BIOMARKERS FOR CARDIOVASCULAR EVENTS

Abstract

The present disclosure relates to methods and uses involving the determination of lipid concentrations in order to diagnose, predict, prevent and/or treat one or more cardiovascular events in a subject. The methods include analyzing lipid concentrations of a sample from the subject and comparing them to a control.

Claims

1. A method for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I: ##STR00005## wherein R.sup.1 is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 11-17 carbon atoms, and wherein R.sup.2 is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 13-25 carbon atoms; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II: ##STR00006## wherein R.sup.3 and R.sup.4 are saturated, mono-unsaturated or polyunsaturated alkyl chains; and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

2. The method of claim 1, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

3. The method of claim 1 or 2, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or additional PC as indicated in Table 1, when compared to a control.

4. The method of any one of the preceding claims, wherein the method further comprises after the determining step (c) and/or (iii), (d) administering a treatment to the subject who is determined to have a risk to develop one or more CV events.

5. A method of treating cardiovascular disease (CVD) or preventing one or more cardiovascular (CV) events in a subject, comprising administering to the subject a treatment, if the subject has been identified as having a risk of developing one or more CV events by the method of any one of claims 1-3.

6. A method of detecting at least two lipids in a sample from a subject, the method comprising detecting a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II.

7. The method of claim 6, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

8. The method of claim 6 or 7, wherein the method further comprises detecting in the sample a concentration of at least one additional Cer and/or additional PC, selected from any of the Cer and PC species referred to in Table 1.

9. The method of any one of claims 6-8, wherein the method comprises comparing the concentration(s) of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I, the concentration(s) of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II and/or the concentration(s) of the at least one additional Cer and/or the at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, to a control.

10. The method of any one of claims 6-9, wherein the method further comprises using a standard combination comprising at least one Cer of Formula I and/or at least one PC of Formula II.

11. The method of claim 10, wherein the standard combination further comprises at least one additional Cer and/or PC, selected from any of the Cer and PC species referred to in Table 1.

12. The method of any one of claims 6-11, wherein the method further comprises (a) comparing the concentration of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I, the concentrations of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II and/or the concentration of the at least one additional Cer and/or PC, selected from any of the Cer and PC species referred to in Table 1, to a control, and (b) determining the subject as having a risk of developing one or more CV events if the concentration of the at least one Cer of Formula I, the at least one PC of Formula II and/or the at least one additional Cer and/or PC is changed, when compared to a control.

13. A method of obtaining data for determining the risk of a subject to develop one or more CV events, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

14. The method of claim 13, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

15. The method of claim 13 or 14, wherein the method further comprises (a) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (b) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

16. The method of any one of claims 13-15, wherein the method further comprises obtaining the sample from the subject.

17. A method of generating quantitative data for a subject, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; and (b) assaying a sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II.

18. The method of claim 17, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

19. The method of claim 17 or 18, wherein the method further comprises (a) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (b) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1.

20. The method of any one of claims 17-19, wherein the assaying is performed with mass spectrometry (MS).

21. A method of evaluating the effectiveness of a CVD treatment in a subject, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the treatment is effective, if the sample contains (a) decreased concentration(s) of the at least one Cer of Formula I and/or (an) increased concentration(s) of the at least one PC of Formula II, when compared to a control.

22. The method of claim 21, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

23. The method of claim 21 or 22, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the treatment is effective, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC, when compared to a control.

24. The method of any one of claims 21-23, wherein the method further comprises after the determining step (c) or (iii), (d) changing, supplementing, or keeping the same an already administered treatment in the subject based on the at least one Cer of Formula I concentration(s), the additional Cer concentration(s), the at least one PC of Formula II concentration(s) and/or the additional PC concentration(s) obtained in the determining step (c) or (iii).

25. The method of any one of claims 21-23, wherein the method further comprises determining that the treatment is not effective in the subject and escalating the treatment of the subject or changing to a different treatment.

26. A method of treating CVD or preventing one or more CV events in a subject undergoing treatment for CVD, wherein the method comprises administering to the subject a drug, and/or providing therapeutic, behavioral and/or lifestyle modification, if the subject has been identified as being ineffectively treated for CVD according to the method of any one of claims 21-23.

27. A method of choosing an appropriate CVD treatment for a subject, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

28. The method of claim 27, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

29. The method of claim 27 or 28, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1. (iii) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

30. The method of any one of claims 27-29, wherein the method further comprises after the determining step (c) or (iii), (d) treating the subject based on the at least one Cer of Formula I concentration(s), the additional Cer concentration(s), the at least one PC o Formula II concentration(s) and/or the additional PC concentration(s) obtained in the determining step (c) or step (iii).

31. The method of any one of claims 27-29, wherein the method further comprises determining that the subject is in need of a treatment or a change in, or a supplementation of, an already administered treatment, and administering to the subject the treatment that the subject is determined to be in need of.

32. A method of treating CVD or preventing one or more CV events in a subject, wherein the method comprises administering to the subject a drug, and/or providing therapeutic, behavioral and/or lifestyle modification, if the subject has been identified as being in need of a change in, or supplementation of an already administered treatment according to the method of any one of claims 27-29.

33. A method of collecting data for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II; and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

34. The method of claim 33, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

35. The method of claim 33 or 34, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

36. A method of collecting data for detecting in a sample from a subject a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II.

37. The method of claim 36, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

38. The method of claim 36 or 37, wherein the method further comprises detecting in the sample a concentration of at least one additional Cer and/or PC, selected from any of the Cer and PC species referred to in Table 1.

39. A method of collecting data for evaluating the effectiveness of a CVD treatment in a subject, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the treatment is effective, if the sample contains (a) decreased concentration(s) of the at least one Cer of Formula I and/or (an) increased concentration(s) of the at least one PC of Formula II, when compared to a control.

40. The method of claim 39, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

41. The method of claim 39 or 40, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the treatment is effective, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC, when compared to a control.

42. A method of collecting data for choosing an appropriate CVD treatment for a subject, wherein the method comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

43. The method of claim 42, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula 2 is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

44. The method of claim 42 or 43, wherein the method further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1 and (iii) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or at least one additional PC as indicated in Table 1, when compared to a control.

45. A cardiovascular disease (CVD) marker combination for determining the risk of a subject to develop one or more cardiovascular events, wherein the CVD marker combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II.

46. The CVD marker combination of claim 45, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

47. The CVD marker combination of claim 45 or 46, wherein the combination further comprises at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1.

48. A use of a cardiovascular disease (CVD) marker combination for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the CVD marker combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II, and wherein the use comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II; and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

49. The use of claim 48, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

50. The use of claim 48 or 49, wherein the CVD marker combination further comprises at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, and wherein the use comprises (i) assaying the sample to determine a concentration of the at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of the at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

51. A use of a cardiovascular disease (CVD) marker combination for detecting in a sample from a subject a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II.

52. The use of claim 51, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

53. The use of claim 51 or 52, wherein the use further comprises detecting in the sample a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

54. The use of any one of claims 51-53, wherein the use comprises comparing the concentration of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I, the concentrations of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II and/or the concentration of the at least one additional Cer and/or the at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, to a control.

55. A use of a cardiovascular disease (CVD) marker combination for obtaining data for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the CVD marker combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II, and wherein the use comprises (a) assaying a sample from the subject to determine a concentration of at least one Cer of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one PC of Formula II; and (c) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

56. The use of claim 55, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

57. The use of claim 55 or 56, wherein the CVD marker combination further comprises at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, and wherein the use comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the subject has a risk to develop one or more CV events, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

58. A use of a cardiovascular disease (CVD) marker combination for evaluating the effectiveness of a CVD treatment in a subject, wherein the use comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the treatment is effective, if the sample contains (a) decreased concentration(s) of the at least one Cer of Formula I and/or (an) increased concentration(s) of the at least one PC of Formula II, when compared to a control.

59. The use of claim 58, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

60. The use of claim 58 or 59, wherein the use further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the treatment is effective, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC, when compared to a control.

61. A use of a cardiovascular disease (CVD) marker combination for choosing an appropriate CVD treatment for a subject, wherein the use comprises (a) assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I; (b) assaying the sample from the subject to determine a concentration of at least one phosphatidylcholine (PC) of Formula II, and (c) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II, when compared to a control.

62. The use of claim 61, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I; and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

63. The use of claim 61 or 62, wherein the use further comprises (i) assaying the sample to determine a concentration of at least one additional Cer, selected from any of the Cer species referred to in Table 1; and/or (ii) assaying the sample to determine a concentration of at least one additional PC, selected from any of the PC species referred to in Table 1; and (iii) determining that the subject is in need of a treatment or a change in, or supplementation of, an already administered treatment, if the sample contains (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control.

64. A standard combination for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the standard combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II.

65. The standard combination of claim 64, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

66. The standard combination of claim 64 or 65, wherein the combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

67. A standard combination for assaying a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II in a sample from a subject in a preparation of a reagent, kit or composition for determining the risk of the subject to develop one or more cardiovascular (CV) events, wherein the standard combination comprises at least one Cer of Formula I and at least one PC of Formula II.

68. The standard combination of claim 67, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

69. The standard combination of claim 67 or 68, wherein the combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

70. A standard combination for assaying a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II in a sample from a subject in a preparation of a reagent, kit or composition for evaluating the effectiveness of a CVD treatment in the subject, wherein the standard combination comprises at least one Cer of Formula I and at least one PC of Formula II.

71. The standard combination of claim 70, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

72. The standard combination of claim 70 or 71, wherein the combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

73. A standard combination for assaying a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II in a sample from a subject in a preparation of a reagent, kit or composition for choosing an appropriate cardiovascular disease (CVD) treatment for the subject, wherein the standard combination comprises at least one Cer of Formula I and at least one PC of Formula II.

74. The standard combination of claim 73, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

75. The standard combination of claim 73 or 74, wherein the combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the additional Cer and PC species referred to in Table 1.

76. The standard combination of any one of claims 64-75, wherein the at least one Cer of Formula I is an isotope-labelled Cer, wherein the at least one PC of Formula II is an isotope-labelled PC and/or wherein the at least one additional Cer and/or the at least one additional PC species referred to in Table 1 is an isotope-labelled Cer and/or isotope-labelled PC.

77. The standard combination of claim 76, wherein the isotope of the at least one isotope-labelled Cer of Formula I, the at least one isotope-labelled PC of Formula II and/or the at least one additional isotope-labelled Cer and/or the at least one additional isotope-labelled PC, selected from any of the Cer and PC species referred to in Table 1, is deuterium, .sup.13C or .sup.15N.

78. A use of the standard combination of claim 64, wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular (CV) events.

79. The use of the standard combination of claim 78, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

80. The use of the standard combination of claim 78 or 79, wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular (CV) events.

81. A use of a standard combination for detecting in a sample from a subject a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II, wherein the standard combination comprises at least one Cer of Formula I and at least one PC of Formula II.

82. The use of claim 81, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

83. The use of claim 81 or 82, wherein the use further comprises detecting in the sample a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, and wherein the standard combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

84. A use of a standard combination for evaluating the effectiveness of a cardiovascular disease (CVD) treatment in a subject, wherein the standard combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II, and wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (a) decreased concentration(s) of the at least one Cer of Formula I and/or (an) increased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the effectiveness of said treatment.

85. The use of claim 84, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

86. The use of claim 84 or 85, wherein the standard combination further comprises at least one additional Cer and/or at least one additional PC selected from any of the Cer and PC species referred to in Table 1, and wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC, when compared to a control, is (are) indicative of the effectiveness of said treatment.

87. A use of a standard combination for choosing an appropriate CVD treatment for a subject, wherein the standard combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II, and wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject being in need of a treatment or a change in, or supplementation of, an already administered treatment.

88. The use of claim 87, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

89. The use of claim 87 or 88, wherein the standard combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, and wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject being in need of a treatment or a change in, or supplementation of, an already administered treatment.

90. A use of a standard combination for obtaining data for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the standard combination comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II, and wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

91. The use of claim 90, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

92. The use of claim 90 or 91, wherein the standard combination further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, and wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

93. The use of any one of claims 78-92, wherein the at least one Cer of Formula I is an isotope-labelled Cer, the at least one PC of Formula II is an isotope-labelled PC and/or the at least one additional Cer and/or the at least one additional PC, selected from any of the Cer and PC species referred to in Table 1 is an isotope-labelled Cer and/or isotope-labelled PC.

94. The use of claim 93, wherein the isotope of the at least one isotope-labelled Cer of Formula I, the isotope of the at least one isotope-labelled PC of Formula II and/or the isotope of the at least one additional isotope-labelled Cer and/or the at least one additional isotope-labelled PC referred to in Table 1 is deuterium, .sup.13C or .sup.15N.

95. A use of one or more reagent(s) in a preparation of a reagent, kit or composition for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

96. The use of claim 95, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

97. The use of claim 95 or 96, wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

98. A use of one or more reagent(s) in a preparation of a reagent, kit or composition for detecting in a sample from a subject a concentration of at least one ceramide of Formula I and a concentration of at least one phosphatidylcholine of Formula II.

99. The use of claim 98, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

100. The use of claim 98 or 99, wherein the use further comprises detecting in the sample a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

101. The use of any one of claims 98-100, wherein the use comprises detecting in the sample from the subject a changed concentration of at least one Cer of Formula I and/or a changed concentration of at least one PC of Formula II.

102. The use of any one of claims 98-101, wherein the use comprises detecting in the sample from the subject an increased concentration of at least one Cer of Formula I and/or a decreased concentration of at least one PC of Formula II.

103. The use of any one of claims 98-102, wherein the use comprises using a standard combination comprising at least one Cer of Formula I and/or at least one PC of Formula II.

104. A use of one or more reagent(s) in a preparation of a reagent, kit or composition for obtaining data for determining the risk of a subject to develop one or more cardiovascular (CV) events, wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

105. The use of claim 104, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

106. The use of claim 104 or 105, wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject having a risk of developing one or more cardiovascular events.

107. A use of one or more reagent(s) in a preparation of a reagent, kit or composition for evaluating the effectiveness of a cardiovascular disease (CVD) treatment in a subject, wherein the use comprises assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (a) decreased concentration(s) of the at least one Cer of Formula I and/or (an) increased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the effectiveness of said treatment.

108. The use of claim 107, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

109. The use of claim 107 or 108, wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC, when compared to a control, is (are) indicative of the effectiveness of said treatment.

110. A use of one or more reagent(s) in a preparation of a reagent, kit or composition for choosing an appropriate cardiovascular disease (CVD) treatment for a subject, the method comprising assaying a sample from the subject to determine a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II, wherein (an) increased concentration(s) of the at least one Cer of Formula I and/or (a) decreased concentration(s) of the at least one PC of Formula II in the sample, when compared to a control, is (are) indicative of the subject being in need of a treatment or a change in, or supplementation of, an already administered treatment.

111. The use of claim 110, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

112. The use of claim 110 or 111, wherein the use further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC biomarker, selected from any of the Cer and PC species referred to in Table 1, wherein (an) increased or decreased concentration(s) of the at least one additional Cer and/or the at least one additional PC as indicated in Table 1, when compared to a control, is (are) indicative of the subject being in need of a treatment or a change in, or supplementation of, an already administered treatment.

113. A composition or kit for diagnosing, predicting or detecting one or more cardiovascular (CV) events in a subject or for performing any of the methods or uses of any one of the preceding claims, wherein the composition or kit comprises at least one ceramide (Cer) of Formula I and at least one phosphatidylcholine (PC) of Formula II.

114. The composition or kit of claim 113, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

115. The composition or kit of claim 113 or 114, wherein the composition or kit further comprises at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

116. The composition or kit of any one of claims 113-115, wherein the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I are isotope-labelled Cers, wherein the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II are isotope-labelled PCs and/or the at least one additional Cer of Formula I and/or the at least one additional PC of Formula II selected from any of the Cer and PC species referred to in Table 1 is an isotope-labelled Cer and/or an isotope-labelled PC.

117. The composition or kit of claim 116, wherein the isotope of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 isotope-labelled Cers of Formula I, the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 isotope-labelled PCs of Formula II and/or the at least one additional isotope-labelled Cer and/or the at least one additional isotope-labelled PC, selected from any of the Cer and PC species referred to in Table 1, is deuterium, .sup.13C or .sup.15N.

118. The composition or kit of any one of claims 113-117, wherein the composition or kit further comprises (a) standard(s), control(s), reagent(s), solution(s), solvent(s), container(s), use instruction(s) and/or other element(s) for performing the methods or uses of any one of the preceding claims.

119. The composition or kit of any one of claims 113-118, wherein the composition or kit comprises (an) element(s) for collecting a blood sample.

120. The composition or kit of any one of claims 113-119, wherein the composition or kit comprises (an) element(s) for collecting a dried blood spot on a filter.

121. The composition or kit of any one of claims 113-120, wherein the composition or kit is a test kit for used in a laboratory or a home use test kit.

122. The composition or kit of any one of claims 113-121, wherein the composition or kit is a combination of any standard(s), control(s), reagent(s), solution(s) or solvent(s), used for diagnosing, predicting or detecting one or more cardiovascular (CV) events in a subject or for performing any of the methods or uses according to any one of the preceding claims.

123. The composition or kit of any one of claims 113-122, wherein the composition or kit is a combination of any standard(s), control(s), reagent(s), solution(s) or solvent(s), used for assaying a sample to determine a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II.

124. The composition or kit of any one of claims 113-123, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

125. The composition or kit of claim 123 or 124, wherein the composition or kit is further used for assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

126. The composition or kit of any one of claims 122-125, wherein the combination of any standard(s), control(s), reagent(s), solution(s) or solvent(s) is purchased from a commercial manufacturer or prepared in-house in a laboratory.

127. The composition or kit of any one of claims 113-127, wherein the composition or kit is used in a mass spectrometry (MS) or nuclear magnetic resonance (NMR) assay.

128. The composition or kit of claim 127, wherein the mass spectrometry (MS) is coupled to gas chromatography (GC), two-dimensional gas chromatography (GCxGC), liquid chromatography (LC), two-dimensional liquid chromatography (LCxLC), high performance liquid chromatography (HPLC) or ultra-high performance liquid chromatography (UHPLC).

129. The method of any one of claim 4, 5, 24-26 or 30-32, wherein the method further comprises requesting a test from a laboratory which provides the results of an assay useful for determining the concentration of the at least one Cer of Formula I and the concentration of the at least one PC of Formula II, and optionally administering to the subject a treatment if the subject has an increased concentration of the at least one Cer of Formula I and a decreased concentration of the at least one PC of Formula II, as compared to the control.

130. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the cardiovascular (CV) event comprises stable angina pectoris, unstable angina pectoris, myocardial infarction (MI), acute myocardial infarction (AMI), acute coronary syndrome (ACS), stroke, transient ischemic attacks, deep vein thrombosis, heart failure, hospitalization for heart failure and cardiovascular death.

131. The method, use, CVD marker combination, standard combination, composition or kit of claim 130, wherein the cardiovascular (CV) event is induced by atherosclerosis.

132. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the subject is a healthy individual with no previous signs or symptoms of CVD, is suffering from CVD, has previously suffered from CVD, is suspected of suffering from CVD or has previously suffered from a CV event.

133. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the subject is suffering from diabetes.

134. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the subject is under a treatment.

135. The method, use, CVD marker combination, standard combination, composition or kit of claim 134, wherein the subject is under a statin treatment.

136. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the subject has normal level(s) of the traditional risk markers, such as total cholesterol, LDL and/or HDL, and/or has no traditional risk factors, such as diabetes, high blood pressure or smoking.

137. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the sample is a biological sample.

138. The method, use, CVD marker combination, standard combination, composition or kit of claim 137, wherein the sample is a blood sample, a serum sample, a plasma sample, a saliva sample, a urine sample, a tissue sample or a fraction thereof, such as a lipoprotein fraction.

139. The method, use, CVD marker combination, standard combination, composition or kit of claim 137, wherein the sample is a dried blood spot.

140. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the control is a control sample or a control value, such as a concentration or a score, obtained from one individual or a population of individuals.

141. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the control is obtained from the previously obtained sample from the same subject.

142. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the control is from a healthy individual, a generalized population of healthy individuals, a CVD patient that has remained free of any major CV events, or a group of CVD patients that have remained free of any major CV events.

143. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the treatment comprises administering a drug and/or providing therapeutic, behavioural and/or lifestyle modification.

144. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the treatment comprises controlling of progression of CVD and/or its complications.

