSK9 QSOX1 0.61 NIDI QSOX1 0.60

CACNA2D1 CD 163 0.61 COMP LPA 0.61 APOE LGALS3BP 0.60

DBH NCAM1 0.61 HGFAC PGLYRP2 0.61 CACNA2D1 CDH5 0.60

HYOU1 TLN1 0.61 MINPP1 PGLYRP2 0.61 GPLD1 QSOX1 0.60

NCAM1 TAGLN2 0.61 PRDX2 QSOX1 0.61 GPX3 VASN 0.60

NCAM1 SEPP1 0.61 MANlAl S100A9 0.61 GPX3 PRDX2 0.60

APOE CPB2 0.61 GPX3 LGALS3BP 0.61 IGF2 PROS1 0.60

HYOU1 SHBG 0.61 LGALS3BP VASN 0.61 APOA1 GP1BA 0.60 IGF2 LPA 0.60 NIDI PEPD 0.60 GP1BA NA 0.59

LCAT S100A9 0.60 APOA1 PCSK9 0.60 ATRN SEPP1 0.59

BCHE CA2 0.60 ATRN BCHE 0.60 HYOU1 TAGLN2 0.59

ATRN VASN 0.60 MANlAl PCSK9 0.60 FCN3 MANlAl 0.59

BCHE CPB2 0.60 HYOU1 PFN1 0.60 ATRN TLN1 0.59

ATRN CNDP1 0.60 LPA TAGLN2 0.60 PRDX2 SEPP1 0.59

ATRN MINPP1 0.60 LPA PFN1 0.60 GP1BA MINPP1 0.59

LGALS3BP MINPP1 0.60 PRDX2 PRG4 0.60 BCHE PRG4 0.59

BCHE LGALS3BP 0.60 BCHE NIDI 0.60 CPB2 LGALS3BP 0.59

CACNA2D1 CPN2 0.60 LGALS3BP MANlAl 0.60 BCHE MANlAl 0.59

MANlAl MST1 0.60 SHBG THBS1 0.60 CKM PGLYRP2 0.59

CPB2 GPX3 0.60 APOA1 MINPP1 0.60 APOA1 GPX3 0.59

S100A9 VCAM1 0.60 CA2 MANlAl 0.60 THBS1 NA 0.59

PRDX2 TGFBI 0.60 LPA PEPD 0.60 APOA1 LGALS3BP 0.59

APOA1 CLEC3B 0.60 QSOX1 SEPP1 0.60 PEPD PGLYRP2 0.59

COMP MINPP1 0.60 CA1 MINPP1 0.60 CPB2 PRG4 0.59

ATRN HGFAC 0.60 CPB2 GP1BA 0.60 HYOU1 LCAT 0.59

CDH5 CNTN1 0.60 GPLD1 VCAM1 0.60 BCHE PCSK9 0.59

PRG4 TLN1 0.60 ATRN SHBG 0.60 ATRN IGF2 0.59

APOA1 HGFAC 0.60 APOE QSOX1 0.60 MINPP1 NIDI 0.59

COMP CPB2 0.60 APOC1 ATRN 0.60 APOA1 MASP2 0.59

ATRN MASP2 0.60 APOA1 PRG4 0.60 BCHE CA1 0.59

NCAM1 VCAM1 0.60 GP1BA MANlAl 0.60 APOE PRG4 0.59

APOA1 SPP2 0.60 LPA MST1 0.60 LPA TLN1 0.59

PEPD PROS1 0.60 GP1BA QSOX1 0.60 GPX3 MINPP1 0.59

GPX3 PCSK9 0.60 COMP TGFBI 0.60 APOA1 CA1 0.59

CLU CNTN1 0.60 BCHE GPX3 0.60 LGALS3BP PRG4 0.59

MINPP1 PCSK9 0.60 CPB2 VASN 0.60 FCN3 GPX3 0.59

CNDP1 LPA 0.60 BCHE QSOX1 0.60 COMP GPLD1 0.59

DBH LPA 0.60 CACNA2D1 MASP1 0.60 APOA1 IGF2 0.59

MINPP1 PRG4 0.60 ATRN MST1 0.60 APOA1 VCAM1 0.59

CKM PRG4 0.60 BCHE GP1BA 0.60 APOE MINPP1 0.59

LPA VASN 0.60 ATRN GP1BA 0.60 NIDI TGFBI 0.59

LUM VCAM1 0.60 APOE BCHE 0.60 APOA1 SHBG 0.59

NIDI SPP2 0.60 FCN3 PRG4 0.60 APOE GPX3 0.59

IGF2 LGALS3BP 0.60 CNDPl PDLIM1 0.60 APOA1 GP5 0.59

ATRN GPLD1 0.60 CACNA2D1 LUM 0.60 CA1 MANlAl 0.59

CKM PROS1 0.60 QSOX1 SPP2 0.60 APOC1 BCHE 0.59

PGLYRP2 VCAM1 0.60 APOA1 MST1 0.59 MANlAl NIDI 0.59

CA2 GPX3 0.60 HGFAC NIDI 0.59 CLEC3B LPA 0.59

CACNA2D1 TNXB 0.60 APOA1 APOC1 0.59 APOE COMP 0.59 MST1 QSOX1 0.59 BCHE MINPP1 0.59 CNTNl HYOU1 0.58

GP1BA SEPP1 0.59 CACNA2D1 PROS1 0.59 APOA1 PFN1 0.58

PCSK9 PRG4 0.59 CA2 TGFBI 0.59 CNDPl CPB2 0.58

CKM LPA 0.59 SPP2 VASN 0.59 LGALS3BP SPP2 0.58

FCN3 MINPP1 0.59 PDLIM1 PRDX2 0.59 CPB2 HGFAC 0.58

APOE GPLD1 0.59 ATRN LCAT 0.59 APOC3 LGALS3BP 0.58

GPX3 VCAM1 0.59 GPLD1 GPX3 0.59 CA2 CPB2 0.58

MINPP1 SPP2 0.59 APOE CA1 0.59 BCHE TGFBI 0.58

APOE NIDI 0.59 NIDI PRDX2 0.59 CA1 QSOX1 0.58