145. The method, use, CVD marker combination, standard combination, composition or kit of claim 143, wherein the drug comprises an HMG-CoA reductase inhibitor (a statin or other HMG-CoA reductase inhibitor), niacin (nicotinic acid), a cholesterol absorption inhibitor (ezetimibe), a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid sequestrant, a fibrate, a phytosterol, an anti-inflammatory drug (e.g. methotrexate, IL-1 mAb, TNF-alpha mAb), acetylsalicylic acid (aspirin) or a PCSK9 inhibitor, or a modulator of lipid concentrations selected from a small molecule, an antibody, an antisense RNA, a small interfering RNA (siRNA), and a natural or modified lipid, or any combination thereof.

146. The method, use, CVD marker combination, standard combination, composition or kit of claim 145, wherein the statin comprises atorvastatin, cerivastatin, fluvastatin, fluvastatin XL, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin, or any combination thereof.

147. The method, use, CVD marker combination, standard combination, composition or kit of claim 145, wherein cholesterol absorption inhibitor is ezetimibe or SCH-48461, a cholesteryl ester transfer protein (CETP) inhibitor is evacetrapib, anacetrapib or dalcetrapib, a bile acid sequestrant is colesevelam, cholestyramine or colestipol, a fibrate is fenofibrate, gemfibrozil, clofibrate, or bezafibrate, and the PCSK9 inhibitor is a PCSK9 specific antibody, an siRNA, and a peptidomimetic.

148. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the CVD marker combination comprises a ratio, sum, difference, product, remainder, value, score, calculation, formula, equation, algorithm, or any combination thereof, of the at least one Cer of Formula I and at least one PC of Formula II.

149. The method, use, CVD marker combination, standard combination, composition or kit of claim 148, wherein the CVD marker combination comprises a concentration ratio of the at least one Cer of Formula I and the at least one PC of Formula II.

150. The method, use, CVD marker combination, standard combination, composition or kit of claim 149, wherein the CVD marker combination further comprises at least one additional Cer and/or one additional PC, selected from any of the Cer and PC species referred to in Table 1.

151. The use of any one of claims 95-112, wherein the reagent comprises any standard(s), control(s), substance(s), compound(s), solution(s), solvent(s), agent(s), ingredient(s), preparation(s), or any combination thereof used for the methods and uses of any of the preceding claims.

152. The use of any one of claims 95-112, wherein the reagent comprises a combination of any standard(s), control(s), substance(s), compound(s), solution(s), solvent(s), agent(s), ingredient(s) or preparation(s) used for the methods and uses of any of the preceding claims.

153. The use of any one of claims 95-112, wherein the reagent is used for assaying in a sample a concentration of the at least one ceramide (Cer) of Formula I and a concentration of the at least one phosphatidylcholine (PC) of Formula II.

154. The use of claim 153, wherein the use further comprises assaying a concentration of the at least one additional Cer and/or the at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

155. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises adding at least one isotope-labelled Cer of Formula I and/or at least one isotope-labelled PC of Formula II to the sample.

156. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises adding at least one additional isotope-labelled Cer and/or at least one additional isotope-labelled PC, selected from any of the Cer and PC species referred to in Table 1, to the sample.

157. The method or use of claim 155 or 156, wherein the isotope of the at least one isotope-labelled Cer of Formula I, the at least one isotope-labelled PC of Formula II, and/or the at least one additional isotope-labelled Cer and/or the at least one additional isotope-labelled PC is deuterium, .sup.13C or .sup.15N.

158. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentration of the at least one Cer of Formula I and the concentration of the at least one PC of Formula II are determined in one assay.

159. The method, use, CVD marker combination, standard combination, composition or kit of claim 158, wherein the one assay comprises determining concentrations of at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and concentrations at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

160. The method, use, CVD marker combination, standard combination, composition or kit of claim 158 or 159, wherein the one assay further comprises determining a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

161. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 158-160, wherein the one assay is performed with mass spectrometry (MS).

162. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentration(s) is (are) determined by using mass spectrometry, nuclear magnetic resonance spectroscopy, fluorescence spectroscopy or dual polarisation interferometry, a high performance separation method such as LC, GC, HPLC, UHPLC or UPLC, an immunoassay such as an ELISA and/or an assay with a binding moiety capable of specifically binding the analyte.

163. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein (a) the method, use, CVD marker combination, standard combination, composition or kit further comprises determining the level of total cholesterol (TC), low-density lipoprotein (LDL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein particle (LDL-P), high-density lipoprotein particle (HDL-P), Apolipoprotein B (ApoB), Apolipoprotein AI (ApoAI), Apolipoprotein AII (ApoAII), and/or Apolipoprotein C (ApoC) in a sample from the subject; and/or (b) the subject does not have elevated levels of one or more of TC, LDL-C, ApoC or ApoB, or a decreased level of HDL-C.

164. A method of monitoring the progress of CVD and/or CV event risk of a subject, wherein the method comprises assaying a sample from the subject to determine a concentration of at least one Cer of Formula I and a concentration of at least one PC of Formula II and comparing the concentrations to those in a previously obtained sample from the same subject.

165. The method of claim 164, wherein the at least one Cer of Formula I is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or wherein the at least one PC of Formula II is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

166. The method of claim 164 or 165, wherein the method further comprises assaying the sample to determine a concentration of at least one additional Cer and/or at least one additional PC, selected from any of the Cer and PC species referred to in Table 1.

167. The method of claim 1, wherein R.sup.3 and/or R.sup.4 of Formula II are alkyl chains comprising 11-26 carbons.

168. The method of claim 1, wherein R.sup.3 and/or R.sup.4 of Formula II are alkyl chains comprising up to 6 double bonds.

169. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one Cer of Formula I is Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:1), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(d18:2/24:1) and/or Cer(d20:1/24:1).

170. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one PC of Formula II is PC 16:0/22:5, PC 14:0/22:6, PC 18:0/20:5, PC 16:0/20:4, PC 18:0/20:4, PC 18:0/20:3, PC 16:0/22:6, PC 16:1/18:2, PC 16:0/18:3, PC 17:0/20:3, PC 17:0/20:4, PC 38:5, PC 36:6, PC 38:5, PC 36:4, PC 38:4, PC 38:3, PC 38:6, PC 38:7, PC 34:3, PC 37:3, PC 37:4, PC 34:4 and/or PC 40:8.

171. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one PC of Formula II is PC 16:0/22:5, PC 14:0/22:6, PC 16:0/22:6, PC 16:0/20:4, PC 18:0/20:4, PC 17:0/20:3, PC 36:8, PC 36:6, PC 36:4, PC 38:4, PC 38:7, PC 34:4 and/or PC 40:8.

172. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one Cer of Formula I is Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:1), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(d18:2/24:1) and/or Cer(d20:1/24:1), and the at least one PC of Formula II is PC 16:0/22:5, PC 14:0/22:6, PC 18:0/20:5, PC 16:0/20:4, PC 18:0/20:4, PC 18:0/20:3, PC 16:0/22:6, PC 16:1/18:2, PC 16:0/18:3, PC 17:0/20:3, PC 17:0/20:4, PC 38:5, PC 36:6, PC 38:5, PC 36:4, PC 38:4, PC 38:3, PC 38:6, PC 38:7, PC 34:3, PC 37:3, PC 37:4, PC 34:4 and/or PC 40:8.

173. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one Cer of Formula I is Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:1), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(d18:2/24:1) and/or Cer(d20:1/24:1), and the at least one PC of Formula II is PC 16:0/22:5, PC 14:0/22:6, PC 16:0/22:6, PC 16:0/20:4, PC 18:0/20:4, PC 17:0/20:3, PC 36:8, PC 36:6, PC 36:4, PC 38:4, PC 38:7, PC 34:4 and/or PC 40:8.

174. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one Cer of Formula I is Cer(d18:1/16:0), Cer(d18:1/18:0) and/or Cer(d18:1/24:1) and the at least one PC of Formula II is PC 16:0/22:5 and/or PC 14:0/22:6.

175. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one additional Cer is Cer(d18:1/24:1), Cer(d18:1/24:0), Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/26:0), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(18:2/24:0), Cer(d18:2/24:1), Cer(d20:1/24:0) and/or Cer(d20:1/24:1).

176. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the at least one additional PC is PC 16:0/16:0, 16:0/22:5, PC 14:0/22:6, PC 18:0/20:5, PC 16:0/20:4, PC 18:0/20:4, PC 18:0/20:3, PC 16:0/22:6, PC 16:1/18:2, PC 16:0/18:3, PC 17:0/20:3, PC 17:0/20:4, PC 38:5, PC 36:6, PC 38:5, PC 36:4, PC 38:4, PC 38:3, PC 38:6, PC 38:7, PC 34:3, PC 37:3, PC 37:4, PC 34:4 and/or PC 40:8.

177. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 14:0/22:6 and PC 16:0/16:0.

178. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 14:0/22:6 and PC 16:0/16:0 are assayed.

179. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 16:0/22:6 and PC 16:0/16:0.

180. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 16:0/22:6 and PC 16:0/16:0 are assayed.

181. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 16:0/22:6 and PC 16:0/18:3.

182. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5, PC 16:0/22:6 and PC 16:0/18:3 are assayed.

183. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5 or at least 6 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), PC 16:0/20:4, PC 18:0/20:4 and PC 38:7.

184. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), PC 16:0/20:4, PC 18:0/20:4 and PC 38:7 are assayed.

185. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein a concentration ratio is calculated from the concentrations of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 Cers of Formula I and/or the concentrations of the at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 PCs of Formula II.

186. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein a concentration ratio is calculated from the concentrations of the at least one additional Cer and/or the at least one additional PC selected from any of the Cer and PC species referred to in Table 1.

187. The method, use, CVD marker combination, standard combination, composition or kit of claim 186, wherein the concentration ratio is a Cer/Cer, Cer/PC, PC/Cer and/or PC/PC ratio.

188. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-187, wherein the concentration ratio is selected from any of the lipid ratios referred to in Table 2, 3, 4, 6, 7, 8, 9, 10, 11 or 12.

189. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-188, wherein the concentration ratio is calculated from at least 2 of the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1), Cer(d18:1/26:0), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(d18:2/24:1), Cer(d16:1/24:0) and/or Cer(d20:1/24:1), PC 16:0/22:5, PC 14:0/22:6, PC 16:0/16:0, PC 18:0/20:5, PC 16:0/20:4, PC 18:0/20:4, PC 18:0/20:3, PC 16:0/22:6, PC 16:1/18:2, PC 16:0/18:3, PC 17:0/20:3, PC 17:0/20:4, PC 38:5, PC 36:6, PC 38:5, PC 36:4, PC 38:4, PC 38:3, PC 38:6, PC 38:7, PC 34:3, PC 37:3, PC 37:4, PC 34:4 and/or PC 40:8.

190. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-189, wherein the concentration ratio is calculated from 2 of the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and/or PC 16:0/16:0.

191. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-190, wherein the concentration ratio is Cer(d18:1/24:1)/Cer(d18:1/24:0), Cer(d18:1/16:0)/PC 16:0/22:5 and/or Cer(d18:1/18:0)/PC 14:0/22:6.

192. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-191, wherein the concentration ratios Cer(d18:1/24:1)/Cer(d18:1/24:0), Cer(d18:1/16:0)/PC 16:0/22:5 and Cer(d18:1/18:0)/PC 14:0/22:6 are assayed and the concentration of PC 16:0/16:0 is assayed.

193. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises determining other cardiovascular biomarkers, such as triglyseride (TG), C-reactive protein (CRP), troponin T (TnT), troponin I (TnI), B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), Cystatin C, glycated haemoglobin A1c (HbA1c), glucose, suppression of tumorigenicity 2 (St2), galectin, trimethylamine-N-oxide (TMAO), lipoprotein-associated phospholipase A2 (Lp-PLA2), growth differentiation factor 15 (GDF15), lipoprotein (a) (Lp(a)), any other lipoprotein subgroup composition or particle number, or any combination thereof.

194. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises using other personal information or health data, such as sex, age, blood pressure, BMI, smoking status, diabetes, lipid lowering treatment or other medication, history of cardiovascular events, ethnic background, geographical location, medical imaging data, such as data from angiography or computed tomography (CT), or any combination thereof.

195. The method or use of any one of the preceding claims, wherein the treatment comprises a surgical operation, such as angioplasty, stent placement or bypass surgery.

196. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the marker combination is constructed by linear combinations, regression models, other unsupervised or supervised frequentist or Bayesian statistical classification or machine learning methods, such as support vector machines, kernel estimations, decision trees or neural networks.

197. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the marker combination is a continuous or discrete scoring systems based on the Cer, PC, Cer/PC, Cer/Cer, PC/Cer, PC/PC and/or other cardiovascular biomarkers.

198. The method, use, CVD marker combination, standard combination, composition or kit of claim 197, wherein the discrete scoring system is based on points given based on intervals with non-equal probabilities, quantiles or other cut-off values, determined from the same or other populations, of the individual score components.

199. The method, use, CVD marker combination, standard combination, composition or kit of claim 197 or 198, wherein the marker combination is a scoring system where the points are given based on the quartiles (Q1-Q4) of the whole study population.

200. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 of the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and/or PC 16:0/16:0.

201. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and/or PC 16:0/16:0.

202. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipid ratios and individual lipid: Cer(d18:1/16:0)/PC 16:0/22:5, Cer(d18:1/18:0)/PC 14:0/22:6, Cer(d18:1/24:1)/Cer(d18:1/24:0) and/or PC 16:0/16:0.

203. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is constructed according to Table 8, 9, 10 or 11.

204. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score further comprises determining other cardiovascular biomarkers, such as triglyseride (TG), C-reactive protein (CRP), troponin T (TNT or TnT), troponin I (TNI or TnI), B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), Cystatin C, glycated haemoglobin A1c (HbA1c), glucose, suppression of tumorigenicity 2 (St2), Galectin, trimethylamine-N-oxide (TMAO), lipoprotein-associated phospholipase A2 (Lp-PLA2), growth differentiation factor 15 (GDF15), lipoprotein (a) (Lp(a)), any other lipoprotein subgroup composition or particle number, or any combination thereof.

205. The method, use, CVD marker combination, standard combination, composition or kit of claim 204, wherein the score further comprises TNT.

206. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score further comprises using other personal information or health data, such as sex, age, blood pressure, BMI, smoking status, diabetes, lipid lowering treatment or other medication, history of cardiovascular events, ethnic background, geographical location, medical imaging data, e.g. from angiography or computed tomography (CT), or any combination thereof.

207. The method, use, CVD marker combination, standard combination, composition or kit of claim 206, wherein the score further comprises medical imaging data.

208. The use of any one of claims 95-112, wherein the at least one Cer of Formula I is an isotope-labelled Cer, wherein the at least one PC of Formula II is an isotope-labelled PC and/or wherein the at least one additional Cer and/or the at least one additional PC species referred to in Table 1 is an isotope-labelled Cer and/or isotope-labelled PC.

209. The use of any one of claims 95-112, wherein the isotope of the at least one isotope-labelled Cer of Formula I, the at least one isotope-labelled PC of Formula II and/or the at least one additional isotope-labelled Cer and/or the at least one additional isotope-labelled PC, selected from any of the Cer and PC species referred to in Table 1, is deuterium, .sup.13C or .sup.15N.

210. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the isotope-labelled Cer and/or PC is selected from the following isotope-labelled lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1), Cer(d18:1/26:0), Cer(d18:1/26:1), Cer(d16:1/16:0), Cer(d16:1/18:0), Cer(d16:1/24:0), Cer(d16:1/24:1), Cer(d18:2/16:0), Cer(d18:2/18:0), Cer(d18:2/24:1), Cer(d18:2/24:0), Cer(d20:1/24:1), PC 16:0/22:5, PC 14:0/22:6, PC 16:0/16:0, PC 18:0/20:5, PC 16:0/20:4, PC 18:0/20:4, PC 18:0/20:3, PC 16:0/22:6, PC 16:1/18:2, PC 16:0/18:3, PC 17:0/20:3, PC 17:0/20:4, PC 38:5, PC 36:6, PC 38:5, PC 36:4, PC 38:4, PC 38:3, PC 38:6, PC 38:7, PC 34:3, PC 37:3, PC 37:4, PC 34:4 and PC 40:8.

211. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the isotope-labelled Cer and/or PC is selected from the following isotope-labelled lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and PC 16:0/16:0.

212. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the isotope-labelled Cers and PCs are Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and PC 16:0/16:0.

213. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the isotope-labelled Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5, PC 14:0/22:6 and/or PC 16:0/16:0 is (are) deuterium-labelled.

214. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the isotope-labelled Cers and/or PCs is (are) d7-Cer(d18:1/16:0), d7-Cer(d18:1/18:0), d7-Cer(d18:1/24:0), d7-Cer(d18:1/24:1), d9-PC 16:0/22:5, d9-PC 14:0/22:6 and/or d9-PC 16:0/16:0.

215. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein R.sup.1 of Formula I is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 11-17 carbon atoms, and wherein R.sup.2 is a saturated alkyl chain having 13-21 carbon atoms, a mono-unsaturated or di-unsaturated alkyl chain having 13-25 carbon atoms.

216. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein R.sup.1 of Formula I is a mono-unsaturated or di-unsaturated alkyl chain having 13-15 carbon atoms, and wherein R.sup.2 is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 15-25 carbon atoms.

217. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein R.sup.1 of Formula I is a mono-unsaturated or di-unsaturated alkyl chain having 13-15 carbon atoms, and wherein R.sup.2 is a saturated alkyl chain having 15-21 carbon atoms, a mono-unsaturated or di-unsaturated alkyl chain having 15-25 carbon atoms.

218. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5 or at least 6 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5 and PC 14:0/22:6.

219. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 16:0/22:5 and PC 14:0/22:6 are assayed.

220. The method, use, CVD marker combination, standard combination, composition or kit of any one of claims 185-191, wherein the concentration ratios Cer(d18:1/24:1)/Cer(d18:1/24:0), Cer(d18:1/16:0)/PC 16:0/22:5 and Cer(d18:1/18:0)/PC 14:0/22:6 are assayed.

221. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 16:0/22:5 and/or PC 14:0/22:6.

222. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipid ratios: Cer(d18:1/16:0)/PC 16:0/22:5, Cer(d18:1/18:0)/PC 14:0/22:6 and/or Cer(d18:1/24:1)/Cer(d18:1/24:0)

223. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the lipid combination is selected from any of the lipid combinations referred to in Tables 2-18.

224. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of at least 2, at least 3, at least 4, at least 5 or at least 6 of the following lipids are assayed: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 36:6 and PC 38:5.

225. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), Cer(d18:1/24:0), PC 36:6 and 38:5 are assayed.

226. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentration ratios Cer(d18:1/24:1)/Cer(d18:1/24:0), Cer(d18:1/16:0)/PC 38:5 and Cer(d18:1/18:0)/PC 36:6 are assayed.

227. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the concentration ratios Cer(d18:1/24:1)/Cer(d18:1/24:0), Cer(d18:1/16:0)/PC 38:5 and Cer(d18:1/18:0)/PC 36:6 are assayed and the concentration of PC 32:0 is assayed.

228. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 38:5 and/or PC 36:6.

229. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipids: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC 38:5, PC 36:6 and/or PC 32:0.

230. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the score is based on the following lipid ratios: Cer(d18:1/16:0)/PC 38:5, Cer(d18:1/18:0)/PC 36:6 and/or Cer(d18:1/24:1)/Cer(d18:1/24:0).

231. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the PC may be a brutto PC or a molecular PC.

232. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the cardiovascular (CV) event comprises stable angina pectoris, unstable angina pectoris, myocardial infarction (MI), acute myocardial infarction (AMI), acute coronary syndrome (ACS), stroke, transient ischemic attacks, deep vein thrombosis, heart failure, hospitalization for heart failure, cardiovascular death, peripheral artery disease and/or arrhythmia.

233. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the sample is a dried plasma or serum collected on a card.

234. The method of any one of claim 4, 5, 24-26 or 30-32, wherein the treatment comprises providing any medical and/or lifestyle management services to a subject.

235. The method, use, CVD marker combination, standard combination, composition or kit of claim 143, wherein the drug comprises any pharmaceutical for treating or preventing CVD, diabetes, metabolic syndrome or other metabolic disorders.

236. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises determining other cardiovascular biomarkers, such as triglyseride (TG), C-reactive protein (CRP), troponin T (TnT), troponin I (TnI), B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), Cystatin C, glycated haemoglobin A1c (HbA1c), glucose, suppression of tumorigenicity 2 (St2), galectin, trimethylamine-N-oxide (TMAO), lipoprotein-associated phospholipase A2 (Lp-PLA2), growth differentiation factor 15 (GDF15), lipoprotein (a) (Lp(a)), any other lipoprotein subgroup composition or particle number, creatine kinase (CK), or any combination thereof.