APOE PCSK9 0.59 FCN3 NIDI 0.59 FCN3 THBS1 0.58

CNDP1 MANlAl 0.59 APOA1 CPB2 0.59 CNDPl MINPP1 0.58

CNDP1 GPX3 0.59 MINPP1 QSOX1 0.59 MANlAl PRG4 0.58

ATRN CKM 0.59 APOA1 CKM 0.59 IGF2 MANlAl 0.58

CPB2 MANlAl 0.59 GPX3 MST1 0.59 CLEC3B GPX3 0.58

FCN3 GPLD1 0.59 CNTNl S100A9 0.59 CPB2 SPP2 0.58

GPLD1 PRG4 0.59 COMP GPX3 0.59 APOE CA2 0.58

APOE VASN 0.59 ATRN PEPD 0.59 PCSK9 TGFBI 0.58

APOA1 MANlAl 0.59 BCHE SEPP1 0.59 CPB2 VCAM1 0.58

GPX3 PRG4 0.59 CACNA2D1 PGLYRP2 0.59 QSOX1 TGFBI 0.58

GP1BA GPLD1 0.59 APOE FCN3 0.59 BCHE GPLD1 0.58

GP1BA NIDI 0.59 CA1 PDLIM1 0.59 APOC1 PDLIM1 0.58

PRG4 SPP2 0.59 NIDI PCSK9 0.59 APOC3 PRG4 0.58

LGALS3BP TGFBI 0.59 GPX3 SPP2 0.59 FCN3 GP1BA 0.58

CPB2 SHBG 0.59 ATRN DBH 0.59 BCHE CNDPl 0.58

CA1 CPB2 0.59 PDLIM1 THBS1 0.59 CPB2 IGF2 0.58

GPLD1 MANlAl 0.59 APOC3 CPB2 0.59 CACNA2D1 NCAM1 0.58

GPLD1 VASN 0.59 APOA1 TAGLN2 0.58 CNDPl QSOX1 0.58

GPLD1 LGALS3BP 0.59 APOC1 GPX3 0.58 BCHE SPP2 0.58

PCSK9 PDLIM1 0.59 CPB2 MST1 0.58 DBH PDLIM1 0.58

GP1BA TGFBI 0.59 APOE TGFBI 0.58 CA2 PDLIM1 0.58

ATRN PFN1 0.59 MANlAl SPP2 0.58 MINPP1 VASN 0.58

GPLD1 PCSK9 0.59 MANlAl MINPP1 0.58 CKM LGALS3BP 0.58

APOE MANlAl 0.59 CA1 TGFBI 0.58 BCHE VCAM1 0.58

CPB2 GPLD1 0.59 GP1BA LGALS3BP 0.58 CPB2 MASP2 0.58

SEPP1 NA 0.59 CA1 GPX3 0.58 CLEC3B CPB2 0.58

NIDI SEPP1 0.59 APOC1 MINPP1 0.58 GPX3 IGF2 0.58

PEPD PRDX2 0.59 CA2 QSOX1 0.58 CPB2 TLN1 0.58

ATRN TAGLN2 0.59 CA1 NIDI 0.58 MINPP1 MST1 0.58

APOA1 TGFBI 0.59 APOA1 DBH 0.58 CPB2 TGFBI 0.58

GPX3 MANlAl 0.59 APOA1 SEPP1 0.58 HGFAC QSOX1 0.58

CNTN1 PRG4 0.59 APOA1 LCAT 0.58 APOA1 GPLD1 0.58 MST1 THBS1 0.58 HGFAC MINPP1 0.58 GPX3 TLN1 0.57

APOA1 PEPD 0.58 GPX3 HGFAC 0.58 CA2 SEPP1 0.57

LGALS3BP SEPP1 0.58 SPP2 TGFBI 0.58 CNTNl PROS1 0.57

MINPP1 SEPP1 0.58 HGFAC LGALS3BP 0.58 COMP PDLIM1 0.57

PRG4 SEPP1 0.58 ATRN CNTN1 0.58 VASN NA 0.57

GP1BA PEPD 0.58 QSOX1 VASN 0.58 CLEC3B TGFBI 0.57

GPLD1 MINPP1 0.58 PEPD QSOX1 0.57 MANlAl SEPP1 0.57

FCN3 TGFBI 0.58 LGALS3BP PEPD 0.57 FCN3 LGALS3BP 0.57

DBH MAN1A1 0.58 GPLD1 SPP2 0.57 LCAT NA 0.57

MAN1A1 VASN 0.58 CACNA2D1 HYOU1 0.57 CPB2 SEPP1 0.57

GPLD1 SEPP1 0.58 HGFAC MANlAl 0.57 APOC1 LPA 0.57

MST1 PRG4 0.58 MST1 NIDI 0.57 BCHE PEPD 0.57

BCHE CLEC3B 0.58 PEPD NA 0.57 GP1BA MST1 0.57

GP1BA HGFAC 0.58 SEPP1 VASN 0.57 APOC3 QSOX1 0.57

CA2 NIDI 0.58 APOE CNDP1 0.57 APOC3 MINPP1 0.57

COMP PEPD 0.58 BCHE VASN 0.57 GPLD1 SHBG 0.57

CLEC3B MINPP1 0.58 GPX3 SEPP1 0.57 GPLD1 TLN1 0.57

APOC1 CPB2 0.58 CKM QSOX1 0.57 LGALS3BP VCAM1 0.57

GP5 PRG4 0.58 MASP2 MINPP1 0.57 CKM CPB2 0.57

MINPP1 TLN1 0.58 NIDI VASN 0.57 APOC1 MANlAl 0.57

HGFAC PRG4 0.58 GPX3 PEPD 0.57 MANlAl SHBG 0.57

CA2 PRG4 0.58 CLEC3B PRG4 0.57 CNTNl GPLD1 0.57

MASP2 QSOX1 0.58 LCAT PRDX2 0.57 GPLD1 MST1 0.57

CLEC3B NIDI 0.58 SPP2 NA 0.57 GPLD1 PRDX2 0.57

BCHE MST1 0.58 APOC3 GPX3 0.57 PEPD PRG4 0.57

CLEC3B MANlAl 0.58 HGFAC TGFBI 0.57 MANlAl TLN1 0.57

PRG4 VCAM1 0.58 GP5 MANlAl 0.57 BCHE MASP2 0.57

APOE SEPP1 0.58 PRG4 SHBG 0.57 MANlAl MASP2 0.57

CPB2 PCSK9 0.58 GP1BA VASN 0.57 DBH TGFBI 0.57

GP5 MINPP1 0.58 APOC3 BCHE 0.57 APOE TLN1 0.57

COMP GP1BA 0.58 CPB2 PEPD 0.57 CLEC3B LGALS3BP 0.57

CNTN1 LPA 0.58 CKM PDLIM1 0.57 QSOX1 SHBG 0.57

GP5 GPX3 0.58 DBH PRG4 0.57 LGALS3BP PCSK9 0.57

PRG4 TGFBI 0.58 CKM MANlAl 0.57 GPX3 LCAT 0.57

GPLD1 LCAT 0.58 MINPP1 TGFBI 0.57 LCAT PRG4 0.57

BCHE GP5 0.58 GP5 NIDI 0.57 GPLD1 TGFBI 0.57

APOC3 MANlAl 0.58 BCHE HGFAC 0.57 GP1BA LCAT 0.57

FCN3 SEPP1 0.58 IGF2 NIDI 0.57 MST1 TGFBI 0.57

BCHE TLN1 0.58 DBH GPX3 0.57 LCAT LGALS3BP 0.57

CNDP1 TGFBI 0.58 CPB2 GP5 0.57 APOC3 NA 0.57

CNTN1 NCAM1 0.58 LGALS3BP PRDX2 0.57 CA1 PRG4 0.57 CPB2 TAGLN2 0.57 MASP2 PRG4 0.57 PCSK9 THBS1 0.56

LCAT QSOX1 0.57 TGFBI VASN 0.57 CLEC3B GP1BA 0.56

CLEC3B GPLD1 0.57 CLEC3B QSOX1 0.57 CACNA2D1 PDLIM1 0.56

APOC3 NIDI 0.57 GP1BA VCAM1 0.57 APOC3 TGFBI 0.56

APOE MST1 0.57 BCHE CKM 0.57 GPX3 PFN1 0.56

CKM MINPP1 0.57 COMP VASN 0.57 IGF2 MINPP1 0.56

GPX3 SHBG 0.57 GPX3 TAGLN2 0.57 APOC1 QSOX1 0.56

CKM GPLD1 0.57 GP1BA SPP2 0.57 CKM GP1BA 0.56

MAN1A1 PEPD 0.57 CPB2 LCAT 0.57 NIDI PFN1 0.56

PRG4 TAGLN2 0.57 APOE HGFAC 0.57 LCAT NIDI 0.56

APOE VCAM1 0.57 APOC3 GP1BA 0.56 BCHE LCAT 0.56

CNDP1 NIDI 0.57 GP5 TGFBI 0.56 MANlAl TGFBI 0.56

CACNA2D1 CPB2 0.57 MINPP1 TAGLN2 0.56 CKM THBS1 0.56

CACNA2D1 THBS1 0.57 APOE MASP2 0.56 CA1 PEPD 0.56

MINPP1 PEPD 0.57 MINPP1 SHBG 0.56 APOE DBH 0.56

APOE GP5 0.57 PCSK9 SEPP1 0.56 APOC3 SPP2 0.56

CNDP1 THBS1 0.57 THBS1 TLN1 0.56 APOE LCAT 0.56

NIDI TAGLN2 0.57 CLEC3B SEPP1 0.56 NIDI TLN1 0.56

BCHE SHBG 0.57 GP1BA TLN1 0.56 CA2 GPLD1 0.56

QSOX1 TLN1 0.57 DBH MINPP1 0.56 PFN1 QSOX1 0.56

CNDP1 GPLD1 0.57 MASP2 NIDI 0.56 CNTNl NIDI 0.56

LCAT MINPP1 0.57 APOE CNTNl 0.56 GPLD1 MASP2 0.56

GP1BA GP5 0.57 COMP NIDI 0.56 QSOX1 TAGLN2 0.56

CPB2 PFN1 0.57 LGALS3BP SHBG 0.56 GPLD1 IGF2 0.56

APOA1 CNTNl 0.57 CPB2 DBH 0.56 LGALS3BP TLN1 0.56

CA1 SEPP1 0.57 GP1BA PRDX2 0.56 MST1 SEPP1 0.56

QSOX1 VCAM1 0.57 GPLD1 HGFAC 0.56 BCHE TAGLN2 0.56

CACNA2D1 NIDI 0.57 CKM GPX3 0.56 SPP2 VCAM1 0.56

APOE PEPD 0.57 LCAT MANlAl 0.56 LGALS3BP TAGLN2 0.56

BCHE DBH 0.57 GPLD1 TAGLN2 0.56 APOE SHBG 0.56

GP5 QSOX1 0.57 BCHE IGF2 0.56 GP5 LGALS3BP 0.56

DBH QSOX1 0.57 GP1BA PCSK9 0.56 NIDI SHBG 0.56

FCN3 PEPD 0.57 HGFAC PRDX2 0.56 APOE CLEC3B 0.56

PFN1 PRG4 0.57 GP1BA IGF2 0.56 GP1BA MASP2 0.56

CNTN1 PDLIM1 0.57 CNDPl SEPP1 0.56 CA2 LGALS3BP 0.56

GPX3 MASP2 0.57 CLEC3B PEPD 0.56 MANlAl VCAM1 0.56

MINPP1 PFN1 0.57 CNTNl CPB2 0.56 SEPP1 TGFBI 0.56

COMP LCAT 0.57 CNTNl QSOX1 0.56 APOC3 APOE 0.56

PEPD VCAM1 0.57 GPX3 TGFBI 0.56 GPLD1 PEPD 0.56

CA2 PEPD 0.57 APOC3 SEPP1 0.56 CNDPl LGALS3BP 0.56

GP5 GPLD1 0.57 APOA1 CACNA2D1 0.56 PCSK9 PEPD 0.56 APOC3 GPLD1 0.56 APOC1 PRG4 0.55 GP1BA SHBG 0.54