237. The method, use, CVD marker combination, standard combination, composition or kit of any one of the preceding claims, wherein the method, use, CVD marker combination, standard combination, composition or kit further comprises using other personal information or health data, such as sex, age, blood pressure, BMI, smoking status, diabetes, lipid lowering treatment or other medication, history of CVD and/or CV events, ethnic background, geographical location, family history of CVD, CV events and/or diabetes, medical imaging data, such as data from angiography or computed tomography (CT), or any combination thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0308] The present disclosure is based on the finding that certain molecules are expressed at higher levels and certain molecules are expressed at lower levels, when compared to a control, in biological samples, e.g., blood of subjects having a risk to develop one or more cardiovascular (CV) events in the future. A combination derived from the concentrations of these molecules were found to be a surprisingly superior predictive biomarker of cardiovascular events, as described herein.

[0309] According to the present disclosure, a combination of the concentrations of at least one ceramide (Cer) and at least one phosphatidylcholine (PC) provide a specific and sensitive diagnostic test which can be used to identify subjects who are in a risk of developing cardiovascular events. The biomarker combination of the present disclosure can be used for predicting CV events when the levels of conventional markers, such as LDL-C (low density lipoprotein cholesterol), HDL-C (high density lipoprotein cholesterol) and total cholesterol, are either normal, increased or decreased. The present biomarker combination can also be used for subjects who have or have not traditional risk factors, such as diabetes, high blood pressure or smoking. In addition, the predictive test according to the present disclosure may advantageously be used for patients who are on statin treatment to assess whether they have a residual risk to develop one or more cardiovascular events. The test can also be used for cardiovascular disease patients who have experienced a CV event to determine whether they have a high risk of developing one or more subsequent CV event.

[0310] The methods of predicting one or more coronary artery disease events according to the present disclosure, comprise the steps of measuring the concentrations of the at least one ceramide and the at least one phosphatidylcholine molecule, and optionally at least one additional ceramide and/or phosphatidylcholine from a sample, such as a blood sample, e.g., a serum and/or plasma sample. The novel combination, derived from the concentrations of the specific Cer and PC molecules, is used as a marker for future cardiovascular events.

[0311] Collecting information on a lipid biomarker, such as a lipid concentration, from the subject's sample, according to the methods of the present disclosure, can be performed via various chemical and high resolution analytical techniques. Particularly suitable analytical techniques include, but are not limited to, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Indeed, any high resolution technique capable of resolving individual lipid species and providing structural information of the same can be used to determine the lipid markers according to the present disclosure. For the purposes of the methods of the present disclosure, the lipid concentrations are typically determined by using mass spectrometry. The MS instrument can be coupled to a direct sample infusion method, such as a robotic nanoflow ion source device, or to a high performance separation method such as LC, GC, HPLC, UHPLC, or UPLC. In addition, nuclear magnetic resonance spectroscopy, fluorescence spectroscopy or dual polarisation interferometry, high performance separation methods such as HPLC, UHPLC or UPLC, an immunoassay, such as an ELISA, and/or the use of a binding moiety capable of specifically binding the lipid analyte are useful in this regard.

[0312] In the present disclosure, a novel combination of lipid biomarkers determined from a biological sample, e.g., a plasma or serum sample has been identified. Surprisingly, combinations of ceramide and phosphatidylcholine concentrations showed superior performance as predictive biomarkers for cardiovascular events, compared to the existing and conventionally used biomarkers.

[0313] Abbreviations

[0314] As used herein, “ACS” is acute coronary syndrome, “AMI” is acute myocardial infarction, “ApoA” is apolipoprotein A, “ApoAI” is apolipoprotein AI, “ApoAII” is apolipoprotein AII, “ApoB” is apolipoprotein B, “ApoC” is apolipoprotein C, “BMI” is body mass index, “BNP” is B-type natriuretic peptide, “.sup.13C” is carbon-13 isotope, “CAC” is coronary artery calcification, “CAD” is coronary artery disease, “Cer” is ceramide, “CETP” is cholesteryl ester transfer protein, “CHD” is coronary heart disease, “CRP” is C-reactive protein, “CT” is computed tomography, “CV” is cardiovascular, “CVD” is cardiovascular disease/coronary vascular disease, “ELISA” is enzyme-linked immunosorbent assay “, FA” is fatty acid, “GC” is gas chromatography, “GCxGC” is two-dimensional gas chromatography, “GDF15” is growth differentiation factor 15, “.sup.2H” is deuterium, “HbA1c” is glycated haemoglobin A1c, “HDL” is high density lipoprotein, “HDL-C” is high density lipoprotein cholesterol, “HDL-P” is high density lipoprotein particle or high density lipoprotein particle number, “HMG-CoA” is 3-hydroxy-3-methyl-glutaryl-coenzyme A, “HPLC” is high performance liquid chromatography, “HR” is hazard ratio, “IHD” is ischemic heart disease, “IL-1 mAb” is interleukin-1 monoclonal antibody, “LC” is liquid chromatography, “LCxLC” is two-dimensional liquid chromatography, “LDL” is low density lipoprotein, “LDL-C” is low density lipoprotein cholesterol, “LDL-P” is low density lipoprotein particle or low density lipoprotein particle number, “Lp(a)” is lipoprotein (a), “Lp-PLA2” is lipoprotein-associated phospholipase A2, “Ml” is myocardial infarction, “MRM” is multiple reaction monitoring, “MS” is mass spectrometry, “.sup.15N” is nitrogen-15 isotope, “NMR” is nuclear magnetic resonance, “NT-proBNP” is N-terminal pro B-type natriuretic peptide, “PC” is phosphatidylcholine, “PCSK9” is proprotein convertase subtilisin/kexin type 9, “RNA” is ribonucleic acid, “SB” is sphingoid base, “SCH-48461” is (3R,45)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone, “SD” is standard deviation, “siRNA” is small interfering RNA, “St2” is suppression of tumorigenicity 2, “TC” is total cholesterol, “TG” is triglyseride, “TMAO” is trimethylamine-N-oxide, “TNF-alpha mAb” is tumor necrosis factor alpha monoclonal antibody, “TNI” or “TnI” is troponin I or high sensitivity troponin I, “TNT” or “TnT” is troponin T or high sensitivity troponin T, “UHPLC” is ultra high performance liquid chromatography, “UPLC” is ultra performance liquid chromatography.

[0315] In addition, the following abbreviations are used in the present disclosure: “ACE” is angiotensin-converting enzyme, “ACL” is adenosine triphosphate citrate lyase, “ALA” is α-linolenic acid, “ARB” is angiotensin II receptor blocker, “ATP” is adenocine triphosphate, “CCTA” is coronary computed tomography angiography, “CK” is creatine kinase, “DHA” is docosahexaenoic acid, “ECG or EKG” is electrocardiography, “EPA” is eicosapentaenoic acid, “GLP1” is glucagon-like peptide 1, “MRI” is magnetic resonance imaging, “NM” is nuclear medicine, “PET” is positron-emission tomography, “SPECT” is single-photon emission computed tomography, “SGLT2” is sodium-glucose transporter 2, “ω-3 or n-3” is omega-3 and “ω-6 or n-6” is omega-6.

[0316] Definitions

[0317] In order that the present invention may be more readily understood, certain terms are defined herein. Additional definitions are set forth throughout the detailed description.

[0318] As used herein, “cardiovascular disease (CVD)” has its general meaning in the art and it is used to classify numerous conditions that affect the heart, heart valves, blood, and vasculature of the body, including coronary artery disease (CAD). The CVD may or may not involve atherosclerosis. In the present disclosure, the terms CVD and CAD may be used interchangeably.

[0319] As used herein, “coronary artery disease (CAD)”, also known as “coronary heart disease (CHD)” and “ischemic heart disease (IHD)”, is characterized by atherosclerosis in the coronary arteries. Atherosclerotic plaques narrow the coronary artery lumen decreasing blood flow to the heart. When the flow of oxygen-rich blood to the heart is reduced or blocked, angina or myocardial infarction can occur.

[0320] In the present disclosure, “cardiovascular (CV) event” comprises stable angina pectoris, unstable angina pectoris, myocardial infarction (MI), acute myocardial infarction (AMI), acute coronary syndrome (ACS), stroke, transient ischemic attacks, deep vein thrombosis, heart failure, hospitalization for heart failure and cardiovascular death. Such events may involve atherosclerosis. In the present disclosure the terms CV event, CVD event, CAD event, CHD event, CV complication, CVD complication, CAD complication, CHD complication, CV outcome, CVD outcome, CAD outcome and CHD outcome may be used interchangeably.

[0321] In the present disclosure, “cardiovascular (CV) event” may also comprise peripheral artery disease (also called peripheral arterial disease) and different forms of arrhythmias, such as atrial fibrillation.

[0322] As used herein, the terms “subject”, “patient” and “individual” are used interchangeably herein to refer to any mammalian subject for whom prediction, diagnosis or therapy is desired, particularly humans. The subject may be a healthy individual with no previous signs or symptoms of CVD. Or, the subject may have previously suffered or is suffering from CVD or CAD. The subject may also be suspected of suffering from CVD and/or being at high risk of developing CV events. The subject may or may not have previously suffered from a cardiovascular event, such as angina pectoris, myocardial infarction or stroke. The subject may or may not suffer from a metabolic disease, such as diabetes. In addition, the subject may or may not have normal levels of traditional lipid markers, such as total cholesterol, LDL or HDL, and/or may or may not have traditional risk factors, such as diabetes, high blood pressure or smoking.

[0323] The subject may be or may have been under a treatment, such as, but not limited to, a statin treatment, or may not have had any previous treatment or medication.

[0324] As used herein, a “sample” is a biological sample obtained from a subject or a group or population of subjects. The sample may be a blood sample, a serum sample, a plasma sample, a saliva sample, a urine sample, a tissue sample or a fraction thereof, such as a lipoprotein fraction. Blood serum and plasma samples are typical. The sample can be prepared with techniques well known in the art. In certain embodiments, the blood sample is a dried blood spot. In certain embodiments, the blood sample is dried on a filter.

[0325] In some embodiments, a blood sample may be collected as dried plasma or serum on a card. The card separates plasma or serum from a drop of blood and the separated plasma or serum sample is dried on the card.

[0326] As used herein, a “control” may be a control sample. A control may also be a concentration determined from a sample from a single healthy individual. The control may also be a sample that represents a combination of samples from a generalized population of healthy individuals. Alternatively, the control may be a control value, a score or a set of data concerning the biomarker in a sample previously determined, calculated or extrapolated, or may have yet to be determined, calculated or extrapolated, or may also be taken from the literature.

[0327] In some embodiments, the control sample may be previously obtained from the same subject or the control value may be obtained from a previously taken sample from the same subject. In other embodiments, the control sample or the control value may be obtained from another subject.

[0328] A “control” as used herein, i.e., a control value or a control sample, is typically representative of a group of subjects or a population of subjects. In this context, “representative” means that the lipid concentration(s) reflected by said control value to which a comparison is made in the context of the present disclosure correspond(s) to the average concentration value(s) of said lipid concentration(s) in corresponding individual samples from the subjects of said group or population. Likewise, in the case of a control sample “representative” means that the lipid concentration(s) in said control sample to which a comparison is made in the context of the present disclosure correspond(s) to the average concentration(s) of said lipid concentration(s) in corresponding individual samples from the subjects of said group or population. Typically, the concentrations of all lipid concentrations in said control sample correspond to the average concentrations of said lipid concentrations in corresponding individual samples from the subjects of said group or population. An individual with such values can be considered a “healthy individual” for the purposes of the present disclosure.

[0329] A control sample can be particularly suitably compared to the subject's sample if it has been obtained from the same type of biological tissue or source in the same, or essentially the same, manner. For example, if the subject's sample is a serum sample or a plasma sample, a corresponding control sample will likewise be a serum sample or a plasma sample, respectively.

[0330] In some embodiments, a control sample from a group of subjects or a control sample from a population of subjects in the sense of the present disclosure is obtained by mixing equal amounts of samples directly obtained from the subjects of said group or population, or by mixing equal amounts of fractions, constituents or reaction products thereof.

[0331] It will be appreciated that a useful control value for the purposes of the present disclosure is typically one that has been, or is, obtained using any one of the suitable control samples described herein.

[0332] In the context of the present disclosure, a control sample can be from a healthy individual, a generalized population of healthy individuals, a CVD patient that has remained free of any major CV events, or a group of CVD patients that have remained free of any major CV events.

[0333] In some embodiments of the methods described herein, a control may be a control value, e.g., a score or a combination value of the concentrations of the at least one ceramide of Formula I and the at least one phosphatidylcholine of Formula II or a combination value of the at least one ceramide of Formula I and the at least one phosphatidylcholine of Formula II and the at least one additional ceramide or phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1.

[0334] For the purposes of the present disclosure, lipids are named according to the following nomenclature: Cer is ceramide and PC is phosphatidylcholine.

[0335] As used herein, the nomenclature of ceramides (Cer) is presented as a first pair of numbers corresponding to the sphingoid base (SB) and a second pair of numbers corresponding to the fatty acid (FA) chain of the molecule. In SB and FA nomenclature, the first number of each pair refers to the number of carbon atoms in the SB or FA chain, and the second number refers to the number of carbon-carbon double bonds of the SB or FA chain.

[0336] As used herein, a ceramide (Cer) of Formula I refers to ceramide species with the following structure:

##STR00003##

[0337] wherein R.sup.1 is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 11-17 carbon atoms, and wherein R.sup.2 is a saturated, mono-unsaturated or di-unsaturated alkyl chain having 13-25 carbon atoms.

[0338] As used herein, the nomenclature of phosphatidylcholines (PC) is presented either as brutto species or molecular species. In brutto nomenclature, a first number refers to the total number of carbon atoms in the molecule and the second number refers to the total number of the carbon-carbon double bonds of the molecule. In molecular nomenclature, a first pair of numbers corresponds to the first fatty acid (FA) chain and a second pair of numbers corresponds to the second FA chain of the molecule. In FA nomenclature, the first number of each pair refers to the number of carbon atoms in the FA chain, and the second number refers to the number of carbon-carbon double bonds of the FA chain. In molecular nomenclature, the first FA chain may be either R.sub.1 or R.sub.2 in Formula II. Accordingly, the second FA chain may also be either R.sub.1 or R.sub.2 in Formula II.

[0339] As used herein, a phosphatidylcholine (PC) of Formula II refers to a phosphatidylcholine species with the following structure:

##STR00004##

[0340] wherein R.sup.3 and R.sup.4 are be saturated, mono-unsaturated or polyunsaturated alkyl chains.

[0341] A “treatment” and “therapy” are used interchangeably in the present disclosure and may comprise any therapeutic treatment typically given to a subject at risk of developing CVD or a subject suffering from CVD, such as, but not limited to, administering a drug and/or providing therapeutic, behavioural and/or lifestyle modification to the subject. Behavioural and/or lifestyle modification may comprise, for example, lifestyle interventions and/or counselling, including, but not limited to, instructions, encouragement and/or follow-up regarding a healthy diet, weight management, physical activity/exercise and/or smoking cessation. A treatment may also be a surgical operation, such as angioplasty, stent placement or bypass surgery. A treatment may also include controlling of progression of CVD and/or its complications.

[0342] As used herein, a treatment may also be any cardiac and/or vascular operation, such as, but not limited to, revascularization, such as angioplasty, stent placement or bypass surgery, and any lifestyle modifications, such as lifestyle interventions and/or counselling, including, but not limited to, instructions, encouragement and/or follow-up regarding a healthy diet, weight management, physical activity/exercise, stress management and/or smoking cessation.

[0343] A treatment may further comprise any cardiac and/or vascular imaging and testing, such as, but not limited to, ultrasound, echocardiography, angiography, electrocardiography (ECG or EKG), cardiac stress test, computed tomography (CT), coronary CT calcium scan, coronary computed tomography angiography (CCTA), magnetic resonance imaging (MRI), nuclear medicine (NM) imaging, positron-emission tomography (PET), single-photon emission computed tomography (SPECT) and/or myocardial perfusion imaging.

[0344] A treatment may also comprise providing any medical and/or lifestyle management services to a subject. A treatment may be given by any healthcare provider, such as, but not limited to, a clinician, a phycisian, a medical doctor, a therapist, a nurse, a psychologist, a physiotherapist, a personal trainer and/or dietician.

[0345] A treatment may also comprise preventive measures, such as, but not limited to, administering a drug and/or providing therapeutic, behavioural and/or lifestyle modification to the subject. Behavioural and/or lifestyle modification may comprise, for example, lifestyle interventions and/or counselling, including, but not limited to, instructions, encouragement and/or follow-up regarding a healthy diet, weight management, physical activity/exercise, stress management and/or smoking cessation.

[0346] A treatment or prevention may further comprise requesting a test, for example, from a commercial laboratory, which provides the results of an assay useful for determining if a subject is in need of a treatment or prevention.

[0347] A “drug”, “pharmaceutical”, “medicament”, “medicine” and “medication” are used interchangeably in the present disclosure and may comprise any pharmaceutical typically given to a subject having CVD, such as a statin, another lipid lowering/modifying drug, and/or a modulator of lipid concentrations.

[0348] As used herein, a drug may be, for example, an HMG-CoA reductase inhibitor (a statin or other HMG-CoA reductase inhibitor), niacin (nicotinic acid), a cholesterol absorption inhibitor (ezetimibe), a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid sequestrant, a fibrate, a phytosterol, an anti-inflammatory drug (e.g. methotrexate, IL-1 mAb, TNF-alpha mAb), acetylsalicylic acid (aspirin) or a PCSK9 inhibitor, or a modulator of lipid concentrations selected from a small molecule, an antibody, an antisense RNA, a small interfering RNA (siRNA), and a natural or modified lipid, or any combination thereof.

[0349] As used herein, a drug may also be any pharmaceutical for treating or preventing CVD, diabetes, metabolic syndrome or other metabolic disorders, including, but not limited to, anticoagulant and antitrombotic drugs (e.g. rivaroxaban), diabetes medication (e.g. insulin, SGLT2 (sodium-glucose transporter 2) inhibitors, metformin, GLP1 (glucagon-like peptide 1) agonists), blood pressure medication (e.g. diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers, alpha-blockers, beta-blockers, renin inhibitors), heart failure medication, omega-3 (ω-3 or n-3) and omega-6 (ω-6 or n-6) polyunsaturated fatty acids (e.g. eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), α-linolenic acid (ALA)), ATP (adenosine triphosphate) citrate lyase (ACL) inhibitor (e.g. bempedoic acid), antisense oligonucleotide, or any combination thereof.

[0350] As used herein, “statins” is a class of lipid-lowering medications (HMG-CoA reductase inhibitors). Statin is selected from, but is not limited to, the group consisting of atorvastatin, cerivastatin, fluvastatin, fluvastatin XL, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or any combination thereof.

[0351] As used herein, statin may also be mevastatin.

[0352] For the purposes of the present disclosure, a “cholesterol absorption inhibitor” may be ezetimibe or SCH-48461; a cholesteryl ester transfer protein (CETP) inhibitor may be evacetrapib, anacetrapib or dalcetrapib; a bile acid sequestrant may be colesevelam, cholestyramine or colestipol; a fibrate may be fenofibrate, gemfibrozil, clofibrate, or bezafibrate, and the PCSK9 inhibitor is selected from, but is not limited to, a PCSK9 specific antibody, an siRNA, and a peptidomimetic.

[0353] A “modulator” according to the present disclosure may be a small molecule (<1500 dalton molecular weight, typically <800 dalton molecular weight), an antibody, an antisense RNA, a small interfering RNA (siRNA), or a natural or modified lipid.

[0354] As used herein, “effectiveness of a treatment” and “effectiveness of a therapy” is taken to mean the ability of a treatment to achieve the therapeutic purpose for which it is administered.

[0355] As used herein, a “CVD marker combination” refers to a specific combination of lipid biomarkers used for the methods and uses of the present disclosure. The CVD marker combination comprises at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the CVD marker combination further comprises at least one additional ceramide and/or at least one additional phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure. As used herein, the combination may be e.g. a ratio, sum, difference, product, remainder, value, score, calculation, formula, equation, algorithm, or any combination thereof, of the at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the combination may be calculated from the concentrations of the at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the CVD marker combination may be a concentration ratio of the at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the combination further comprises at least one additional ceramide and/or at least one additional phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure.

[0356] In some embodiments, the at least one additional Cer is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 additional Cers, selected from any of the Cer species referred to in Table 1. In some embodiments, the at least one additional Cer is a combination, including, but not limited to, a Cer/Cer ratio, of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 additional Cers. The combination may also be another combination as described herein.

[0357] In some embodiments, the at least one additional PC is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 additional PCs, selected from any of the PC species referred to in Table 1. In some embodiments, the at least one additional PC is a combination, including, but not limited to, a PC/PC ratio, of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 additional PCs. The combination may also be another combination as described herein.

[0358] In some embodiments, the CVD marker combination further comprises other cardiovascular biomarkers, including, but not limited to, LDL, LDL-C, LDL-P, HDL, HDL-C, HDL-P, any other lipoprotein subgroup composition or particle number, TC, TG, CRP, troponin T, troponin I, BNP, NT-proBNP, Cystatin C, HbA1c, glucose, St2, Galectin, TMAO, Lp-PLA2, GDF15, Lp(a), ApoB, ApoAI, ApoAII, ApoC, or any combination thereof. In some embodiments, the CVD marker combination further comprises other personal information or health data, such as sex, age, blood pressure, smoking status, diabetes, lipid lowering treatment or other medication, history of cardiovascular events, ethnic background, geographical location, medical imaging data, e.g. from angiography or computed tomography (CT), or any combination thereof. In some embodiments, the marker combination may be constructed by linear combinations, regression models, other unsupervised or supervised frequentist or Bayesian statistical classification or machine learning methods, such as support vector machines, kernel estimations, decision trees or, neural networks.

[0359] In some embodiments, the CVD marker combination may further comprise any other cardiovascular or metabolic biomarker, including, but not limited to creatine kinase (CK).

[0360] In some embodiments, the marker combination is a continuous or discrete scoring systems based on the Cer, PC, Cer/PC, Cer/Cer, PC/Cer, PC/PC or other cardiovascular biomarkers. For discrete scoring, the points may be given based on intervals with non-equal probabilities, quantiles or other cut-off values, determined from the same or other populations, of the individual score components.

[0361] In the present disclosure, the terms CVD marker combination, CVD biomarker combination, CV marker combination, CV biomarker combination, marker combination, biomarker combination, lipid marker combination and combination may be used interchangeable.

[0362] As used herein, a “standard combination” refers to a specific combination of lipid standards used for the methods and uses of the present disclosure. The standard combination comprises at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the standard combination further comprises at least one additional ceramide and/or phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure. In some embodiments, one or more of the components of the standard combination is isotope-labelled. In some embodiments, the isotope of the isotope-labelled component is deuterium (.sup.2H). In some embodiments, the isotope of the isotope-labelled component is .sup.13C or .sup.15N.

[0363] As used herein, a “composition” or “kit” may be any combination of any standard(s), control(s), reagent(s), solution(s) or solvent(s) used for the methods and uses of the present disclosure. The composition or kit may comprise at least one ceramide of Formula I and at least one phosphatidylcholine of Formula II. In some embodiments, the composition or kit further comprises at least one additional ceramide and/or phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure. In some embodiments, one or more of the components of the composition or kit is isotope-labelled. In some embodiments, the isotope of the isotope-labelled component is deuterium. In some embodiments, the isotope of the isotope-labelled component is .sup.13C or .sup.15N.

[0364] As used herein, the composition or kit may further include container(s), use instruction(s) for the methods or uses disclosed herein, and/or other element(s) for performing the methods or uses disclosed in the present disclosure. In some embodiments, the composition or kit includes element(s) for collecting a blood sample, for example, a dried blood spot on a filter.

[0365] The composition or kit may be purchased from a commercial manufacturer or prepared in-house in a laboratory. The composition or kit may be a test kit for used in a laboratory or a home use test kit (over-the-counter test).

[0366] In certain embodiments, the composition or kit is a combination of any standard(s), control(s), reagent(s), solution(s) or solvent(s) used for assaying a concentration of at least one ceramide of Formula I and a concentration of at least one phosphatidylcholine of Formula II and optionally a concentration of at least one additional ceramide and/or phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure.

[0367] The composition or kit may be used in assays performed with various chemical and high-resolution analytical techniques, such as, but not limited to, mass spectrometry (MS) and nuclear magnetic resonance (NMR). The MS analysis can be coupled to another high performance separation method, such as gas chromatography (GC), two-dimensional gas chromatography (GCxGC), liquid chromatography (LC), two-dimensional liquid chromatography (LCxLC), high performance liquid chromatography (HPLC) or ultra-high performance liquid chromatography (UHPLC).

[0368] As used herein, a “reagent” may be any standard(s), control(s), substance(s), compound(s), solution(s), solvent(s), agent(s), ingredient(s), preparation(s), or any combination thereof used for the methods and uses of the present disclosure. A reagent may also be a combination or mixture of any standard(s), control(s), substance(s), compound(s), solution(s), solvent(s), agent(s), ingredient(s) and preparation(s) used in the methods and uses of the present disclosure.

[0369] In some embodiments, one or more of any components of a reagent is isotope-labelled. In some embodiments, the isotope of the isotope-labelled component is deuterium. In some embodiments, the isotope of the isotope-labelled component is .sup.13C or .sup.15N.

[0370] In some embodiments, a reagent is used for assaying in a sample a concentration of at least one ceramide (Cer) of Formula I and a concentration of at least one phosphatidylcholine (PC) of Formula II. In some embodiments, a reagent is further used for assaying a concentration of at least one additional ceramide and/or phosphatidylcholine, selected from any of the Cer and PC species referred to in Table 1 of the present disclosure.

[0371] In some embodiments, a reagent is used in a preparation of a reagent, kit or composition for performing the methods and uses of the present disclosure.

[0372] For the purposes of the present disclosure, the terms “obtaining data”, “collecting data”, “obtaining information” and “collecting information” may be used interchangeably.

[0373] As used herein, “determining” in reference to a biomarker as disclosed herein refers to quantitatively or relatively determining an amount of a biomarker in a sample. For quantitative determination, either the absolute or precise amount of the biomarker in a sample is determined. The relative amount or level of a biomarker in a sample, may alternatively be determined, e.g., the biomarker amount in the sample is determined to be enlarged or diminished with respect to a control as described herein.

[0374] As used herein, “assaying”, “detecting”, “analyzing” or “generating quantitative data” refers to a measurement of a quantity, amount, abundance, level or concentration of the biomarkers of the present disclosure in a sample using a laboratory apparatus, equipment or device, such as, but not limited to, mass spectrometry.

[0375] As used herein, a “biomarker”, “marker”, “CVD marker”, “CVD biomarker”, “CV marker”, “CV biomarker”, “lipid marker” and “lipid biomarker” may be used interchangeably.

[0376] As used herein, a “combination”, “group”, “set”, “composition” and “mixture” may be used interchangeably.

[0377] As used herein, and according to Table 1, a “direction of change” refers to a change in a quantity, amount, abundance, level or concentration of the biomarker in a sample from a subject when the subject is having a risk of developing one or more cardiovascular events, when compared to a control. When evaluating the effectiveness of a CVD treatment in a subject, according to some aspects of the precent disclosure, directions of change are opposite of which are presented in Table 1.

[0378] As used herein, a “risk” refers to a low, intermediate or high risk of developing one or more cardiovascular events.

[0379] The terms “the disclosure, description or invention”, “in accordance with the disclosure, description or invention”, “according to the disclosure, description or invention”, “the present disclosure, description or invention”, as used herein, are intended to refer to all aspects and embodiments of the disclosure described and/or claimed herein.

[0380] As used herein, the term “comprising” is to be construed as encompassing both “including” and “consisting of”.

EXAMPLES

Example 1

Materials and Methods

[0381] Description of Study Cohorts and Samples

[0382] Plasma samples were obtained from 3700 adult subjects, with suspected stable angina pectoris, who underwent coronary angiography. These subjects were followed up on average for 10 years for cardiovascular (CV) death or CV events.

[0383] In addition to the first study cohort, samples were also analysed from another study cohort, a population study cohort. 7300 serum samples were analysed from adult subjects of the cohort. The subjects were followed up on average 16 years for several cardiovascular outcomes, e.g. myocardial infarction, heart failure and CV death.

[0384] Analytical Methods

[0385] For quantification of lipids, serum samples were extracted using a modified Folch lipid extraction performed on a Hamilton Microlab Star robot, as described in Jung HR et al., High throughput quantitative molecular lipidomics. Biochim Biophys Acta. 2011 November; 1811(11):925-34, which is hereby incorporated by reference in its entirety. Samples were spiked with known amounts of non-endogeneous synthetic internal standards. After lipid extraction, samples were reconstituted in chloroform:methanol (1:2, v/v) and a synthetic external standard was post-extract spiked to the extracts. The extracts were stored at −20° C. prior to MS analysis.

[0386] Ceramides and phospholipids (e.g. phosphatidylcholines) were analyzed on a hybrid triple quadrupole/linear ion trap mass spectrometer (5500 QTRAP) equipped with an ultra high pressure liquid chromatography (UHPLC) system (Eksigent ultraLC 100 system) using multiple reaction monitoring (MRM). Ceramides were analysed based on method in negative ion mode based on the description by Sullards MC et al., Structure-specific, quantitative methods for analysis of sphingolipids by liquid chromatography-tandem mass spectrometry: “inside-out” sphingolipidomics. Methods Enzymol. 2007; 432:83-115. Phospholipids were analyzed based on previously published method by Niemi et al., Ovarian tumours of different histologic type and clinical stage induce similar changes in lipid metabolism. British Journal of Cancer. 2018; 119:847-854.

[0387] Statistical Analyses

[0388] All statistical analyses were performed using R software. Cox proportional hazards models (constructed using the R package survival) were used to determine the association of variables or their combinations to outcome of the study subjects. The hazard ratios (HRs) obtained from the cox regression models are expressed per standard deviation (SD). Linear combinations of variables were constructed using binary logistic regression models, and C-statistics for cox regression models were calculated using the Hmisc package.

Example 2

Results

[0389] Tables 2-12 present results of the first study cohort and tables 13-18 of the second study cohort.

[0390] Table 2 shows that ceramide vs. phosphatidylcholine or ceramide vs. ceramide ratios predict more accurately the CV events than the corresponding ceramides or phosphatidylcholines alone. In this example, the cox models were adjusted with age and stratified for sex. As shown in the Table 2, lipid ratios have lower p-values and higher C-statistics as compared to the individual lipid components.