SEPP1 SPP2 0.56 PRDX2 VCAM1 0.55 CACNA2D1 PRG4 0.54

MINPP1 VCAM1 0.56 CA2 GP1BA 0.55 HGFAC PEPD 0.54

APOC1 GPLD1 0.56 CA2 THBS1 0.55 APOC1 SEPP1 0.54

TGFBI VCAM1 0.56 PEPD SPP2 0.55 APOE TAGLN2 0.54

PEPD VASN 0.56 HGFAC SEPP1 0.55 LCAT PCSK9 0.54

APOC1 THBS1 0.56 DBH GP1BA 0.55 GP5 VASN 0.54

CA1 LGALS3BP 0.56 MASP2 TGFBI 0.55 BCHE CNTNl 0.54

GPLD1 PFN1 0.56 HGFAC SPP2 0.55 CNTNl MANlAl 0.54

ATRN CACNA2D1 0.56 CA1 GP1BA 0.55 MASP2 PEPD 0.54

APOE IGF2 0.56 APOC1 APOE 0.55 LCAT SPP2 0.54

MAN1A1 TAGLN2 0.56 MST1 SPP2 0.55 APOC3 PEPD 0.54

SEPP1 TLN1 0.56 LGALS3BP MASP2 0.55 CA2 HGFAC 0.54

CKM NIDI 0.56 LCAT VASN 0.55 CA1 THBS1 0.54

GP5 SEPP1 0.56 GP1BA PFN1 0.55 PCSK9 VASN 0.54

APOC3 VASN 0.56 PEPD TLN1 0.55 CA1 LCAT 0.54

PEPD TGFBI 0.56 CACNA2D1 GPX3 0.55 LCAT MST1 0.54

FCN3 VASN 0.56 TAGLN2 TGFBI 0.55 IGF2 SPP2 0.54

HGFAC NA 0.56 PFN1 TGFBI 0.55 CNDPl GP1BA 0.54

APOE CKM 0.56 CNDP1 LCAT 0.55 LCAT SEPP1 0.54

TGFBI TLN1 0.56 HGFAC VCAM1 0.55 GP5 PEPD 0.54

IGF2 SEPP1 0.56 PRDX2 THBS1 0.55 CLEC3B VCAM1 0.54

APOC1 LGALS3BP 0.56 CACNA2D1 MANlAl 0.55 APOC3 FCN3 0.54

SHBG TGFBI 0.56 CA1 GPLD1 0.55 MASP2 VASN 0.54

IGF2 QSOX1 0.55 APOC1 TGFBI 0.55 FCN3 HGFAC 0.54

BCHE PFN1 0.55 DBH LGALS3BP 0.55 APOC1 NIDI 0.54

CNTN1 GPX3 0.55 LCAT TGFBI 0.55 MASP2 SPP2 0.54

IGF2 TGFBI 0.55 FCN3 LCAT 0.55 CNTNl TGFBI 0.54

PEPD SEPP1 0.55 NIDI VCAM1 0.55 CA1 HGFAC 0.54

PRDX2 SPP2 0.55 DBH SEPP1 0.55 CACNA2D1 MINPP1 0.54

GP1BA TAGLN2 0.55 COMP LGALS3BP 0.55 APOC1 PEPD 0.54

SHBG VASN 0.55 COMP VCAM1 0.55 MST1 PEPD 0.54

MAN1A1 PFN1 0.55 PRDX2 VASN 0.55 SEPP1 SHBG 0.54

CKM TGFBI 0.55 CA2 LCAT 0.55 MASP2 SEPP1 0.54

HGFAC VASN 0.55 CACNA2D1 LPA 0.55 HGFAC IGF2 0.54

DBH GPLD1 0.55 CKM SEPP1 0.55 PCSK9 VCAM1 0.54

DBH NIDI 0.55 APOC1 GP1BA 0.55 CKM PEPD 0.54

LGALS3BP PFN1 0.55 CNTNl GP1BA 0.54 IGF2 VASN 0.54

SEPP1 VCAM1 0.55 CNDPl PEPD 0.54 APOC3 VCAM1 0.54

LGALS3BP MST1 0.55 APOE PFN1 0.54 APOC3 PRDX2 0.54

VCAM1 NA 0.55 FCN3 SPP2 0.54 MST1 NA 0.54 CNTN1 MINPP1 0.54 CNTNl PRDX2 0.53 CACNA2D1 TGFBI 0.52

LCAT TAGLN2 0.54 PEPD SHBG 0.53 CA1 CNTNl 0.52

SEPP1 TAGLN2 0.54 DBH LCAT 0.53 APOC3 MASP2 0.52

CACNA2D1 QSOX1 0.54 COMP THBS1 0.53 CLEC3B NA 0.52

DBH THBS1 0.54 LCAT VCAM1 0.53 MASP2 VCAM1 0.52

HGFAC LCAT 0.54 CACNA2D1 LGALS3BP 0.53 CLEC3B COMP 0.52

HGFAC PCSK9 0.54 LCAT TLN1 0.53 CLEC3B SPP2 0.52

BCHE CACNA2D1 0.54 DBH VASN 0.53 CLEC3B HGFAC 0.52

LCAT PEPD 0.54 TAGLN2 VCAM1 0.53 CLEC3B PRDX2 0.52

IGF2 LCAT 0.54 CNTNl VASN 0.53 APOC3 CA2 0.52

PFN1 SEPP1 0.54 LCAT MASP2 0.53 CNTNl NA 0.52

TAGLN2 VASN 0.54 CA2 SPP2 0.53 PFN1 VCAM1 0.52

APOC3 LCAT 0.54 SPP2 TAGLN2 0.53 COMP MASP2 0.52

MST1 VASN 0.54 CNTNl PEPD 0.53 CNTNl LCAT 0.52

PEPD TAGLN2 0.53 VASN VCAM1 0.52 MASP2 NA 0.51

COMP MST1 0.53 APOC3 PCSK9 0.52 CLEC3B MASP2 0.51

GP5 LCAT 0.53 MST1 PRDX2 0.52 CKM VCAM1 0.51

FCN3 MST1 0.53 CLEC3B FCN3 0.52 MST1 PCSK9 0.51