TABLE-US-00002 TABLE 2 The p-value of lipid ratios are lower than the corresponding lipids alone. Lipid ratio Denominator lipid Numerator lipid Lipid ratio HR (95% CI) p-value C-stat HR (95% CI) p-value C-stat HR (95% CI) p-value C-stat Cer(d18:1/16:0)/ 1.27 (1.20, 1.35) 3.9E−15 0.639 1.23 (1.15, 1.31) 4.4E−10 0.629 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/24:1)/ 1.26 (1.19, 1.34) 6.1E−15 0.641 1.16 (1.09, 1.24) 6.7E−06 0.626 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/18:0)/ 1.25 (1.18, 1.33) 4.7E−14 0.639 1.21 (1.13, 1.28) 7.8E−09 0.630 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/16:0)/ 1.21 (1.15, 1.28) 6.7E−13 0.635 1.23 (1.15, 1.31) 4.4E−10 0.629 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/16:0)/ 1.27 (1.19, 1.35) 7.9E−13 0.634 1.23 (1.15, 1.31) 4.4E−10 0.629 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:1/18:0)/ 1.24 (1.17, 1.32) 9.8E−13 0.634 1.21 (1.13, 1.28) 7.8E−09 0.630 0.83 (0.76, 0.89) 2.4E−06 0.629 PC 39:6 Cer(d18:1/24:1)/ 1.22 (1.15, 1.29) 1.6E−12 0.638 1.16 (1.09, 1.24) 6.7E−06 0.626 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/18:0)/ 1.20 (1.14, 1.27) 6.1E−12 0.636 1.21 (1.13, 1.28) 7.8E−09 0.630 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/18:0)/ 1.24 (1.17, 1.33) 7.8E−12 0.635 1.21 (1.13, 1.28) 7.8E−09 0.630 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:1/16:0)/ 1.22 (1.16, 1.30) 8.5E−12 0.633 1.23 (1.15, 1.31) 4.4E−10 0.629 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:1/20:0)/ 1.23 (1.16, 1.30) 1.0E−11 0.635 1.15 (1.08, 1.22) 4.9E−06 0.625 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/18:0)/ 1.24 (1.16, 1.32) 1.1E−11 0.635 1.21 (1.13, 1.28) 7.8E−09 0.630 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:1/16:0)/ 1.22 (1.15, 1.30) 1.6E−11 0.632 1.23 (1.15, 1.31) 4.4E−10 0.629 0.83 (0.76, 0.89) 2.4E−06 0.629 PC 39:6 Cer(d18:1/24:1)/ 1.22 (1.15, 1.29) 1.7E−11 0.633 1.16 (1.09, 1.24) 6.7E−06 0.626 0.83 (0.76, 0.89) 2.4E−06 0.629 PC 39:6 Cer(d18:1/24:1)/ 1.20 (1.13, 1.26) 7.0E−11 0.634 1.16 (1.09, 1.24) 6.7E−06 0.626 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.22 (1.15, 1.30) 1.8E−10 0.634 1.09 (1.01, 1.17) 1.9E−02 0.619 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/18:0)/ 1.16 (1.11, 1.22) 7.5E−10 0.631 1.21 (1.13, 1.28) 7.8E−09 0.630 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d18:1/20:0)/ 1.16 (1.11, 1.22) 9.0E−10 0.632 1.15 (1.08, 1.22) 4.9E−06 0.625 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/24:1)/ 1.21 (1.14, 1.29) 1.2E−09 0.631 1.16 (1.09, 1.24) 6.7E−06 0.626 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d18:1/20:0)/ 1.20 (1.13, 1.28) 1.3E−09 0.630 1.15 (1.08, 1.22) 4.9E−06 0.625 0.83 (0.76, 0.89) 2.4E−06 0.629 PC 39:6 Cer(d18:1/22:0)/ 1.21 (1.14, 1.29) 1.3E−09 0.632 1.14 (1.07, 1.22) 1.1E−04 0.624 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d18:1/24:1)/ 1.16 (1.10, 1.21) 1.5E−09 0.631 1.16 (1.09, 1.24) 6.7E−06 0.626 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d16:1/16:0)/ 1.23 (1.15, 1.31) 1.9E−09 0.633 1.08 (1.01, 1.16) 2.6E−02 0.620 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d16:1/16:0)/ 1.20 (1.13, 1.28) 2.7E−09 0.632 1.08 (1.01, 1.16) 2.6E−02 0.620 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/18:0)/ 1.21 (1.14, 1.29) 3.9E−09 0.633 1.21 (1.13, 1.28) 7.8E−09 0.630 1.00 (0.93, 1.08) 9.7E−01 0.619 PC 17:0/18:1 Cer(d18:2/24:1)/ 1.20 (1.13, 1.28) 4.4E−09 0.633 1.06 (0.98, 1.13) 1.3E−01 0.619 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:1/20:0)/ 1.21 (1.13, 1.29) 4.8E−09 0.630 1.15 (1.08, 1.22) 4.9E−06 0.625 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:1/18:0)/ 1.20 (1.13, 1.28) 5.0E−09 0.633 1.21 (1.13, 1.28) 7.8E−09 0.630 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:1/24:1)/ 1.21 (1.13, 1.29) 6.0E−09 0.631 1.16 (1.09, 1.24) 6.7E−06 0.626 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:1/22:0)/ 1.21 (1.13, 1.29) 6.4E−09 0.631 1.14 (1.07, 1.22) 1.1E−04 0.624 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:2/16:0)/ 1.18 (1.12, 1.25) 9.0E−09 0.630 1.09 (1.01, 1.17) 1.9E−02 0.619 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/20:0)/ 1.20 (1.13, 1.28) 1.1E−08 0.629 1.15 (1.08, 1.22) 4.9E−06 0.625 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d20:1/24:1)/ 1.19 (1.12, 1.27) 1.5E−08 0.631 1.09 (1.02, 1.16) 1.3E−02 0.622 0.83 (0.76, 0.89) 2.4E−06 0.629 PC 39:6 Cer(d18:1/22:0)/ 1.19 (1.12, 1.26) 2.0E−08 0.631 1.14 (1.07, 1.22) 1.1E−04 0.624 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/20:0)/ 1.16 (1.10, 1.21) 2.3E−08 0.629 1.15 (1.08, 1.22) 4.9E−06 0.625 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d16:1/18:0)/ 1.21 (1.13, 1.29) 2.4E−08 0.631 1.08 (1.01, 1.16) 3.2E−02 0.620 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d18:2/18:0)/ 1.19 (1.12, 1.27) 5.8E−08 0.631 1.06 (0.99, 1.14) 8.7E−02 0.619 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d20:1/24:1)/ 1.17 (1.10, 1.23) 6.1E−08 0.628 1.09 (1.02, 1.16) 1.3E−02 0.622 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d20:1/24:1)/ 1.16 (1.10, 1.22) 7.0E−08 0.631 1.09 (1.02, 1.16) 1.3E−02 0.622 0.82 (0.76, 0.89) 3.0E−06 0.630 PC 37:6 Cer(d16:1/18:0)/ 1.19 (1.12, 1.27) 7.5E−08 0.631 1.08 (1.01, 1.16) 3.2E−02 0.620 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/24:1)/ 1.18 (1.11, 1.25) 8.4E−08 0.626 1.16 (1.09, 1.24) 6.7E−06 0.626 0.88 (0.81, 0.95) 9.7E−04 0.622 PC 18:0/20:5 Cer(d20:1/24:1)/ 1.16 (1.10, 1.23) 9.3E−08 0.628 1.09 (1.02, 1.16) 1.3E−02 0.622 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d18:1/24:1)/ 1.17 (1.10, 1.24) 1.5E−07 0.629 1.16 (1.09, 1.24) 6.7E−06 0.626 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:1/24:1)/ 1.18 (1.11, 1.25) 1.5E−07 0.626 1.16 (1.09, 1.24) 6.7E−06 0.626 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d20:1/24:1)/ 1.15 (1.09, 1.21) 2.2E−07 0.630 1.09 (1.02, 1.16) 1.3E−02 0.622 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/20:0)/ 1.19 (1.11, 1.26) 2.3E−07 0.627 1.15 (1.08, 1.22) 4.9E−06 0.625 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:1/20:0)/ 1.12 (1.07, 1.17) 2.3E−07 0.627 1.15 (1.08, 1.22) 4.9E−06 0.625 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d18:1/22:0)/ 1.19 (1.11, 1.27) 2.7E−07 0.628 1.14 (1.07, 1.22) 1.1E−04 0.624 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d18:2/16:0)/ 1.15 (1.09, 1.21) 3.1E−07 0.627 1.09 (1.01, 1.17) 1.9E−02 0.619 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d20:1/24:1)/ 1.17 (1.10, 1.24) 3.5E−07 0.627 1.09 (1.02, 1.16) 1.3E−02 0.622 0.88 (0.81, 0.95) 9.7E−04 0.622 PC 18:0/20:5 Cer(d20:1/22:0)/ 1.16 (1.10, 1.23) 4.2E−07 0.629 1.10 (1.03, 1.18) 4.6E−03 0.622 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/24:1)/ 1.13 (1.08, 1.19) 6.2E−07 0.627 1.16 (1.09, 1.24) 6.7E−06 0.626 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d16:1/20:0)/ 1.17 (1.10, 1.25) 7.0E−07 0.628 1.08 (1.00, 1.16) 4.3E−02 0.619 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/22:0)/ 1.15 (1.09, 1.21) 9.3E−07 0.627 1.14 (1.07, 1.22) 1.1E−04 0.624 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d20:1/22:0)/ 1.15 (1.09, 1.21) 9.6E−07 0.626 1.10 (1.03, 1.18) 4.6E−03 0.622 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d18:2/24:1)/ 1.16 (1.09, 1.23) 1.2E−06 0.630 1.06 (0.98, 1.13) 1.3E−01 0.619 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d20:1/24:1)/ 1.17 (1.10, 1.24) 1.2E−06 0.626 1.09 (1.02, 1.16) 1.3E−02 0.622 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d18:1/22:0)/ 1.17 (1.10, 1.25) 1.2E−06 0.626 1.14 (1.07, 1.22) 1.1E−04 0.624 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:1/22:0)/ 1.16 (1.09, 1.23) 1.4E−06 0.625 1.14 (1.07, 1.22) 1.1E−04 0.624 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d18:2/18:0)/ 1.16 (1.09, 1.23) 1.6E−06 0.629 1.06 (0.99, 1.14) 8.7E−02 0.619 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:1/20:0)/ 1.15 (1.09, 1.22) 1.8E−06 0.626 1.15 (1.08, 1.22) 4.9E−06 0.625 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d16:1/18:0)/ 1.16 (1.09, 1.24) 3.0E−06 0.626 1.08 (1.01, 1.16) 3.2E−02 0.620 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d18:1/20:0)/ 1.15 (1.09, 1.22) 3.1E−06 0.628 1.15 (1.08, 1.22) 4.9E−06 0.625 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d16:1/16:0)/ 1.13 (1.07, 1.19) 3.9E−06 0.625 1.08 (1.01, 1.16) 2.6E−02 0.620 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d20:1/24:1)/ 1.16 (1.09, 1.23) 3.9E−06 0.628 1.09 (1.02, 1.16) 1.3E−02 0.622 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d16:1/18:0)/ 1.14 (1.08, 1.20) 4.1E−06 0.626 1.08 (1.01, 1.16) 3.2E−02 0.620 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d20:1/24:1)/ 1.16 (1.09, 1.23) 4.3E−06 0.625 1.09 (1.02, 1.16) 1.3E−02 0.622 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d18:1/20:0)/ 1.15 (1.09, 1.23) 4.4E−06 0.626 1.15 (1.08, 1.22) 4.9E−06 0.625 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d20:1/23:0)/ 1.15 (1.08, 1.22) 4.6E−06 0.627 1.05 (0.98, 1.13) 1.4E−01 0.620 0.86 (0.79, 0.93) 1.8E−04 0.627 PC 36:6 Cer(d18:2/16:0)/ 1.17 (1.09, 1.25) 6.0E−06 0.624 1.09 (1.01, 1.17) 1.9E−02 0.619 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d18:2/24:1)/ 1.16 (1.09, 1.23) 8.4E−06 0.626 1.06 (0.98, 1.13) 1.3E−01 0.619 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d18:2/18:0)/ 1.13 (1.07, 1.20) 9.2E−06 0.626 1.06 (0.99, 1.14) 8.7E−02 0.619 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d18:2/18:0)/ 1.16 (1.09, 1.24) 9.4E−06 0.625 1.06 (0.99, 1.14) 8.7E−02 0.619 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d16:1/16:0)/ 1.16 (1.09, 1.24) 9.5E−06 0.625 1.08 (1.01, 1.16) 2.6E−02 0.620 0.84 (0.78, 0.91) 4.1E−05 0.625 PC 35:5 Cer(d18:1/22:0)/ 1.15 (1.08, 1.22) 1.3E−05 0.627 1.14 (1.07, 1.22) 1.1E−04 0.624 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:1/22:0)/ 1.16 (1.08, 1.23) 1.4E−05 0.625 1.14 (1.07, 1.22) 1.1E−04 0.624 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.15 (1.08, 1.22) 1.6E−05 0.624 1.09 (1.01, 1.17) 1.9E−02 0.619 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.11 (1.06, 1.16) 1.8E−05 0.624 1.09 (1.01, 1.17) 1.9E−02 0.619 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d20:1/23:0)/ 1.13 (1.07, 1.19) 2.0E−05 0.625 1.05 (0.98, 1.13) 1.4E−01 0.620 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d18:1/22:0)/ 1.12 (1.06, 1.17) 2.2E−05 0.626 1.14 (1.07, 1.22) 1.1E−04 0.624 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d18:2/24:1)/ 1.12 (1.06, 1.18) 2.5E−05 0.626 1.06 (0.98, 1.13) 1.3E−01 0.619 0.88 (0.81, 0.96) 3.4E−03 0.625 PC 38:7 Cer(d20:1/22:0)/ 1.14 (1.07, 1.21) 2.5E−05 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d16:1/16:0)/ 1.16 (1.08, 1.24) 2.5E−05 0.624 1.08 (1.01, 1.16) 2.6E−02 0.620 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/24:1)/ 1.12 (1.06, 1.19) 2.6E−05 0.624 1.09 (1.02, 1.16) 1.3E−02 0.622 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d20:1/22:0)/ 1.15 (1.08, 1.23) 2.6E−05 0.627 1.10 (1.03, 1.18) 4.6E−03 0.622 0.98 (0.91, 1.06) 6.4E−01 0.619 PC 40:1 Cer(d16:1/16:0)/ 1.12 (1.06, 1.18) 3.3E−05 0.625 1.08 (1.01, 1.16) 2.6E−02 0.620 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d18:1/22:0)/ 1.16 (1.08, 1.24) 3.6E−05 0.626 1.14 (1.07, 1.22) 1.1E−04 0.624 1.03 (0.95, 1.11) 4.7E−01 0.618 PC 17:0/18:2 Cer(d18:1/22:0)/ 1.15 (1.08, 1.23) 3.6E−05 0.627 1.14 (1.07, 1.22) 1.1E−04 0.624 0.99 (0.92, 1.07) 8.5E−01 0.620 PC 17:0/20:3 Cer(d18:1/22:0)/ 1.14 (1.07, 1.22) 4.8E−05 0.626 1.14 (1.07, 1.22) 1.1E−04 0.624 0.98 (0.91, 1.06) 6.4E−01 0.619 PC 40:1 Cer(d18:1/22:0)/ 1.14 (1.07, 1.21) 5.0E−05 0.625 1.14 (1.07, 1.22) 1.1E−04 0.624 1.07 (0.99, 1.15) 8.5E−02 0.619 Cer(d18:1/24:0) Cer(d18:1/22:0)/ 1.14 (1.07, 1.22) 5.1E−05 0.625 1.14 (1.07, 1.22) 1.1E−04 0.624 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d20:1/24:1)/ 1.14 (1.07, 1.22) 5.1E−05 0.624 1.09 (1.02, 1.16) 1.3E−02 0.622 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d20:1/22:0)/ 1.14 (1.07, 1.22) 5.1E−05 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/24:1)/ 1.14 (1.07, 1.22) 5.2E−05 0.626 1.09 (1.02, 1.16) 1.3E−02 0.622 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d16:1/16:0)/ 1.15 (1.07, 1.23) 5.4E−05 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d18:1/22:0)/ 1.14 (1.07, 1.22) 6.5E−05 0.626 1.14 (1.07, 1.22) 1.1E−04 0.624 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d20:1/22:0)/ 1.15 (1.07, 1.23) 6.8E−05 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d20:1/22:0)/ 1.12 (1.06, 1.18) 8.1E−05 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d18:1/22:0)/ 1.14 (1.07, 1.22) 9.5E−05 0.624 1.14 (1.07, 1.22) 1.1E−04 0.624 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:2/16:0)/ 1.14 (1.07, 1.22) 1.0E−04 0.622 1.09 (1.01, 1.17) 1.9E−02 0.619 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d18:2/18:0)/ 1.14 (1.06, 1.22) 1.3E−04 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.88 (0.81, 0.95) 9.7E−04 0.622 PC 18:0/20:5 Cer(d18:2/16:0)/ 1.12 (1.06, 1.19) 1.4E−04 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d16:1/16:0)/ 1.14 (1.06, 1.21) 1.5E−04 0.625 1.08 (1.01, 1.16) 2.6E−02 0.620 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d16:1/18:0)/ 1.14 (1.06, 1.22) 1.5E−04 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.88 (0.81, 0.95) 9.7E−04 0.622 PC 18:0/20:5 Cer(d16:1/18:0)/ 1.14 (1.07, 1.22) 1.5E−04 0.624 1.08 (1.01, 1.16) 3.2E−02 0.620 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/22:0)/ 1.13 (1.06, 1.20) 1.6E−04 0.626 1.10 (1.03, 1.18) 4.6E−03 0.622 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d20:1/24:1)/ 1.08 (1.04, 1.12) 1.7E−04 0.624 1.09 (1.02, 1.16) 1.3E−02 0.622 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d16:1/18:0)/ 1.14 (1.06, 1.22) 1.8E−04 0.623 1.08 (1.01, 1.16) 3.2E−02 0.620 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d20:1/22:0)/ 1.13 (1.06, 1.20) 1.9E−04 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:2/18:0)/ 1.12 (1.05, 1.18) 1.9E−04 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d16:1/26:0)/ 0.86 (0.79, 0.93) 2.1E−04 0.631 0.90 (0.83, 0.98) 1.0E−02 0.629 1.11 (1.03, 1.20) 8.5E−03 0.620 PC 16:0/20:3 Cer(d20:1/22:0)/ 1.13 (1.06, 1.20) 2.1E−04 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.88 (0.81, 0.95) 9.7E−04 0.622 PC 18:0/20:5 Cer(d18:2/16:0)/ 1.13 (1.06, 1.21) 2.2E−04 0.623 1.09 (1.01, 1.17) 1.9E−02 0.619 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d20:1/24:1)/ 1.13 (1.06, 1.20) 2.2E−04 0.625 1.09 (1.02, 1.16) 1.3E−02 0.622 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/24:1)/ 1.13 (1.06, 1.21) 2.3E−04 0.624 1.09 (1.02, 1.16) 1.3E−02 0.622 0.95 (0.88, 1.02) 1.5E−01 0.619 PC 40:6 Cer(d18:2/18:0)/ 1.13 (1.06, 1.21) 2.3E−04 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d20:1/22:0)/ 1.13 (1.06, 1.20) 2.5E−04 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/18:0)/ 1.12 (1.05, 1.19) 2.6E−04 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d20:1/22:0)/ 1.09 (1.04, 1.15) 2.7E−04 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d20:1/22:0)/ 1.13 (1.06, 1.21) 2.8E−04 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d20:1/22:0)/ 1.13 (1.06, 1.20) 2.9E−04 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d20:1/22:0)/ 1.14 (1.06, 1.22) 2.9E−04 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d16:1/18:0)/ 1.10 (1.05, 1.16) 3.1E−04 0.623 1.08 (1.01, 1.16) 3.2E−02 0.620 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d16:1/26:0)/ 0.52 (0.36, 0.74) 3.2E−04 0.633 0.90 (0.83, 0.98) 1.0E−02 0.629 1.08 (1.00, 1.15) 4.5E−02 0.621 Cer(d20:1/24:0) Cer(d20:1/22:0)/ 1.13 (1.06, 1.21) 3.2E−04 0.626 1.10 (1.03, 1.18) 4.6E−03 0.622 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d16:1/16:0)/ 1.13 (1.06, 1.21) 3.4E−04 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d16:1/26:0)/ 0.86 (0.80, 0.94) 3.9E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.12 (1.04, 1.20) 2.7E−03 0.619 PC 16:0/18:2 Cer(d18:2/16:0)/ 1.13 (1.06, 1.21) 4.2E−04 0.620 1.09 (1.01, 1.17) 1.9E−02 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d20:1/24:1)/ 1.10 (1.04, 1.16) 4.4E−04 0.622 1.09 (1.02, 1.16) 1.3E−02 0.622 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d18:2/18:0)/ 1.13 (1.06, 1.21) 4.4E−04 0.623 1.06 (0.99, 1.14) 8.7E−02 0.619 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d16:1/18:0)/ 1.11 (1.05, 1.17) 4.5E−04 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/18:0)/ 1.13 (1.05, 1.21) 4.7E−04 0.624 1.08 (1.01, 1.16) 3.2E−02 0.620 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d16:1/16:0)/ 1.13 (1.05, 1.21) 4.7E−04 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d16:1/26:0)/ 0.86 (0.80, 0.94) 5.2E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.09 (1.02, 1.18) 1.7E−02 0.620 PC 36:3 Cer(d20:1/22:0)/ 1.12 (1.05, 1.19) 5.3E−04 0.622 1.10 (1.03, 1.18) 4.6E−03 0.622 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d16:1/20:0)/ 1.12 (1.05, 1.19) 5.4E−04 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d16:1/18:0)/ 1.13 (1.05, 1.21) 5.5E−04 0.623 1.08 (1.01, 1.16) 3.2E−02 0.620 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.11 (1.05, 1.18) 5.6E−04 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/16:0)/ 1.13 (1.05, 1.21) 5.7E−04 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.12 (1.05, 1.20) 5.8E−04 0.624 1.09 (1.01, 1.17) 1.9E−02 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d20:1/22:0)/ 1.13 (1.05, 1.20) 5.9E−04 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d16:1/16:0)/ 1.12 (1.05, 1.19) 6.2E−04 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d20:1/22:0)/ 1.12 (1.05, 1.20) 6.2E−04 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d18:2/18:0)/ 1.12 (1.05, 1.20) 6.2E−04 0.623 1.06 (0.99, 1.14) 8.7E−02 0.619 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d16:1/20:0)/ 1.13 (1.05, 1.20) 6.5E−04 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d18:2/16:0)/ 1.12 (1.05, 1.20) 6.8E−04 0.622 1.09 (1.01, 1.17) 1.9E−02 0.619 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d16:1/26:0)/ 0.87 (0.80, 0.94) 7.6E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.09 (1.01, 1.17) 3.3E−02 0.620 PC 36:4 Cer(d16:1/16:0)/ 1.11 (1.04, 1.17) 8.0E−04 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/26:0)/ 0.87 (0.80, 0.94) 8.5E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.09 (1.01, 1.18) 2.3E−02 0.620 PC 16:0/20:4 Cer(d16:1/26:0)/ 0.87 (0.81, 0.95) 9.1E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.11 (1.04, 1.19) 2.9E−03 0.621 PC 16:0/18:1 Cer(d20:1/22:0)/ 1.10 (1.04, 1.17) 9.2E−04 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d16:1/26:0)/ 0.87 (0.80, 0.95) 9.2E−04 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.10 (1.04, 1.16) 1.6E−03 0.621 PC 18:1/18:1 Cer(d20:1/22:0)/ 1.12 (1.05, 1.19) 9.6E−04 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d18:2/24:1)/ 1.09 (1.04, 1.15) 9.8E−04 0.623 1.06 (0.98, 1.13) 1.3E−01 0.619 0.90 (0.84, 0.97) 8.0E−03 0.623 PC 40:8 Cer(d18:2/24:1)/ 1.12 (1.05, 1.19) 9.9E−04 0.622 1.06 (0.98, 1.13) 1.3E−01 0.619 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d16:1/16:0)/ 1.12 (1.05, 1.19) 1.1E−03 0.624 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d18:2/18:0)/ 1.10 (1.04, 1.17) 1.1E−03 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/26:0)/ 0.87 (0.81, 0.95) 1.1E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.10 (1.02, 1.18) 1.1E−02 0.619 PC 18:0/18:2 Cer(d20:1/22:0)/ 1.09 (1.03, 1.14) 1.2E−03 0.622 1.10 (1.03, 1.18) 4.6E−03 0.622 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d16:1/26:0)/ 0.87 (0.80, 0.95) 1.2E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.09 (1.01, 1.17) 3.5E−02 0.619 PC 18:0/20:3 Cer(d16:1/20:0)/ 1.12 (1.05, 1.20) 1.2E−03 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/22:0)/ 1.11 (1.04, 1.17) 1.2E−03 0.625 1.10 (1.03, 1.18) 4.6E−03 0.622 0.99 (0.92, 1.07) 8.5E−01 0.620 PC 17:0/20:3 Cer(d16:1/26:0)/ 0.87 (0.81, 0.95) 1.2E−03 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.07 (0.99, 1.15) 8.5E−02 0.619 Cer(d18:1/24:0) Cer(d20:1/24:1)/ 1.11 (1.04, 1.19) 1.3E−03 0.625 1.09 (1.02, 1.16) 1.3E−02 0.622 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d18:2/18:0)/ 1.12 (1.04, 1.20) 1.4E−03 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d18:2/24:1)/ 1.10 (1.04, 1.17) 1.4E−03 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d18:2/16:0)/ 1.12 (1.04, 1.20) 1.4E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d16:1/18:0)/ 1.11 (1.04, 1.19) 1.5E−03 0.623 1.08 (1.01, 1.16) 3.2E−02 0.620 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d20:1/22:0)/ 1.11 (1.04, 1.19) 1.5E−03 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d16:1/16:0)/ 1.09 (1.03, 1.14) 1.5E−03 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d16:1/26:0)/ 0.87 (0.80, 0.95) 1.5E−03 0.630 0.90 (0.83, 0.98) 1.0E−02 0.629 1.07 (0.99, 1.15) 7.4E−02 0.619 PC 38:4 Cer(d20:1/24:1)/ 1.11 (1.04, 1.18) 1.5E−03 0.625 1.09 (1.02, 1.16) 1.3E−02 0.622 0.98 (0.91, 1.06) 6.4E−01 0.619 PC 40:1 Cer(d16:1/16:0)/ 1.12 (1.04, 1.20) 1.5E−03 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d20:1/22:0)/ 1.12 (1.04, 1.20) 1.5E−03 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 1.03 (0.95, 1.11) 4.7E−01 0.618 PC 17:0/18:2 Cer(d20:1/24:1)/ 1.10 (1.04, 1.17) 1.6E−03 0.623 1.09 (1.02, 1.16) 1.3E−02 0.622 0.94 (0.87, 1.01) 7.2E−02 0.620 PC 40:3 Cer(d16:1/16:0)/ 1.09 (1.03, 1.15) 1.8E−03 0.624 1.08 (1.01, 1.16) 2.6E−02 0.620 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d16:1/18:0)/ 1.12 (1.04, 1.20) 1.8E−03 0.620 1.08 (1.01, 1.16) 3.2E−02 0.620 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d20:1/23:0)/ 1.11 (1.04, 1.19) 1.8E−03 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.89 (0.82, 0.96) 3.5E−03 0.621 PC 38:5 Cer(d16:1/26:0)/ 0.88 (0.81, 0.95) 1.9E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.10 (1.02, 1.18) 8.9E−03 0.620 PC 34:1 Cer(d16:1/16:0)/ 1.11 (1.04, 1.19) 2.0E−03 0.620 1.08 (1.01, 1.16) 2.6E−02 0.620 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d20:1/24:1)/ 1.10 (1.04, 1.17) 2.0E−03 0.623 1.09 (1.02, 1.16) 1.3E−02 0.622 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d16:1/18:0)/ 1.11 (1.04, 1.19) 2.1E−03 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d18:2/24:1)/ 1.11 (1.04, 1.18) 2.1E−03 0.623 1.06 (0.98, 1.13) 1.3E−01 0.619 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d16:1/20:0)/ 1.11 (1.04, 1.19) 2.3E−03 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d16:1/16:0)/ 1.11 (1.04, 1.19) 2.3E−03 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d20:1/23:0)/ 1.11 (1.04, 1.18) 2.4E−03 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.90 (0.83, 0.97) 5.1E−03 0.621 PC 16:0/20:5 Cer(d16:1/20:0)/ 1.11 (1.04, 1.18) 2.6E−03 0.623 1.08 (1.00, 1.16) 4.3E−02 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:2/24:1)/ 1.10 (1.03, 1.17) 2.8E−03 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/26:0)/ 0.89 (0.82, 0.96) 2.8E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.07 (1.00, 1.14) 5.0E−02 0.619 PC 18:0/18:1 Cer(d20:1/24:1)/ 1.10 (1.03, 1.16) 2.9E−03 0.622 1.09 (1.02, 1.16) 1.3E−02 0.622 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d20:1/23:0)/ 1.11 (1.04, 1.19) 2.9E−03 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.90 (0.84, 0.98) 9.3E−03 0.622 PC 16:0/22:6 Cer(d18:2/16:0)/ 1.11 (1.04, 1.19) 3.0E−03 0.623 1.09 (1.01, 1.17) 1.9E−02 0.619 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d20:1/22:0)/ 1.08 (1.03, 1.13) 3.1E−03 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d20:1/23:0)/ 1.10 (1.03, 1.17) 3.1E−03 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/26:0)/ 0.88 (0.82, 0.96) 3.1E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.08 (1.00, 1.16) 6.2E−02 0.619 PC 18:0/20:4 Cer(d20:1/24:1)/ 1.10 (1.03, 1.18) 3.4E−03 0.623 1.09 (1.02, 1.16) 1.3E−02 0.622 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d20:1/23:0)/ 1.11 (1.03, 1.18) 3.4E−03 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d16:1/18:0)/ 1.11 (1.03, 1.19) 3.5E−03 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d16:1/20:0)/ 1.11 (1.03, 1.19) 3.6E−03 0.622 1.08 (1.00, 1.16) 4.3E−02 0.619 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d18:1/23:0)/ 1.11 (1.03, 1.19) 3.6E−03 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d18:2/18:0)/ 1.10 (1.03, 1.18) 3.7E−03 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:2/24:1)/ 1.10 (1.03, 1.18) 3.7E−03 0.622 1.06 (0.98, 1.13) 1.3E−01 0.619 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d16:1/20:0)/ 1.09 (1.03, 1.16) 3.8E−03 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d18:2/16:0)/ 1.07 (1.02, 1.12) 4.0E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d20:1/22:0)/ 1.09 (1.03, 1.16) 4.1E−03 0.624 1.10 (1.03, 1.18) 4.6E−03 0.622 1.00 (0.93, 1.08) 9.5E−01 0.619 PC 14:0/18:2 Cer(d20:1/22:0)/ 1.10 (1.03, 1.18) 4.2E−03 0.623 1.10 (1.03, 1.18) 4.6E−03 0.622 1.00 (0.93, 1.08) 9.7E−01 0.619 PC 17:0/18:1 Cer(d18:1/26:1)/ 0.89 (0.82, 0.96) 4.4E−03 0.619 0.96 (0.89, 1.03) 2.9E−01 0.619 1.07 (1.01, 1.15) 3.3E−02 0.619 PC 16:0/18:3 Cer(d20:1/24:1)/ 1.09 (1.03, 1.17) 5.0E−03 0.622 1.09 (1.02, 1.16) 1.3E−02 0.622 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/18:0)/ 1.09 (1.03, 1.15) 5.1E−03 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d20:1/24:1)/ 1.09 (1.03, 1.17) 5.1E−03 0.623 1.09 (1.02, 1.16) 1.3E−02 0.622 0.99 (0.92, 1.06) 7.8E−01 0.619 PC 38:1 Cer(d18:2/18:0)/ 1.10 (1.03, 1.17) 5.2E−03 0.623 1.06 (0.99, 1.14) 8.7E−02 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:1/26:1)/ 0.90 (0.83, 0.97) 5.4E−03 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.10 (1.02, 1.18) 8.9E−03 0.620 PC 34:1 Cer(d20:1/23:0)/ 1.11 (1.03, 1.19) 5.4E−03 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:2/24:1)/ 1.10 (1.03, 1.18) 5.6E−03 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/18:0)/ 1.08 (1.02, 1.14) 5.7E−03 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d20:1/23:0)/ 1.09 (1.02, 1.16) 6.0E−03 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d18:2/16:0)/ 1.09 (1.03, 1.16) 6.1E−03 0.622 1.09 (1.01, 1.17) 1.9E−02 0.619 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d18:2/16:0)/ 1.08 (1.02, 1.15) 6.1E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d16:1/20:0)/ 1.10 (1.03, 1.18) 6.1E−03 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d16:1/16:0)/ 1.10 (1.03, 1.17) 6.2E−03 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d16:1/18:0)/ 1.10 (1.03, 1.18) 6.2E−03 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d16:1/20:0)/ 1.09 (1.02, 1.16) 6.4E−03 0.622 1.08 (1.00, 1.16) 4.3E−02 0.619 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d18:1/23:0)/ 1.10 (1.03, 1.18) 6.6E−03 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.93 (0.86, 1.01) 7.4E−02 0.620 PC 16:0/22:5 Cer(d20:1/24:1)/ 1.10 (1.03, 1.18) 6.7E−03 0.622 1.09 (1.02, 1.16) 1.3E−02 0.622 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d18:2/16:0)/ 1.08 (1.02, 1.15) 6.9E−03 0.622 1.09 (1.01, 1.17) 1.9E−02 0.619 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d16:1/26:0)/ 0.89 (0.82, 0.97) 6.9E−03 0.629 0.90 (0.83, 0.98) 1.0E−02 0.629 1.09 (1.01, 1.18) 3.0E−02 0.620 PC 40:5 Cer(d18:2/16:0)/ 1.10 (1.03, 1.18) 7.0E−03 0.620 1.09 (1.01, 1.17) 1.9E−02 0.619 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d20:1/23:0)/ 1.09 (1.02, 1.17) 7.1E−03 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.98 (0.91, 1.06) 6.4E−01 0.619 PC 40:1 Cer(d18:2/16:0)/ 1.09 (1.02, 1.15) 7.2E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/18:0)/ 1.10 (1.03, 1.18) 7.3E−03 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d20:1/23:0)/ 1.09 (1.02, 1.16) 7.4E−03 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d16:1/20:0)/ 1.10 (1.03, 1.18) 7.4E−03 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d18:2/16:0)/ 1.10 (1.03, 1.18) 7.5E−03 0.620 1.09 (1.01, 1.17) 1.9E−02 0.619 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d20:1/23:0)/ 1.10 (1.03, 1.18) 7.6E−03 0.620 1.05 (0.98, 1.13) 1.4E−01 0.620 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d16:1/18:0)/ 1.08 (1.02, 1.15) 7.6E−03 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d16:1/16:0)/ 1.10 (1.02, 1.17) 7.8E−03 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.07) 8.5E−01 0.620 PC 17:0/20:3 Cer(d16:1/18:0)/ 1.09 (1.02, 1.16) 8.0E−03 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/16:0)/ 1.08 (1.02, 1.15) 8.4E−03 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/16:0)/ 1.09 (1.02, 1.16) 8.5E−03 0.623 1.08 (1.01, 1.16) 2.6E−02 0.620 1.00 (0.93, 1.08) 1.0E+00 0.619 PC 33:2 Cer(d16:1/20:0)/ 1.07 (1.02, 1.13) 8.6E−03 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d18:1/23:0)/ 1.09 (1.02, 1.16) 8.8E−03 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d18:2/16:0)/ 1.09 (1.02, 1.16) 8.9E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d18:2/24:1)/ 1.09 (1.02, 1.16) 8.9E−03 0.620 1.06 (0.98, 1.13) 1.3E−01 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d18:1/26:1)/ 0.90 (0.83, 0.97) 9.1E−03 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.09 (1.02, 1.18) 1.7E−02 0.620 PC 36:3 Cer(d18:2/16:0)/ 1.10 (1.02, 1.18) 9.3E−03 0.621 1.09 (1.01, 1.17) 1.9E−02 0.619 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d16:1/20:0)/ 1.09 (1.02, 1.17) 9.7E−03 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d16:1/18:0)/ 1.09 (1.02, 1.17) 9.8E−03 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d18:2/24:1)/ 1.09 (1.02, 1.16) 9.8E−03 0.622 1.06 (0.98, 1.13) 1.3E−01 0.619 0.92 (0.85, 0.99) 3.1E−02 0.620 PC 38:6 Cer(d18:1/26:1)/ 0.91 (0.84, 0.98) 9.8E−03 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.07 (1.00, 1.14) 5.0E−02 0.619 PC 18:0/18:1 Cer(d18:2/18:0)/ 1.10 (1.02, 1.17) 1.0E−02 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d20:1/24:1)/ 1.09 (1.02, 1.16) 1.0E−02 0.623 1.09 (1.02, 1.16) 1.3E−02 0.622 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d16:1/16:0)/ 1.08 (1.02, 1.14) 1.0E−02 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d18:2/18:0)/ 1.09 (1.02, 1.17) 1.0E−02 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d16:1/16:0)/ 1.09 (1.02, 1.17) 1.0E−02 0.620 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d16:1/18:0)/ 1.10 (1.02, 1.17) 1.0E−02 0.620 1.08 (1.01, 1.16) 3.2E−02 0.620 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d18:1/26:1)/ 0.90 (0.83, 0.98) 1.1E−02 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.08 (1.00, 1.16) 4.8E−02 0.619 PC 34:2 Cer(d18:2/24:1)/ 1.09 (1.02, 1.17) 1.1E−02 0.623 1.06 (0.98, 1.13) 1.3E−01 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:1/26:1)/ 0.91 (0.84, 0.98) 1.1E−02 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.09 (1.01, 1.17) 3.3E−02 0.620 PC 36:4 Cer(d16:1/20:0)/ 1.09 (1.02, 1.17) 1.1E−02 0.622 1.08 (1.00, 1.16) 4.3E−02 0.619 0.99 (0.92, 1.07) 8.5E−01 0.620 PC 17:0/20:3 Cer(d20:1/23:0)/ 1.09 (1.02, 1.17) 1.2E−02 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d18:1/26:0)/ 1.08 (1.02, 1.15) 1.3E−02 0.619 1.01 (0.94, 1.08) 8.1E−01 0.618 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d16:1/18:0)/ 1.09 (1.02, 1.17) 1.3E−02 0.623 1.08 (1.01, 1.16) 3.2E−02 0.620 0.99 (0.92, 1.07) 8.5E−01 0.620 PC 17:0/20:3 Cer(d16:1/20:0)/ 1.09 (1.02, 1.17) 1.3E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d16:1/16:0)/ 1.09 (1.02, 1.16) 1.4E−02 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.07) 8.8E−01 0.619 PC 32:2 Cer(d18:1/26:0)/ 1.08 (1.01, 1.14) 1.4E−02 0.620 1.01 (0.94, 1.08) 8.1E−01 0.618 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d18:2/24:1)/ 1.08 (1.02, 1.14) 1.4E−02 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d18:2/16:0)/ 1.09 (1.02, 1.17) 1.4E−02 0.619 1.09 (1.01, 1.17) 1.9E−02 0.619 0.95 (0.88, 1.02) 1.5E−01 0.619 PC 40:6 Cer(d16:1/20:0)/ 1.09 (1.02, 1.17) 1.4E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d16:1/16:0)/ 1.09 (1.02, 1.17) 1.5E−02 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d18:2/18:0)/ 1.08 (1.02, 1.16) 1.5E−02 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/22:0)/ 1.09 (1.02, 1.17) 1.5E−02 0.620 1.02 (0.95, 1.10) 5.6E−01 0.619 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d18:1/26:1)/ 0.90 (0.83, 0.98) 1.6E−02 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.06 (0.98, 1.13) 1.3E−01 0.619 PC 34:3 Cer(d16:1/20:0)/ 1.08 (1.02, 1.15) 1.6E−02 0.622 1.08 (1.00, 1.16) 4.3E−02 0.619 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d16:1/18:0)/ 1.08 (1.01, 1.15) 1.6E−02 0.622 1.08 (1.01, 1.16) 3.2E−02 0.620 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d18:1/23:0)/ 1.09 (1.02, 1.17) 1.6E−02 0.621 1.04 (0.97, 1.11) 3.3E−01 0.619 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d18:2/18:0)/ 1.09 (1.02, 1.17) 1.6E−02 0.622 1.06 (0.99, 1.14) 8.7E−02 0.619 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d20:1/23:0)/ 1.08 (1.01, 1.15) 1.7E−02 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d18:1/26:1)/ 1.09 (1.01, 1.17) 1.8E−02 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 0.91 (0.85, 0.99) 2.3E−02 0.620 PC 36:5 Cer(d18:1/26:1)/ 0.83 (0.71, 0.97) 1.9E−02 0.622 0.96 (0.89, 1.03) 2.9E−01 0.619 1.08 (1.00, 1.15) 4.5E−02 0.621 Cer(d20:1/24:0) Cer(d16:1/18:0)/ 1.09 (1.01, 1.17) 1.9E−02 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d18:2/18:0)/ 1.07 (1.01, 1.13) 1.9E−02 0.620 1.06 (0.99, 1.14) 8.7E−02 0.619 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d18:2/18:0)/ 1.07 (1.01, 1.13) 1.9E−02 0.620 1.06 (0.99, 1.14) 8.7E−02 0.619 0.98 (0.91, 1.05) 5.7E−01 0.619 PC 39:4 Cer(d16:1/18:0)/ 1.08 (1.01, 1.16) 1.9E−02 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 1.03 (0.96, 1.12) 3.9E−01 0.617 PC 16:1/18:2 Cer(d20:1/23:0)/ 1.08 (1.01, 1.16) 2.0E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.94 (0.87, 1.01) 1.1E−01 0.620 PC 40:5 Cer(d16:1/16:0)/ 1.09 (1.01, 1.16) 2.0E−02 0.621 1.08 (1.01, 1.16) 2.6E−02 0.620 1.03 (0.96, 1.12) 3.9E−01 0.617 PC 16:1/18:2 Cer(d16:1/16:0)/ 1.09 (1.01, 1.16) 2.0E−02 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 1.03 (0.96, 1.11) 4.2E−01 0.618 PC 14:0/18:1 Cer(d18:1/23:0)/ 1.09 (1.01, 1.17) 2.1E−02 0.621 1.04 (0.97, 1.11) 3.3E−01 0.619 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d18:2/18:0)/ 1.08 (1.01, 1.16) 2.1E−02 0.620 1.06 (0.99, 1.14) 8.7E−02 0.619 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d18:2/24:1)/ 1.08 (1.01, 1.16) 2.2E−02 0.622 1.06 (0.98, 1.13) 1.3E−01 0.619 0.99 (0.92, 1.06) 7.0E−01 0.619 PC 31:0 Cer(d16:1/16:0)/ 1.08 (1.01, 1.15) 2.2E−02 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 1.00 (0.93, 1.08) 9.5E−01 0.619 PC 14:0/18:2 Cer(d16:1/20:0)/ 1.08 (1.01, 1.15) 2.3E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d18:2/18:0)/ 1.07 (1.01, 1.14) 2.4E−02 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d16:1/23:0)/ 1.07 (1.01, 1.13) 2.4E−02 0.620 1.00 (0.93, 1.08) 9.8E−01 0.618 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d18:2/24:1)/ 1.08 (1.01, 1.15) 2.4E−02 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.94 (0.87, 1.01) 7.2E−02 0.620 PC 40:3 Cer(d16:1/20:0)/ 1.08 (1.01, 1.16) 2.4E−02 0.622 1.08 (1.00, 1.16) 4.3E−02 0.619 1.03 (0.96, 1.11) 4.2E−01 0.618 PC 14:0/18:1 Cer(d16:1/16:0)/ 1.08 (1.01, 1.15) 2.5E−02 0.622 1.08 (1.01, 1.16) 2.6E−02 0.620 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d20:1/23:0)/ 1.08 (1.01, 1.15) 2.5E−02 0.622 1.05 (0.98, 1.13) 1.4E−01 0.620 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d16:1/18:0)/ 1.08 (1.01, 1.15) 2.6E−02 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 1.00 (0.93, 1.08) 1.0E+00 0.619 PC 33:2 Cer(d20:1/23:0)/ 1.08 (1.01, 1.15) 2.6E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d16:1/20:0)/ 1.08 (1.01, 1.15) 2.7E−02 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 1.00 (0.93, 1.08) 1.0E+00 0.619 PC 33:2 Cer(d18:1/23:0)/ 1.08 (1.01, 1.15) 2.7E−02 0.621 1.04 (0.97, 1.11) 3.3E−01 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d18:1/26:1)/ 0.92 (0.85, 0.99) 2.7E−02 0.620 0.96 (0.89, 1.03) 2.9E−01 0.619 1.07 (0.99, 1.15) 8.5E−02 0.619 Cer(d18:1/24:0) Cer(d16:1/20:0)/ 1.08 (1.01, 1.16) 2.8E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d16:1/22:0)/ 1.07 (1.01, 1.14) 2.8E−02 0.620 1.02 (0.95, 1.10) 5.6E−01 0.619 0.98 (0.91, 1.05) 5.1E−01 0.619 PC 39:2 Cer(d18:1/23:0)/ 1.07 (1.01, 1.14) 2.9E−02 0.621 1.04 (0.97, 1.11) 3.3E−01 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d18:1/26:0)/ 1.07 (1.01, 1.13) 2.9E−02 0.621 1.01 (0.94, 1.08) 8.1E−01 0.618 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d16:1/18:0)/ 1.08 (1.01, 1.16) 3.0E−02 0.621 1.08 (1.01, 1.16) 3.2E−02 0.620 1.00 (0.93, 1.08) 9.7E−01 0.619 PC 17:0/18:1 Cer(d20:1/23:0)/ 1.08 (1.01, 1.15) 3.0E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0) Cer(d18:2/18:0)/ 1.08 (1.01, 1.15) 3.1E−02 0.621 1.06 (0.99, 1.14) 8.7E−02 0.619 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d20:1/23:0)/ 1.08 (1.01, 1.16) 3.1E−02 0.620 1.05 (0.98, 1.13) 1.4E−01 0.620 0.95 (0.88, 1.02) 1.5E−01 0.619 PC 40:6 Cer(d16:1/20:0)/ 1.08 (1.01, 1.16) 3.1E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 1.03 (0.95, 1.11) 4.7E−01 0.618 PC 17:0/18:2 Cer(d20:1/23:0)/ 1.08 (1.01, 1.15) 3.2E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 1.01 (0.94, 1.08) 8.7E−01 0.618 PC 36:0 Cer(d20:1/23:0)/ 1.06 (1.01, 1.13) 3.2E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 1.03 (0.97, 1.11) 3.2E−01 0.619 PC 39:0 Cer(d18:1/23:0)/ 1.07 (1.01, 1.13) 3.3E−02 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d20:1/23:0)/ 1.06 (1.01, 1.13) 3.3E−02 0.620 1.05 (0.98, 1.13) 1.4E−01 0.620 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d18:1/26:1)/ 0.92 (0.85, 0.99) 3.3E−02 0.619 0.96 (0.89, 1.03) 2.9E−01 0.619 1.05 (0.98, 1.12) 2.0E−01 0.618 PC 38:2 Cer(d16:1/20:0)/ 1.08 (1.01, 1.16) 3.3E−02 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 1.00 (0.93, 1.08) 9.7E−01 0.619 PC 17:0/18:1 Cer(d16:1/20:0)/ 1.08 (1.01, 1.15) 3.4E−02 0.620 1.08 (1.00, 1.16) 4.3E−02 0.619 1.03 (0.96, 1.12) 3.9E−01 0.617 PC 16:1/18:2 Cer(d18:1/26:1)/ 0.92 (0.85, 0.99) 3.6E−02 0.619 0.96 (0.89, 1.03) 2.9E−01 0.619 1.06 (0.98, 1.14) 1.4E−01 0.619 PC 36:2 Cer(d18:1/23:0)/ 1.07 (1.00, 1.14) 3.8E−02 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 37:2 Cer(d18:2/24:1)/ 1.05 (1.00, 1.11) 3.9E−02 0.620 1.06 (0.98, 1.13) 1.3E−01 0.619 0.98 (0.91, 1.06) 6.3E−01 0.619 PC 37:4 Cer(d16:1/20:0)/ 1.07 (1.00, 1.14) 4.0E−02 0.621 1.08 (1.00, 1.16) 4.3E−02 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d18:1/26:1)/ 0.92 (0.86, 1.00) 4.1E−02 0.619 0.96 (0.89, 1.03) 2.9E−01 0.619 1.04 (0.97, 1.11) 3.0E−01 0.618 PC 33:1 Cer(d18:2/24:1)/ 1.07 (1.00, 1.13) 4.1E−02 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.96 (0.89, 1.04) 2.9E−01 0.620 PC 35:0 Cer(d16:1/22:0)/ 1.07 (1.00, 1.15) 4.1E−02 0.621 1.02 (0.95, 1.10) 5.6E−01 0.619 0.95 (0.88, 1.02) 1.7E−01 0.620 PC 35:4 Cer(d16:1/22:0)/ 1.07 (1.00, 1.14) 4.2E−02 0.621 1.02 (0.95, 1.10) 5.6E−01 0.619 0.99 (0.92, 1.06) 7.9E−01 0.619 PC 30:2 Cer(d18:2/18:0)/ 1.07 (1.00, 1.15) 4.2E−02 0.620 1.06 (0.99, 1.14) 8.7E−02 0.619 0.95 (0.88, 1.02) 1.5E−01 0.619 PC 40:6 Cer(d18:2/24:1)/ 1.07 (1.00, 1.15) 4.3E−02 0.621 1.06 (0.98, 1.13) 1.3E−01 0.619 0.97 (0.90, 1.05) 4.5E−01 0.620 Cer(d18:2/24:0) Cer(d20:1/23:0)/ 1.07 (1.00, 1.15) 4.6E−02 0.620 1.05 (0.98, 1.13) 1.4E−01 0.620 0.99 (0.92, 1.07) 8.5E−01 0.619 PC 17:0/20:4 Cer(d18:1/26:0)/ 1.06 (1.00, 1.13) 4.7E−02 0.620 1.01 (0.94, 1.08) 8.1E−01 0.618 0.98 (0.91, 1.06) 6.6E−01 0.619 PC 34:4 Cer(d20:1/23:0)/ 1.07 (1.00, 1.15) 4.8E−02 0.621 1.05 (0.98, 1.13) 1.4E−01 0.620 1.01 (0.94, 1.09) 7.4E−01 0.618 PC 35:2 Cer(d18:1/23:0)/ 1.07 (1.00, 1.15) 4.9E−02 0.620 1.04 (0.97, 1.11) 3.3E−01 0.619 0.96 (0.90, 1.04) 3.4E−01 0.619 Cer(d16:1/24:0)