CKM LCAT 0.53 APOC3 CNTNl 0.52 APOC3 CLEC3B 0.51

PEPD PFN1 0.53 GP5 HGFAC 0.52 LCAT SHBG 0.51

CA2 VCAM1 0.53 LCAT PFN1 0.52 CNTNl HGFAC 0.51

CACNA2D1 SEPP1 0.53 HGFAC MASP2 0.52 CNTNl SPP2 0.51

APOE CACNA2D1 0.53 CA2 VASN 0.52 APOC1 HGFAC 0.51

COMP SPP2 0.53 IGF2 VCAM1 0.52 SHBG SPP2 0.51

APOC3 MST1 0.53 CNDPl SPP2 0.52 CKM MASP2 0.51

APOC3 COMP 0.53 TAGLN2 TLN1 0.52 HGFAC SHBG 0.51

CNTN1 VCAM1 0.53 CACNA2D1 VCAM1 0.52 APOC3 TLN1 0.51

APOC1 VASN 0.53 PCSK9 SPP2 0.52 CNTNl TAGLN2 0.51

CA1 VASN 0.53 TLN1 VASN 0.52 APOC3 IGF2 0.51

CA1 VCAM1 0.53 HGFAC MST1 0.52 APOC3 CKM 0.51

FCN3 VCAM1 0.53 APOC1 SPP2 0.52 CNTNl FCN3 0.51

CLEC3B VASN 0.53 CKM SPP2 0.52 PFN1 TLN1 0.51

DBH PEPD 0.53 CKM VASN 0.52 CKM FCN3 0.51

CNTN1 SEPP1 0.53 CACNA2D1 GPLD1 0.52 CNDPl VCAM1 0.51

APOC3 CA1 0.53 PFN1 SPP2 0.52 SHBG VCAM1 0.51

MST1 VCAM1 0.53 CA1 SPP2 0.52 APOC3 GP5 0.51

PFN1 VASN 0.53 GP5 VCAM1 0.52 IGF2 MST1 0.51

CNDP1 VASN 0.53 SPP2 TLN1 0.52 DBH SPP2 0.51

APOC3 HGFAC 0.53 CLEC3B MST1 0.52 CKM MST1 0.51

IGF2 PEPD 0.53 GP5 SPP2 0.52 CNTNl MST1 0.51

CLEC3B LCAT 0.53 CNDPl HGFAC 0.52 GP5 MST1 0.51 APOC1 LCAT 0.51 PFN1 NA 0.49 CKM PFN1 0.47

CACNA2D1 GP1BA 0.51 IGF2 MASP2 0.49 GP5 NA 0.47

HGFAC TAGLN2 0.50 CNTNl DBH 0.49 SHBG NA 0.47

CKM HGFAC 0.50 MST1 TAGLN2 0.49 CLEC3B GP5 0.47

TLN1 VCAM1 0.50 PFN1 PRDX2 0.49 GP5 TAGLN2 0.47

APOC3 DBH 0.50 FCN3 NA 0.49 CKM GP5 0.47

DBH VCAM1 0.50 CA1 MASP2 0.49 FCN3 PRDX2 0.47

CA2 CNTN1 0.50 CKM CNTNl 0.49 CA2 PFN1 0.47

APOC3 CNDP1 0.50 GP5 MASP2 0.49 CNTNl TLN1 0.47

HGFAC TLN1 0.50 MST1 PFN1 0.49 CA2 PRDX2 0.47

COMP HGFAC 0.50 MASP2 TAGLN2 0.49 SHBG TAGLN2 0.47

CKM PRDX2 0.50 MST1 TLN1 0.49 CKM COMP 0.47

CNTN1 PCSK9 0.50 CLEC3B CNTNl 0.49 IGF2 SHBG 0.47

APOC3 TAGLN2 0.50 CNTNl COMP 0.48 FCN3 TAGLN2 0.47

DBH HGFAC 0.50 FCN3 IGF2 0.48 CA1 CKM 0.47

HGFAC PFN1 0.50 CA1 CLEC3B 0.48 APOC1 CLEC3B 0.47

APOC3 SHBG 0.50 PRDX2 TAGLN2 0.48 CLEC3B CNDPl 0.47

CNTN1 IGF2 0.50 APOC1 MST1 0.48 DBH MASP2 0.47

APOC1 APOC3 0.50 CNTNl SHBG 0.48 CA1 PFN1 0.47

MASP2 PRDX2 0.50 CACNA2D1 SPP2 0.48 CKM SHBG 0.47

CNTN1 MASP2 0.50 IGF2 PCSK9 0.48 FCN3 SHBG 0.47

CNTN1 PFN1 0.50 CKM TAGLN2 0.48 MASP2 SHBG 0.47

APOC3 PFN1 0.50 MASP2 PFN1 0.48 IGF2 TAGLN2 0.47

CA1 MST1 0.50 FCN3 GP5 0.48 CLEC3B TLN1 0.47

APOC1 VCAM1 0.50 CACNA2D1 CNTNl 0.48 CNDPl MASP2 0.47

CACNA2D1 VASN 0.50 MASP2 PCSK9 0.48 CA2 TAGLN2 0.47

CA2 MST1 0.50 CA2 CLEC3B 0.48 GP5 PFN1 0.47

CLEC3B PCSK9 0.50 CA2 MASP2 0.48 FCN3 PCSK9 0.47

IGF2 NA 0.49 CACNA2D1 MASP2 0.48 IGF2 PFN1 0.47

CACNA2D1 PEPD 0.49 CKM CLEC3B 0.48 FCN3 PFN1 0.47

CNDP1 CNTN1 0.49 MASP2 TLN1 0.48 PFN1 SHBG 0.46

MST1 SHBG 0.49 APOC3 CACNA2D1 0.48 CA1 TAGLN2 0.46

FCN3 MASP2 0.49 GP5 PRDX2 0.48 CACNA2D1 MST1 0.46

DBH MST1 0.49 CKM PCSK9 0.48 CLEC3B IGF2 0.46

CACNA2D1 LCAT 0.49 CLEC3B SHBG 0.48 GP5 IGF2 0.46

CNTN1 GP5 0.49 CLEC3B TAGLN2 0.48 CACNA2D1 HGFAC 0.46

MASP2 MST1 0.49 PCSK9 TAGLN2 0.48 COMP IGF2 0.46

APOC1 CNTN1 0.49 PRDX2 NA 0.48 COMP GP5 0.46

CKM NA 0.49 CLEC3B PFN1 0.48 GP5 SHBG 0.46

CNDP1 MST1 0.49 IGF2 PRDX2 0.48 CA1 NA 0.46

TAGLN2 NA 0.49 PCSK9 PFN1 0.47 CA2 CKM 0.46 PRDX2 SHBG 0.46 CNDPl GP5 0.44 APOC1 SHBG 0.42

CKM CNDP1 0.46 CA2 SHBG 0.44 CA2 CACNA2D1 0.42

CNDP1 FCN3 0.46 APOC1 PFN1 0.44 CA2 COMP 0.42

CLEC3B DBH 0.46 IGF2 TLN1 0.44 CA1 DBH 0.42

CNDP1 IGF2 0.46 CA1 CACNA2D1 0.44 COMP TLN1 0.42

DBH TAGLN2 0.46 CACNA2D1 FCN3 0.44 CA2 DBH 0.42

CA1 IGF2 0.46 CA1 PCSK9 0.44 CNDPl TLN1 0.42

CKM IGF2 0.46 DBH NA 0.44 DBH TLN1 0.42

APOC1 MASP2 0.46 CA1 PRDX2 0.44 APOC1 CA2 0.42

CA1 FCN3 0.46 CNDPl NA 0.44 CACNA2D1 TAGLN2 0.42

CA1 GP5 0.46 COMP NA 0.44 APOC1 TLN1 0.41

APOC1 FCN3 0.46 DBH PRDX2 0.44 CACNA2D1 PFN1 0.41

CA2 FCN3 0.46 PFN1 TAGLN2 0.44 CA2 TLN1 0.41

COMP PFN1 0.46 PRDX2 TLN1 0.44 APOC1 CNDPl 0.41

CA2 IGF2 0.46 SHBG TLN1 0.44 CACNA2D1 GP5 0.41

COMP TAGLN2 0.45 DBH SHBG 0.44 CACNA2D1 TLN1 0.41

CNDP1 TAGLN2 0.45 CNDPl SHBG 0.44 CACNA2D1 COMP 0.41

DBH PFN1 0.45 CA2 PCSK9 0.43 CACNA2D1 PCSK9 0.41

CNDP1 PFN1 0.45 APOC1 NA 0.43 APOC1 DBH 0.41

GP5 TLN1 0.45 CACNA2D1 CLEC3B 0.43 COMP DBH 0.40

CACNA2D1 PRDX2 0.45 CACNA2D1 IGF2 0.43 APOC1 CACNA2D1 0.40

CA2 GP5 0.45 APOC1 GP5 0.43 CACNA2D1 CNDPl 0.40

GP5 PCSK9 0.45 PCSK9 TLN1 0.43 CACNA2D1 DBH 0.40

APOC1 TAGLN2 0.45 CACNA2D1 SHBG 0.43

APOC1 CKM 0.45 CACNA2D1 CKM 0.43

DBH FCN3 0.45 APOC1 CA1 0.43

CA1 SHBG 0.45 CA1 CNDPl 0.43

PCSK9 PRDX2 0.45 CA1 TLN1 0.43

COMP FCN3 0.45 CA1 CA2 0.43

COMP SHBG 0.45 DBH GP5 0.43

PCSK9 SHBG 0.45 COMP PRDX2 0.43

CKM DBH 0.45 CNDPl PCSK9 0.43

DBH IGF2 0.45 DBH PCSK9 0.43

APOC1 IGF2 0.45 APOC1 PCSK9 0.43

FCN3 TLN1 0.45 CACNA2D1 NA 0.43

PCSK9 NA 0.45 CA2 CNDPl 0.43

CNDP1 PRDX2 0.45 APOC1 COMP 0.42

CA2 NA 0.45 CNDPl COMP 0.42

TLN1 NA 0.44 CNDPl DBH 0.42

CKM TLN1 0.44 CA1 COMP 0.42

APOC1 PRDX2 0.44 COMP PCSK9 0.42 Table 3. Panel Combinations of Three Candidate Latent TB Biomarkers

APOE CLEC3B ECM1 0.80

CLEC3B ECM1 TLN1 0.80

CLEC3B ECM1 GP1BA 0.80

APOA1 CLEC3B ECM1 0.80

CLEC3B ECM1 GP5 0.80

CLEC3B ECM1 FCN3 0.80

CLEC3B ECM1 PROS 1 0.80

CLEC3B ECM1 QSOX1 0.80

CA2 CLEC3B ECM1 0.80

CLEC3B ECM1 MAN1A1 0.80

CLEC3B ECM1 VCAM1 0.80

CLEC3B ECM1 IGFBP3 0.80

CLEC3B ECM1 MASP2 0.80

CLEC3B CNDP1 ECM1 0.80

CLEC3B ECM1 ORM1 0.80

APOC3 CLEC3B ECM1 0.79

APOC1 CLEC3B ECM1 0.79

CA1 CLEC3B ECM1 0.79

CLEC3B ECM1 NIDI 0.79

CLEC3B ECM1 GPX3 0.79

CD 163 CLEC3B ECM1 0.79

CLEC3B ECM1 HGFAC 0.79

CLEC3B ECM1 MINPP1 0.79

CLEC3B ECM1 PGLYRP2 0.79

CLEC3B ECM1 S 100A8 0.79

CLEC3B ECM1 VASN 0.79

CLEC3B DBH ECM1 0.79

CLEC3B ECM1 IGF2 0.79

CLEC3B CPB2 ECM1 0.79

CLEC3B ECM1 MASP1 0.79

CLEC3B ECM1 PCSK9 0.79

CLEC3B ECM1 LUM 0.79

CLEC3B ECM1 SEPP1 0.79

CACNA2D1 CLEC3B ECM1 0.79

CLEC3B ECM1 S 100A9 0.79

CLEC3B CNTN1 ECM1 0.76 Table 4. Panel Combinations of Four Candidate Latent TB Biomarkers