[0391] In the examples below (Tables 3-12) the combinations of variables have been constructed using logistic regression, and unadjusted cox regression models were used to assess the predictive value of individual lipids or lipid ratios or their combinations. The results are presented both for all CV events as well as for CV death, as hazard ratios and C-statistics.

[0392] Table 3 presents an example, where combination of two ceramide/phosphatidylcholine ratios yields lower p-value and higher C-statistics as compared to individual ceramide/phosphatidylcholine ratios alone. Furthermore, additional ceramide/ceramide ratio and an individual phosphatidylcholine increases the predictive value. In addition, high sensitivity troponin (TNT) also leads into more accurate prediction.

TABLE-US-00003 TABLE 3 Example of combinations of lipid ratios, an individual lipid concentration and other cardiovascular biomarker (TNT). CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/16:0)/PC 16:0/22:5 1.26 (1.18, 1.34) 5.79E−13 0.568 1.41 (1.29, 1.54) 6.18E−14 0.607 Cer(d18:1/18:0)/PC 14:0/22:6 1.18 (1.11, 1.24) 7.85E−09 0.561 1.23 (1.13, 1.32) 3.47E−07 0.579 Cer(d18:1/16:0)/PC 16:0/22:5 + 1.26 (1.19, 1.34) 3.40E−14 0.573 1.39 (1.28, 1.51) 2.12E−14 0.610 Cer(d18:1/18:0)/PC 14:0/22:6 Cer(d18:1/16:0)/PC 16:0/22:5 + 1.32 (1.24, 1.41) 2.31E−19 0.586 1.52 (1.40, 1.65) 1.74E−22 0.644 Cer(d18:1/18:0)/PC 14:0/22:6 + Cer(d18:1/24:1)/Cer(d18:1/24:0) Cer(d18:1/16:0)/PC 16:0/22:5 + 1.37 (1.29, 1.45) 3.85E−24 0.598 1.59 (1.46, 1.73) 1.13E−27 0.653 Cer(d18:1/18:0)/PC 14:0/22:6 + Cer(d18:1/24:1)/Cer(d18:1/24:0) + PC 16:0/16:0 Cer(d18:1/16:0)/PC 16:0/22:5 + 1.58 (1.50, 1.67) 3.32E−61 0.659 1.86 (1.73, 2.01) 5.47E−59 0.739 Cer(d18:1/18:0)/PC 14:0/22:6 + Cer(d18:1/24:1)/Cer(d18:1/24:0) + TNT Cer(d18:1/16:0)/PC 16:0/22:5 + 1.61 (1.52, 1.70) 2.55E−65 0.661 1.92 (1.78, 2.07) 1.60E−63 0.740 Cer(d18:1/18:0)/PC 14:0/22:6 + Cer(d18:1/24:1)/Cer(d18:1/24:0) + PC 16:0/16:0 + TNT

[0393] Table 4 presents an example, where a combination of a ceramide/phosphatidylcholine ratio and a ceramide/ceramide ratio yields lower p-value and higher C-statistics as compared to individual lipid ratios alone. Furthermore, additional ceramide/phosphatidylcholine ratio and an individual phosphatidylcholine increases the predictive value.

TABLE-US-00004 TABLE 4 Example of combinations of lipid ratios and an individual lipid concentration. CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/24:1)/PC 16:0/22:5 1.27 (1.19, 1.35) 3.86E−14 0.576 1.42 (1.30, 1.55) 7.52E−15 0.619 Cer(d18:1/16:0)/Cer(d18:1/24:0) 1.20 (1.13, 1.28) 2.73E−09 0.565 1.34 (1.23, 1.45) 1.72E−12 0.610 Cer(d18:1/24:1)/PC 16:0/22:5 + 1.33 (1.25, 1.42) 7.87E−20 0.594 1.55 (1.42, 1.69) 2.40E−23 0.646 Cer(d18:1/16:0)/Cer(d18:1/24:0) Cer(d18:1/24:1)/PC 16:0/22:5 + 1.38 (1.30, 1.46) 1.72E−24 0.599 1.61 (1.48, 1.75) 2.54E−27 0.650 Cer(d18:1/16:0)/Cer(d18:1/24:0) + Cer(d18:1/18:0)/PC 16:0/22:6 + PC 16:0/16:0

[0394] Table 5 presents an example, where combinations of individual lipid concentrations of ceramides and phosphatidylcholines yield lower p-values and higher C-statistics when more lipids are incorporated into the model.

TABLE-US-00005 TABLE 5 Example of combinations of lipid concentrations. CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/16:0) 1.20 (1.13, 1.28) 1.39E−08 0.554 1.29 (1.18, 1.41) 2.01E−08 0.577 Cer(d18:1/16:0) + Cer(d18:1/24:0) 1.31 (1.23, 1.40) 1.36E−15 0.575 1.53 (1.39, 1.68) 5.53E−18 0.623 Cer(d18:1/16:0) + Cer(d18:1/18:0) + 1.34 (1.25, 1.43) 1.09E−17 0.583 1.54 (1.41, 1.70) 1.76E−19 0.628 Cer(d18:1/24:0) + Cer(d18:1/24:1) Cer(d18:1/16:0) + Cer(d18:1/18:0) + 1.38 (1.29, 1.48) 1.08E−21 0.596 1.63 (1.48, 1.79) 1.98E−23 0.644 Cer(d18:1/24:0) + Cer(d18:1/24:1) + PC 14:0/22:6 Cer(d18:1/16:0) + Cer(d18:1/18:0) + 1.39 (1.30, 1.48) 1.76E−22 0.596 1.62 (1.48, 1.78) 1.05E−24 0.645 Cer(d18:1/24:0) + Cer(d18:1/24:1) + PC 14:0/22:6 + PC 16:0/16:0 Cer(d18:1/16:0) + Cer(d18:1/18:0) + 1.43 (1.34, 1.52) 4.36E−26 0.601 1.72 (1.57, 1.89) 1.93E−29 0.658 Cer(d18:1/24:0) + Cer(d18:1/24:1) + PC 14:0/22:6 + PC 16:0/16:0 + PC 16:0/22:5

[0395] Table 6 presents an example, where a combination of a ceramide/ceramide ratio and a ceramide/phosphatidylcholine ratio yields lower p-value and higher C-statistics as compared to individual lipid ratios alone. Furthermore, additional ceramide/phosphatidylcholine ratio and an individual phosphatidylcholine increases the predictive value.

TABLE-US-00006 TABLE 6 Example of combinations of lipid ratios and an individual lipid concentration. CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/24:1)/Cer(d18:1/24:0) 1.14 (1.07, 1.21) 3.10E−05 0.563 1.25 (1.15, 1.36) 1.01E−07 0.598 Cer(d18:1/16:0)/PC 16:0/22:5 1.26 (1.18, 1.34) 5.79E−13 0.568 1.41 (1.29, 1.54) 6.18E−14 0.607 Cer(d18:1/24:1)/Cer(d18:1/24:0) + 1.32 (1.24, 1.41) 2.56E−18 0.588 1.54 (1.41, 1.68) 2.91E−22 0.643 Cer(d18:1/16:0)/PC 16:0/22:5 Cer(d18:1/24:1)/Cer(d18:1/24:0) + 1.36 (1.28, 1.45) 1.64E−22 0.596 1.61 (1.48, 1.76) 1.07E−27 0.659 Cer(d18:1/16:0)/PC 16:0/22:5 + Cer(d18:1/18:0)/PC 40:8 + PC 16:0/18:3

[0396] Table 7 presents an example, where a combination of ceramide and phosphatidylcholine concentrations yields lower p-value and higher C-statistics as compared to individual lipids alone. Furthermore, additional ceramide/phosphatidylcholine ratios increase the predictive value.

TABLE-US-00007 TABLE 7 Example of combinations of lipid ratios and an individual lipid concentration. CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/18:0) 1.17 (1.10, 1.25) 4.87E−07 0.556 1.19 (1.08, 1.31) 2.37E−04 0.562 PC 16:0/20:4 0.93 (0.87, 1.01) 6.90E−02 0.521 0.79 (0.70, 0.89) 1.15E−04 0.565 Cer(d18:1/18:0) + PC 16:0/20:4 1.23 (1.15, 1.32) 5.93E−10 0.561 1.36 (1.24, 1.50) 1.93E−10 0.601 Cer(d18:1/18:0) + PC 16:0/20:4 + 1.26 (1.18, 1.33) 8.57E−14 0.569 1.38 (1.27, 1.50) 1.65E−14 0.614 Cer(d18:1/16:0)/PC 38:7 Cer(d18:1/18:0) + PC 16:0/20:4 + 1.29 (1.22, 1.37) 2.82E−17 0.573 1.46 (1.35, 1.58) 8.13E−20 0.626 Cer(d18:1/16:0)/PC 38:7 + Cer(d18:1/24:1)/PC 18:0/20:4

[0397] Table 8 and 9 present simplifying scoring systems (points 0-12 and 0-9, respectively), where the points are given based on the quartiles (Q1-Q4) of the whole study population. For example, if the Cer(d18:1/16:0)/PC 16:0/22:5 ratio of a person belongs to the highest quartile, the person will receive 3 points. The same evaluation will be performed for the other three lipid biomarkers, and summed up.

TABLE-US-00008 TABLE 8 Example of a scoring system based on lipids. Q1 Q2 Q3 Q4 Cer(d18:1/16:0)/PC 16:0/22:5 0 1 2 3 Cer(d18:1/18:0)/PC 14:0/22:6 0 1 2 3 Cer(d18:1/24:1)/Cer(d18:1/24:0) 0 1 2 3 PC 16:0/16:0 0 1 2 3

TABLE-US-00009 TABLE 9 Another example of a scoring system based on lipids. Q1 Q2 Q3 Q4 Cer(d18:1/16:0)/PC 16:0/22:5 0 1 2 3 Cer(d18:1/18:0)/PC 14:0/22:6 0 1 2 3 Cer(d18:1/24:1)/Cer(d18:1/24:0) 0 1 2 3

[0398] Table 10 and 11 present additional examples, where also a non-lipid cardiovascular biomarker, TNT, has been added into the scoring systems. In this case, the scale of scoring system is 0-15 and 0-12, respectively.

TABLE-US-00010 TABLE 10 Example of a scoring system based on lipids and TNT. Q1 Q2 Q3 Q4 Cer(d18:1/16:0)/PC 16:0/22:5 0 1 2 3 Cer(d18:1/18:0)/PC 14:0/22:6 0 1 2 3 Cer(d18:1/24:1)/Cer(d18:1/24:0) 0 1 2 3 PC 16:0/16:0 0 1 2 3 TNT 0 1 2 3

TABLE-US-00011 TABLE 11 Another example of a scoring system based on lipids and TNT. Q1 Q2 Q3 Q4 Cer(d18:1/16:0)/PC 16:0/22:5 0 1 2 3 Cer(d18:1/18:0)/PC 14:0/22:6 0 1 2 3 Cer(d18:1/24:1)/Cer(d18:1/24:0) 0 1 2 3 TNT 0 1 2 3

[0399] Table 12 presents an example of the predictive value of the scoring systems. In this example, CV score (3 components) refers to the scoring system presented in Table 9, CV score (4 components) to the scoring system presented in Table 8 and CV score (4 components+TNT) to the scoring system presented in Table 10. As shown in this example, the scores give lower p-values and higher C-statistics than e.g. individual ceramide/phosphatidylcholine ratios.

TABLE-US-00012 TABLE 12 Predictive value of the scoring systems as compared to individual lipid ratios. CV events CV death HR p-value C-stat HR p-value C-stat Cer(d18:1/16:0)/PC 16:0/22:5 1.26 (1.18, 1.34) 5.79E−13 0.568 1.41 (1.29, 1.54) 6.18E−14 0.607 Cer(d18:1/18:0)/PC 14:0/22:6 1.18 (1.11, 1.24) 7.85E−09 0.561 1.23 (1.13, 1.32) 3.47E−07 0.579 CV score (3 components) 1.40 (1.30, 1.50) 1.15E−19 0.591 1.61 (1.44, 1.80) 4.11E−17 0.628 CV score (4 components) 1.41 (1.31, 1.51) 5.44E−21 0.590 1.66 (1.49, 1.85) 2.81E−20 0.633 CV score (4 components + TNT) 1.67 (1.56, 1.80) 2.90E−46 0.637 2.20 (1.97, 2.45) 1.42E−45 0.705

[0400] Tables 13-18 show results of the second study cohort. Table 13 presents examples of ceramide and phosphatidylcholine combinations which predict acute coronary syndrome in the population study cohort subjects.

TABLE-US-00013 TABLE 13 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who developed acute coronary syndrome during the follow-up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Acute coronary syndrome Lipid combination HR 95% CI p-value Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.35 (1.25, 1.45) 2.8E−15 CV score (4 components) 1.34 (1.23, 1.47) 3.1E−10 Cer(d18:1/18:0)/PC 38:7 1.26 (1.17, 1.35) 1.5E−09 Cer(d18:1/18:0)/PC 16:0/22:5 1.27 (1.17, 1.37) 4.0E−09 Cer(d18:1/22:0)/PC 40:8 1.14 (1.09, 1.19) 7.1E−09 Cer(d18:1/24:1)/PC 38:7 1.26 (1.16, 1.36) 9.1E−09 Cer(d18:1/24:1)/PC 40:8 1.25 (1.16, 1.35) 1.7E−08 Cer(d20:1/24:1)/PC 40:8 1.16 (1.10, 1.22) 4.1E−08 CV score (3 components) 1.29 (1.18, 1.41) 4.2E−08 Cer(d18:1/24:1)/PC 16:0/22:5 1.25 (1.15, 1.36) 8.2E−08 Cer(d18:1/22:0)/PC 38:7 1.22 (1.13, 1.31) 1.3E−07 Cer(d20:1/22:0)/PC 16:0/22:5 1.22 (1.13, 1.32) 1.6E−07 Cer(d18:1/16:0)/PC 16:0/22:5 1.25 (1.15, 1.35) 1.9E−07 Cer(d20:1/24:1)/PC 38:7 1.20 (1.12, 1.28) 3.5E−07 Cer(d18:1/18:0)/PC 36:6 1.21 (1.12, 1.30) 3.6E−07 Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.15 (1.09, 1.22) 1.2E−06 Cer(d18:1/22:0)/PC 16:0/22:5 1.22 (1.12, 1.32) 2.2E−06 Cer(d18:1/20:0)/PC 16:0/22:5 1.21 (1.11, 1.31) 4.4E−06 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.07 (1.04, 1.10) 9.0E−06 Cer(d16:1/18:0)/PC 38:7 1.10 (1.05, 1.15) 1.4E−05 Cer(d20:1/24:1)/PC 40:6 1.17 (1.09, 1.26) 1.5E−05 Cer(d18:1/24:1)/PC 36:6 1.18 (1.10, 1.28) 1.6E−05 Cer(d20:1/24:1)/PC 36:6 1.17 (1.08, 1.25) 3.0E−05 Cer(d18:1/22:0)/PC 35:2 1.16 (1.08, 1.24) 3.3E−05 Cer(d18:1/22:0)/PC 37:2 1.18 (1.09, 1.28) 4.9E−05 Cer(d20:1/24:1)/PC 16:0/22:5 1.17 (1.08, 1.26) 5.1E−05 Cer(d18:1/22:0)/PC 36:6 1.18 (1.09, 1.28) 5.4E−05 Cer(d20:1/24:1)/PC 39:4 1.15 (1.07, 1.23) 5.5E−05 Cer(d18:1/16:0)/PC 36:6 1.18 (1.09, 1.28) 5.7E−05 Cer(d18:1/20:0)/PC 36:6 1.13 (1.06, 1.21) 1.1E−04 Cer(d18:1/20:0)/PC 38:7 1.07 (1.03, 1.10) 1.3E−04 Cer(d16:1/18:0)/PC 36:6 1.16 (1.07, 1.25) 1.4E−04 Cer(d16:1/20:0)/Cer(d18:2/24:0) 1.11 (1.05, 1.17) 1.5E−04 Cer(d18:1/22:0)/PC 36:0 1.17 (1.08, 1.26) 1.6E−04 Cer(d20:1/24:1)/PC 37:2 1.14 (1.07, 1.23) 1.9E−04 Cer(d16:1/20:0)/PC 36:6 1.09 (1.04, 1.15) 2.9E−04 Cer(d20:1/22:0)/PC 36:6 1.06 (1.03, 1.10) 3.1E−04 Cer(d20:1/24:1)/PC 40:5 1.15 (1.06, 1.24) 3.1E−04 Cer(d20:1/24:1)/PC 35:4 1.12 (1.05, 1.19) 4.1E−04 Cer(d20:1/24:1)/PC 36:0 1.15 (1.06, 1.24) 4.1E−04 Cer(d16:1/18:0)/Cer(d18:2/24:0) 1.15 (1.07, 1.25) 4.3E−04 Cer(d20:1/22:0)/PC 36:0 1.06 (1.03, 1.09) 4.5E−04 Cer(d20:1/24:1)/PC 38:1 1.15 (1.06, 1.25) 5.0E−04 Cer(d16:1/20:0)/PC 16:0/22:5 1.16 (1.06, 1.25) 5.7E−04 Cer(d16:1/18:0)/PC 16:0/22:5 1.15 (1.06, 1.25) 5.9E−04 Cer(d16:1/18:0)/PC 40:8 1.06 (1.02, 1.10) 1.1E−03 Cer(d16:1/18:0)/PC 39:4 1.09 (1.04, 1.16) 1.4E−03 Cer(d16:1/18:0)/PC 37:2 1.11 (1.04, 1.19) 3.1E−03 Cer(d18:1/22:0)/Cer(d18:1/24:0) 1.13 (1.04, 1.23) 5.3E−03 Cer(d16:1/18:0)/PC 35:0 1.12 (1.03, 1.22) 5.5E−03 Cer(d16:1/20:0)/PC 35:0 1.12 (1.03, 1.22) 5.6E−03 Cer(d16:1/16:0)/Cer(d18:2/24:0) 1.08 (1.02, 1.14) 6.3E−03 Cer(d20:1/22:0)/PC 37:2 1.04 (1.01, 1.08) 7.4E−03 Cer(d18:2/16:0)/PC 38:7 1.09 (1.02, 1.16) 9.3E−03

[0401] Table 14 presents examples of ceramide and phosphatidylcholine combinations which predict cardiovascular death in the population study cohort subjects.