CLEC3B ECM1 MASP1 PON1 0.87

CLEC3B ECM1 HGFAC PON1 0.87

CLEC3B ECM1 PCSK9 PON1 0.87

CLEC3B ECM1 GP5 PON1 0.87

BCHE CLEC3B ECM1 PON1 0.87

CLEC3B ECM1 GPLD1 PON1 0.87

CLEC3B ECM1 PON1 SPP2 0.87

CLEC3B ECM1 PON1 VASN 0.86

CLEC3B ECM1 PON1 PTGDS 0.86

CLEC3B ECM1 PON1 THBS 1 0.86

CLEC3B ECM1 PON1 TNXB 0.86

CLEC3B ECM1 LCP1 PON1 0.86

CLEC3B ECM1 PON1 PRDX2 0.86

APOE CLEC3B ECM1 PON1 0.86

APOC3 CLEC3B ECM1 PON1 0.86

CLEC3B ECM1 MASP2 PON1 0.86

CLEC3B ECM1 LGALS3BP PON1 0.86

CLEC3B ECM1 PON1 SHBG 0.86

CLEC3B ECM1 PON1 S 100A9 0.86

CLEC3B ECM1 PON1 SEPP1 0.86

CLEC3B ECM1 LUM PON1 0.86

CKM CLEC3B ECM1 PON1 0.86

CLEC3B ECM1 PON1 S 100A8 0.86

CLEC3B ECM1 PDLIM1 PON1 0.86

CLEC3B ECM1 PON1 VWF 0.86

CA1 CLEC3B ECM1 PON1 0.86

CLEC3B ECM1 PON1 PROS 1 0.86

CLEC3B ECM1 IGF2 PON1 0.86

CLEC3B ECM1 FCN3 PON1 0.86

CD14 CLEC3B ECM1 PON1 0.85

CLEC3B DBH ECM1 PON1 0.85

CLEC3B CPB2 ECM1 PON1 0.85

CLEC3B ECM1 ORM1 PON1 0.85

CLEC3B ECM1 LRG1 PON1 0.85

CLEC3B CNTN1 ECM1 PON1 0.84

Table 5. Panel Combinations of Four Candidate Latent TB Biomarkers CLEC3B ECM1 IGFBP3 VTN 0.88

CLEC3B ECM1 LPA VTN 0.88

CLEC3B ECM1 IGFALS VTN 0.87

CLEC3B CPN2 ECM1 VTN 0.87

CLEC3B ECM1 VASN VTN 0.87

CLEC3B ECM1 PEPD VTN 0.86

CLEC3B ECM1 SPP2 VTN 0.86

CLEC3B CPN1 ECM1 VTN 0.86

CLEC3B CLU ECM1 VTN 0.86

CACNA2D1 CLEC3B ECM1 VTN 0.86

CLEC3B ECM1 TAGLN2 VTN 0.86

CLEC3B ECM1 QSOX1 VTN 0.86

CLEC3B ECM1 PFN1 VTN 0.86

CLEC3B ECM1 PRG4 VTN 0.86

CLEC3B ECM1 LUM VTN 0.86

CLEC3B ECM1 VTN VWF 0.86

CLEC3B ECM1 GPX3 VTN 0.85

CA1 CLEC3B ECM1 VTN 0.85

CLEC3B ECM1 NCAM1 VTN 0.85

CLEC3B COMP ECM1 VTN 0.85

CLEC3B ECM1 PRDX2 VTN 0.85

ATRN CLEC3B ECM1 VTN 0.85

CLEC3B ECM1 MST1 VTN 0.85

CA2 CLEC3B ECM1 VTN 0.85

CLEC3B ECM1 SELL VTN 0.85

APOA4 CLEC3B ECM1 VTN 0.84

CLEC3B ECM1 GPLD1 VTN 0.84

APOC1 CLEC3B ECM1 VTN 0.84

CLEC3B ECM1 GP1BA VTN 0.84

APOE CLEC3B ECM1 VTN 0.84

CLEC3B ECM1 HABP2 VTN 0.84

CLEC3B ECM1 PTGDS VTN 0.84

BCHE CLEC3B ECM1 VTN 0.84

CLEC3B ECM1 TLN1 VTN 0.84

CLEC3B ECM1 LRG1 VTN 0.83

CD 163 CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 MASP1 VTN 0.83

CLEC3B ECM1 TNXB VTN 0.83

CLEC3B ECM1 PCSK9 VTN 0.83

CLEC3B ECM1 MASP2 VTN 0.83

CLEC3B ECM1 THBS 1 VTN 0.83 CLEC3B ECM1 SHBG VTN 0.83

CKM CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 TGFBI VTN 0.83

APOC3 CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 PDLIM1 VTN 0.83

CLEC3B ECM1 LGALS3BP VTN 0.83

BTD CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 NIDI VTN 0.83

APOA1 CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 VCAM1 VTN 0.83

CLEC3B ECM1 LCP1 VTN 0.83

CLEC3B CPB2 ECM1 VTN 0.83

CDH5 CLEC3B ECM1 VTN 0.83

CLEC3B ECM1 LCAT VTN 0.83

CLEC3B ECM1 MINPP1 VTN 0.83

CLEC3B ECM1 MAN1A1 VTN 0.83

CLEC3B ECM1 ORM1 VTN 0.83

CLEC3B ECM1 HYOU1 VTN 0.83

CLEC3B ECM1 PGLYRP2 VTN 0.83

CLEC3B ECM1 FCN3 VTN 0.82

CD14 CLEC3B ECM1 VTN 0.82

CLEC3B ECM1 IGF2 VTN 0.82

CLEC3B ECM1 HGFAC VTN 0.82

CLEC3B ECM1 SEPP1 VTN 0.82

CLEC3B ECM1 GP5 VTN 0.82

CLEC3B ECM1 PROS 1 VTN 0.82

CLEC3B ECM1 S 100A8 VTN 0.82

CLEC3B ECM1 S 100A9 VTN 0.82

CLEC3B DBH ECM1 VTN 0.82

CLEC3B CNTN1 ECM1 VTN 0.82

Table 6. Panel Combinations of Two or Three Active TB Biomarkers

PGLYRP2 SELL NA 0.73

LGALS3BP QSOX1 SELL 0.72

QSOX1 SELL SEPP1 0.72

PGLYRP2 QSOX1 SELL 0.72

CD14 PEPD SELL 0.72

CD14 SELL SEPP1 0.72

SELL TAGLN2 NA 0.72

PFN1 SELL NA 0.72

PEPD QSOX1 SELL 0.72

SELL VASN NA 0.72

CPN2 PEPD SELL 0.72

QSOX1 SELL TAGLN2 0.71

LGALS3BP SELL SEPP1 0.71

QSOX1 SELL VASN 0.71

CPN2 SELL SEPP1 0.71

CD14 LGALS3BP SELL 0.71

LGALS3BP PEPD SELL 0.71

PEPD SELL SEPP1 0.71

PFN1 QSOX1 SELL 0.71

CD14 SELL VASN 0.70

CD14 CPN2 SELL 0.70

CD14 PFN1 SELL 0.70

PGLYRP2 SELL SEPP1 0.70

PEPD PGLYRP2 SELL 0.70

CD14 SELL TAGLN2 0.70

LGALS3BP PGLYRP2 SELL 0.70

CPN2 LGALS3BP SELL 0.70

LGALS3BP SELL TAGLN2 0.70

LGALS3BP PFN1 SELL 0.70

CD14 PGLYRP2 SELL 0.69

PEPD SELL TAGLN2 0.69

PGLYRP2 SELL TAGLN2 0.69

PFN1 PGLYRP2 SELL 0.69

CPN2 PFN1 SELL 0.69

PEPD PFN1 SELL 0.69

CPN2 SELL TAGLN2 0.69

SELL SEPP1 VASN 0.69

CD14 CPN2 NA 0.69

CPN2 SELL VASN 0.69

SELL SEPP1 TAGLN2 0.69

PEPD SELL VASN 0.69 PGLYRP2 QSOX1 VASN 0.60

CPN2 PFN1 QSOX1 0.60

PEPD PGLYRP2 NA 0.59

CPN2 SEPP1 VASN 0.59

PGLYRP2 QSOX1 TAGLN2 0.59

CPN2 QSOX1 TAGLN2 0.59

PGLYRP2 SEPP1 VASN 0.59

CPN2 TAGLN2 VASN 0.59

LGALS3BP QSOX1 VASN 0.59

CPN2 LGALS3BP PEPD 0.59

CPN2 PFN1 VASN 0.59

PGLYRP2 SEPP1 TAGLN2 0.59

PFN1 PGLYRP2 QSOX1 0.59

LGALS3BP QSOX1 SEPP1 0.58

LGALS3BP PEPD PGLYRP2 0.58

CPN2 LGALS3BP PFN1 0.58

PFN1 PGLYRP2 SEPP1 0.58

PGLYRP2 TAGLN2 VASN 0.58

CPN2 LGALS3BP TAGLN2 0.58

LGALS3BP SEPP1 NA 0.58

PFN1 PGLYRP2 VASN 0.58

LGALS3BP PEPD QSOX1 0.58

CPN2 LGALS3BP SEPP1 0.58

PEPD PGLYRP2 QSOX1 0.58

QSOX1 VASN NA 0.58

CPN2 PFN1 TAGLN2 0.57

PEPD QSOX1 NA 0.57

LGALS3BP PEPD NA 0.57

LGALS3BP QSOX1 TAGLN2 0.57

SEPP1 VASN NA 0.57

CPN2 SEPP1 TAGLN2 0.57

LGALS3BP SEPP1 VASN 0.57

LGALS3BP PFN1 QSOX1 0.57

CPN2 PEPD SEPP1 0.57

PFN1 PGLYRP2 TAGLN2 0.57

PEPD PGLYRP2 SEPP1 0.57

CPN2 PFN1 SEPP1 0.57

PEPD PGLYRP2 VASN 0.57

CPN2 PEPD TAGLN2 0.57

PEPD PGLYRP2 TAGLN2 0.57

LGALS3BP PEPD VASN 0.57 Table 7. Panel Combinations of Active TB and Latent TB Biomarkers

Table 8. Cross-Sectional Comparison of Differential Intensity (DI) Ratios for Select Latent TB Biomarkers

Table 9. Longitudinal Comparison of Differential Intensity (DI) Ratios for Select Latent TB Biomarkers

Equivalents

In describing exemplary embodiments, specific terminology is used for the sake of clarity. For purposes of description, each specific term is intended to at least include all technical and functional equivalents that operate in a similar manner to accomplish a similar purpose. Additionally, in some instances where a particular exemplary embodiment includes a plurality of system elements or method steps, those elements or steps may be replaced with a single element or step. Likewise, a single element or step may be replaced with a plurality of elements or steps that serve the same purpose. Further, where parameters for various properties are specified herein for exemplary embodiments, those parameters may be adjusted up or down by l/20th, 1/lOth, l/5th, l/3rd, ½, etc., or by rounded-off approximations thereof, unless otherwise specified. Moreover, while exemplary embodiments have been shown and described with references to particular embodiments thereof, those of ordinary skill in the art will understand that various substitutions and alterations in form and details may be made therein without departing from the scope of the invention. Further still, other aspects, functions and advantages are also within the scope of the invention.

Incorporation by Reference

The contents of all references, including patents and patent applications, cited throughout this application are hereby incorporated herein by reference in their entirety. The appropriate components and methods of those references may be selected for the invention and embodiments thereof. Still further, the components and methods identified in the Background section are integral to this disclosure and can be used in conjunction with or substituted for components and methods described elsewhere in the disclosure within the scope of the invention.

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