TABLE-US-00014 TABLE 14 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who died due to cardiovascular reasons during the follow-up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Cardiovascular death Lipid combination HR 95% CI p-value Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.57 (1.40, 1.77) 6.5E−14 Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.24 (1.14, 1.33) 4.9E−08 CV score (4 components) 1.59 (1.34, 1.88) 5.4E−08 Cer(d20:1/24:1)/PC 40:8 1.24 (1.15, 1.34) 5.9E−08 Cer(d18:1/22:0)/PC 40:8 1.19 (1.11, 1.27) 8.9E−07 Cer(d18:1/18:0)/PC 38:7 1.35 (1.19, 1.53) 4.2E−06 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.10 (1.05, 1.14) 4.9E−06 CV score (3 components) 1.46 (1.24, 1.72) 6.6E−06 Cer(d16:1/20:0)/Cer(d18:2/24:0) 1.17 (1.09, 1.25) 8.1E−06 Cer(d18:1/18:0)/PC 36:6 1.32 (1.17, 1.50) 9.4E−06 Cer(d16:1/16:0)/Cer(d18:2/24:0) 1.14 (1.07, 1.21) 4.3E−05 Cer(d20:1/24:1)/PC 40:6 1.27 (1.13, 1.43) 4.5E−05 Cer(d16:1/18:0)/Cer(d18:2/24:0) 1.30 (1.15, 1.48) 4.7E−05 Cer(d18:1/18:0)/PC 16:0/22:5 1.32 (1.15, 1.50) 4.9E−05 Cer(d16:1/18:0)/PC 36:6 1.27 (1.13, 1.43) 5.4E−05 Cer(d18:1/24:1)/PC 40:8 1.31 (1.15, 1.49) 6.6E−05 Cer(d16:1/18:0)/PC 38:7 1.14 (1.07, 1.22) 7.5E−05 Cer(d18:1/20:0)/PC 36:6 1.21 (1.10, 1.32) 8.3E−05 Cer(d16:1/18:0)/PC 37:2 1.21 (1.10, 1.33) 1.0E−04 Cer(d20:1/24:1)/PC 36:6 1.26 (1.12, 1.42) 1.2E−04 Cer(d20:1/24:1)/PC 37:2 1.24 (1.11, 1.38) 1.2E−04 Cer(d18:1/22:0)/Cer(d18:1/24:0) 1.32 (1.14, 1.53) 1.6E−04 Cer(d18:1/16:0)/PC 36:6 1.30 (1.13, 1.49) 1.9E−04 Cer(d20:1/24:1)/PC 38:7 1.25 (1.11, 1.41) 2.2E−04 Cer(d16:1/18:0)/PC 40:8 1.09 (1.04, 1.15) 2.5E−04 Cer(d18:2/16:0)/PC 37:2 1.15 (1.07, 1.25) 3.5E−04 Cer(d16:1/20:0)/PC 36:6 1.14 (1.06, 1.22) 4.6E−04 Cer(d18:1/16:0)/PC 16:0/22:5 1.28 (1.11, 1.47) 4.8E−04 Cer(d18:1/18:0)/PC 35:4 3.63 (1.75, 7.56) 5.6E−04 Cer(d18:1/22:0)/PC 37:2 1.26 (1.10, 1.44) 9.3E−04 Cer(d18:1/22:0)/PC 38:7 1.25 (1.09, 1.44) 1.5E−03 Cer(d20:1/22:0)/PC 16:0/22:5 1.23 (1.08, 1.41) 1.8E−03 Cer(d18:1/20:0)/PC 16:0/22:5 1.24 (1.08, 1.43) 2.1E−03 Cer(d16:1/18:0)/PC 16:0/22:5 1.24 (1.08, 1.42) 2.3E−03 Cer(d18:1/20:0)/PC 38:7 1.09 (1.03, 1.15) 2.4E−03 Cer(d18:1/22:0)/PC 36:6 1.25 (1.08, 1.44) 2.6E−03 Cer(d18:1/24:1)/PC 36:6 1.23 (1.07, 1.41) 2.9E−03 Cer(d16:1/18:0)/PC 35:0 1.23 (1.07, 1.41) 3.7E−03 Cer(d18:1/24:1)/PC 38:7 1.24 (1.07, 1.44) 3.9E−03 Cer(d20:1/22:0)/PC 36:6 1.08 (1.03, 1.14) 4.0E−03 Cer(d16:1/16:0)/PC 37:2 1.07 (1.02, 1.13) 4.4E−03 Cer(d18:2/16:0)/PC 40:8 1.09 (1.03, 1.15) 4.7E−03 Cer(d16:1/18:0)/PC 39:4 1.13 (1.04, 1.24) 5.2E−03 Cer(d16:1/16:0)/PC 36:6 1.10 (1.03, 1.18) 5.8E−03 Cer(d18:2/18:0)/Cer(d18:2/24:0) 1.20 (1.05, 1.37) 6.3E−03 Cer(d16:1/18:0)/PC 35:4 1.31 (1.07, 1.60) 7.6E−03 Cer(d18:2/18:0)/PC 36:6 1.18 (1.04, 1.34) 8.8E−03 Cer(d20:1/22:0)/PC 37:2 1.06 (1.02, 1.11) 9.1E−03 Cer(d18:2/16:0)/PC 40:6 1.11 (1.03, 1.20) 9.1E−03 Cer(d16:1/18:0)/PC 36:0 1.20 (1.05, 1.38) 9.5E−03 Cer(d18:1/22:0)/PC 16:0/22:5 1.21 (1.05, 1.40) 1.0E−02 Cer(d20:1/22:0)/PC 36:0 1.08 (1.02, 1.14) 1.1E−02 Cer(d16:1/18:0)/PC 40:5 1.09 (1.02, 1.17) 1.2E−02 Cer(d20:1/24:1)/PC 16:0/22:5 1.18 (1.03, 1.34) 1.4E−02 Cer(d16:1/18:0)/PC 35:2 1.11 (1.02, 1.20) 1.4E−02 Cer(d18:1/18:0)/PC 37:6 1.13 (1.02, 1.24) 1.4E−02 Cer(d16:1/20:0)/PC 16:0/22:5 1.19 (1.03, 1.37) 1.5E−02 Cer(d20:1/24:1)/PC 35:4 1.23 (1.04, 1.46) 1.6E−02 Cer(d16:1/16:0)/PC 35:0 1.18 (1.03, 1.35) 1.8E−02 Cer(d18:2/18:0)/PC 37:2 1.12 (1.02, 1.24) 1.8E−02 Cer(d16:1/20:0)/PC 37:2 1.08 (1.01, 1.15) 2.0E−02 Cer(d16:1/16:0)/PC 16:0/22:5 1.19 (1.02, 1.38) 2.3E−02 Cer(d18:1/22:0)/PC 35:2 1.17 (1.02, 1.34) 2.5E−02 Cer(d18:2/18:0)/PC 38:7 1.09 (1.01, 1.17) 2.5E−02 Cer(d18:2/16:0)/Cer(d18:2/24:0) 1.16 (1.02, 1.32) 2.6E−02 Cer(d20:1/24:1)/PC 40:5 1.16 (1.01, 1.33) 3.1E−02 Cer(d18:2/16:0)/PC 38:7 1.12 (1.01, 1.24) 3.2E−02 Cer(d18:2/16:0)/PC 37:6 1.12 (1.01, 1.24) 3.3E−02 Cer(d18:2/18:0)/PC 40:6 1.07 (1.01, 1.14) 3.3E−02 Cer(d18:1/22:0)/PC 36:0 1.16 (1.01, 1.33) 3.6E−02 Cer(d20:1/24:1)/PC 35:5 1.15 (1.01, 1.30) 3.6E−02 Cer(d20:1/24:1)/PC 39:4 1.13 (1.01, 1.27) 3.7E−02 Cer(d20:1/24:1)/PC 36:0 1.15 (1.01, 1.31) 3.8E−02 Cer(d18:1/16:0)/PC 37:6 1.11 (1.00, 1.23) 4.1E−02 Cer(d18:1/20:0)/PC 35:4 1.52 (1.01, 2.28) 4.2E−02 Cer(d16:1/18:0)/PC 35:5 1.15 (1.00, 1.33) 4.7E−02

[0402] Table 15 presents examples of ceramide and phosphatidylcholine combinations which predict heart failure in the population study cohort subjects.

TABLE-US-00015 TABLE 15 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who developed heart failure during the follow-up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Heart failure Lipid combination HR 95% CI p-value Cer(d18:1/24:1)/PC 40:8 1.35 (1.26, 1.45) 1.1E−16 Cer(d18:1/22:0)/PC 40:8 1.14 (1.10, 1.19) 7.5E−12 Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.28 (1.19, 1.37) 3.0E−11 Cer(d18:1/18:0)/PC 38:7 1.28 (1.19, 1.37) 7.4E−11 Cer(d20:1/24:1)/PC 40:8 1.17 (1.12, 1.23) 1.3E−10 Cer(d16:1/20:0)/Cer(d18:2/24:0) 1.13 (1.08, 1.18) 3.2E−09 Cer(d18:1/24:1)/PC 38:7 1.27 (1.17, 1.37) 3.3E−09 Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.16 (1.10, 1.22) 1.7E−08 Cer(d18:1/18:0)/PC 36:6 1.22 (1.13, 1.31) 4.3E−08 CV score (4 components) 1.27 (1.17, 1.39) 5.7E−08 Cer(d16:1/18:0)/PC 38:7 1.11 (1.07, 1.15) 1.3E−07 Cer(d18:1/18:0)/PC 16:0/22:5 1.22 (1.13, 1.31) 1.4E−07 Cer(d18:2/24:1)/PC 40:8 1.20 (1.12, 1.28) 1.5E−07 Cer(d16:1/18:0)/Cer(d18:2/24:0) 1.21 (1.12, 1.30) 3.2E−07 Cer(d16:1/18:0)/PC 40:8 1.07 (1.04, 1.10) 5.5E−07 Cer(d16:1/18:0)/PC 36:6 1.19 (1.11, 1.28) 8.3E−07 CV score (3 components) 1.23 (1.13, 1.34) 2.1E−06 Cer(d20:1/24:1)/PC 38:7 1.19 (1.11, 1.28) 2.6E−06 Cer(d18:1/24:1)/PC 36:6 1.20 (1.11, 1.30) 3.2E−06 Cer(d18:1/20:0)/PC 36:6 1.14 (1.08, 1.21) 5.0E−06 Cer(d18:2/16:0)/PC 40:8 1.07 (1.04, 1.10) 6.5E−06 Cer(d18:1/22:0)/PC 38:7 1.19 (1.10, 1.29) 7.0E−06 Cer(d16:1/20:0)/PC 36:6 1.10 (1.05, 1.15) 1.3E−05 Cer(d18:1/16:0)/PC 36:6 1.19 (1.10, 1.29) 1.4E−05 Cer(d16:1/18:0)/PC 35:0 1.18 (1.09, 1.27) 3.1E−05 Cer(d18:1/24:1)/PC 16:0/22:5 1.17 (1.09, 1.27) 5.0E−05 Cer(d16:1/20:0)/PC 35:0 1.17 (1.08, 1.26) 5.5E−05 Cer(d18:1/20:0)/PC 38:7 1.07 (1.03, 1.10) 5.7E−05 Cer(d20:1/24:1)/PC 36:6 1.17 (1.08, 1.26) 7.6E−05 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.06 (1.03, 1.10) 8.8E−05 Cer(d18:1/16:0)/PC 16:0/22:5 1.16 (1.08, 1.25) 9.5E−05 Cer(d16:1/18:0)/PC 37:2 1.13 (1.06, 1.20) 1.1E−04 Cer(d16:1/18:0)/PC 36:0 1.16 (1.07, 1.25) 1.4E−04 Cer(d18:1/22:0)/PC 36:6 1.17 (1.08, 1.28) 1.9E−04 Cer(d18:2/16:0)/PC 38:7 1.10 (1.05, 1.16) 2.3E−04 Cer(d16:1/18:0)/PC 35:2 1.08 (1.04, 1.13) 2.6E−04 Cer(d18:1/20:0)/PC 16:0/22:5 1.15 (1.07, 1.24) 3.3E−04 Cer(d16:1/20:0)/PC 36:0 1.09 (1.04, 1.15) 3.5E−04 Cer(d16:1/18:0)/PC 16:0/22:5 1.15 (1.07, 1.24) 3.6E−04 Cer(d16:1/18:0)/PC 35:5 1.14 (1.06, 1.23) 4.9E−04 Cer(d20:1/24:1)/PC 36:0 1.13 (1.05, 1.21) 9.0E−04 Cer(d18:1/24:1)/PC 35:5 1.14 (1.05, 1.23) 9.6E−04 Cer(d16:1/18:0)/PC 39:4 1.09 (1.04, 1.15) 1.1E−03 Cer(d20:1/24:1)/PC 35:5 1.13 (1.05, 1.22) 1.3E−03 Cer(d16:1/16:0)/Cer(d18:2/24:0) 1.08 (1.03, 1.14) 1.4E−03 Cer(d20:1/24:1)/PC 40:6 1.14 (1.05, 1.23) 1.5E−03 Cer(d18:2/24:1)/PC 38:7 1.15 (1.05, 1.25) 1.6E−03 Cer(d20:1/22:0)/PC 16:0/22:5 1.13 (1.05, 1.22) 1.7E−03 Cer(d18:1/22:0)/PC 36:0 1.13 (1.05, 1.22) 1.7E−03 Cer(d18:1/20:0)/PC 35:5 1.11 (1.04, 1.18) 1.9E−03 Cer(d16:1/20:0)/PC 37:2 1.06 (1.02, 1.10) 2.0E−03 Cer(d18:1/22:0)/PC 37:2 1.13 (1.05, 1.23) 2.3E−03 Cer(d16:1/18:0)/PC 40:5 1.07 (1.02, 1.11) 2.3E−03 Cer(d16:1/20:0)/PC 16:0/22:5 1.13 (1.04, 1.22) 2.3E−03 Cer(d20:1/24:1)/PC 16:0/22:5 1.12 (1.04, 1.21) 2.7E−03 Cer(d18:1/22:0)/PC 35:2 1.12 (1.04, 1.20) 3.1E−03 Cer(d20:1/24:1)/PC 37:2 1.11 (1.04, 1.20) 3.4E−03 Cer(d20:1/24:1)/PC 35:4 1.11 (1.03, 1.18) 4.2E−03 Cer(d20:1/22:0)/PC 36:0 1.05 (1.02, 1.09) 5.4E−03 Cer(d20:1/24:1)/PC 40:5 1.11 (1.03, 1.20) 5.7E−03 Cer(d18:1/22:0)/PC 16:0/22:5 1.12 (1.03, 1.21) 6.1E−03 Cer(d16:1/18:0)/PC 38:5 1.08 (1.02, 1.14) 6.1E−03 Cer(d18:2/18:0)/PC 36:6 1.11 (1.03, 1.20) 6.9E−03 Cer(d18:2/24:1)/PC 36:6 1.13 (1.03, 1.23) 6.9E−03 Cer(d20:1/22:0)/PC 36:6 1.05 (1.01, 1.09) 7.4E−03 Cer(d18:2/18:0)/PC 38:7 1.06 (1.02, 1.11) 7.5E−03 Cer(d18:2/16:0)/PC 36:6 1.12 (1.03, 1.22) 7.8E−03 Cer(d20:1/24:1)/PC 39:4 1.10 (1.02, 1.18) 8.3E−03 Cer(d16:1/16:0)/PC 36:6 1.07 (1.02, 1.12) 8.5E−03

[0403] Table 16 presents examples of ceramide and phosphatidylcholine combinations which predict myocardial infarction in the population study cohort subjects.

TABLE-US-00016 TABLE 16 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who developed myocardial infarction during the follow-up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Myocardial infarction Lipid combination HR 95% CI p-value Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.36 (1.23, 1.50) 4.1E−10 CV score (4 components) 1.47 (1.30, 1.66) 4.8E−10 Cer(d18:1/18:0)/PC 16:0/22:5 1.31 (1.19, 1.45) 1.0E−07 CV score (3 components) 1.38 (1.22, 1.55) 1.5E−07 Cer(d18:1/22:0)/PC 40:8 1.15 (1.09, 1.21) 2.7E−07 Cer(d18:1/24:1)/PC 16:0/22:5 1.30 (1.17, 1.44) 5.8E−07 Cer(d20:1/22:0)/PC 16:0/22:5 1.27 (1.15, 1.39) 7.6E−07 Cer(d18:1/24:1)/PC 40:8 1.28 (1.16, 1.42) 1.2E−06 Cer(d18:1/20:0)/PC 16:0/22:5 1.27 (1.15, 1.41) 2.3E−06 Cer(d18:1/16:0)/PC 16:0/22:5 1.28 (1.15, 1.42) 2.9E−06 Cer(d18:1/22:0)/PC 16:0/22:5 1.26 (1.14, 1.40) 6.5E−06 Cer(d20:1/24:1)/PC 40:8 1.17 (1.09, 1.25) 1.3E−05 Cer(d18:1/18:0)/PC 38:7 1.24 (1.12, 1.37) 1.6E−05 Cer(d18:1/24:1)/PC 38:7 1.24 (1.12, 1.38) 3.6E−05 Cer(d16:1/20:0)/PC 16:0/22:5 1.23 (1.11, 1.36) 6.3E−05 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.07 (1.04, 1.11) 8.2E−05 Cer(d16:1/18:0)/PC 16:0/22:5 1.22 (1.11, 1.36) 9.9E−05 Cer(d18:1/22:0)/PC 38:7 1.21 (1.09, 1.33) 1.9E−04 Cer(d16:1/18:0)/PC 38:7 1.11 (1.05, 1.17) 2.6E−04 Cer(d20:1/24:1)/PC 16:0/22:5 1.19 (1.08, 1.31) 3.8E−04 Cer(d18:1/18:0)/PC 36:6 1.20 (1.08, 1.32) 4.3E−04 Cer(d16:1/20:0)/PC 35:0 1.20 (1.08, 1.32) 4.3E−04 Cer(d18:1/18:0)/PC 35:4 2.71 (1.55, 4.72) 4.4E−04 Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.15 (1.06, 1.24) 4.7E−04 Cer(d16:1/20:0)/Cer(d18:2/24:0) 1.12 (1.05, 1.19) 5.7E−04 Cer(d20:1/24:1)/PC 38:7 1.18 (1.07, 1.29) 6.4E−04 Cer(d16:1/18:0)/PC 40:8 1.07 (1.03, 1.12) 1.2E−03 Cer(d16:1/18:0)/PC 35:0 1.18 (1.07, 1.31) 1.2E−03 Cer(d18:1/22:0)/PC 36:0 1.18 (1.07, 1.31) 1.3E−03 Cer(d18:1/20:0)/PC 36:6 1.14 (1.05, 1.24) 1.5E−03 Cer(d18:1/22:0)/PC 35:2 1.16 (1.06, 1.27) 1.5E−03 Cer(d16:1/20:0)/PC 36:6 1.10 (1.04, 1.17) 1.6E−03 Cer(d18:1/24:1)/PC 36:6 1.18 (1.06, 1.30) 1.7E−03 Cer(d16:1/18:0)/PC 36:6 1.17 (1.06, 1.29) 1.8E−03 Cer(d18:1/20:0)/PC 38:7 1.07 (1.02, 1.11) 2.0E−03 Cer(d20:1/22:0)/PC 36:0 1.06 (1.02, 1.11) 2.0E−03 Cer(d16:1/18:0)/Cer(d18:2/24:0) 1.17 (1.06, 1.30) 2.2E−03 Cer(d18:1/22:0)/Cer(d18:1/24:0) 1.19 (1.06, 1.32) 2.2E−03 Cer(d18:1/22:0)/PC 37:2 1.17 (1.06, 1.30) 2.7E−03 Cer(d16:1/18:0)/PC 35:4 1.25 (1.08, 1.44) 2.7E−03 Cer(d18:1/22:0)/PC 36:6 1.18 (1.06, 1.31) 3.0E−03 Cer(d18:1/22:0)/PC 35:4 1.93 (1.25, 2.98) 3.0E−03 Cer(d20:1/24:1)/PC 38:1 1.17 (1.05, 1.29) 3.2E−03 Cer(d16:1/18:0)/PC 39:4 1.10 (1.03, 1.18) 3.9E−03 Cer(d16:1/20:0)/PC 36:0 1.10 (1.03, 1.17) 4.6E−03 Cer(d20:1/24:1)/PC 40:5 1.15 (1.04, 1.27) 4.6E−03 Cer(d16:1/22:0)/PC 35:4 2.26 (1.28, 3.99) 4.9E−03 Cer(d20:1/22:0)/PC 36:6 1.06 (1.02, 1.11) 7.1E−03 Cer(d16:1/18:0)/PC 36:0 1.15 (1.04, 1.28) 7.4E−03 Cer(d20:1/24:1)/PC 36:6 1.14 (1.04, 1.26) 7.6E−03 Cer(d18:1/16:0)/PC 36:6 1.16 (1.04, 1.30) 8.7E−03 Cer(d16:1/18:0)/PC 37:2 1.12 (1.03, 1.23) 8.9E−03

[0404] Table 17 presents examples of ceramide and phosphatidylcholine combinations which predict peripheral artery disease in the population study cohort subjects.

TABLE-US-00017 TABLE 17 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who developed peripheral artery disease during the follow-up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Peripheral artery disease Lipid combination HR 95% CI p-value Cer(d18:1/24:1)/PC 40:8 1.34 (1.18, 1.53) 1.3E−05 Cer(d18:1/18:0)/PC 38:7 1.32 (1.16, 1.51) 3.5E−05 Cer(d20:1/24:1)/PC 40:8 1.19 (1.09, 1.30) 5.3E−05 CV score (4 components) 1.39 (1.18, 1.64) 7.9E−05 Cer(d18:1/24:1)/PC 38:7 1.32 (1.15, 1.52) 8.0E−05 Cer(d18:2/18:0)/PC 36:5 2.41 (1.52, 3.80) 1.7E−04 Cer(d20:1/24:1)/PC 38:7 1.26 (1.12, 1.43) 1.8E−04 Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.18 (1.08, 1.29) 2.1E−04 CV score (3 components) 1.36 (1.15, 1.60) 2.6E−04 Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.29 (1.13, 1.48) 2.7E−04 Cer(d18:1/18:0)/PC 36:6 1.24 (1.11, 1.40) 2.8E−04 Cer(d18:1/22:0)/PC 40:8 1.14 (1.06, 1.24) 6.4E−04 Cer(d18:1/24:1)/PC 36:6 1.25 (1.09, 1.42) 1.1E−03 Cer(d18:1/18:0)/PC 16:0/22:5 1.26 (1.09, 1.45) 1.3E−03 Cer(d18:1/16:0)/PC 36:6 1.24 (1.08, 1.42) 1.8E−03 Cer(d18:1/20:0)/PC 36:6 1.17 (1.06, 1.29) 2.0E−03 Cer(d20:1/24:1)/PC 36:6 1.22 (1.07, 1.39) 3.0E−03 Cer(d20:1/24:1)/PC 36:0 1.20 (1.06, 1.36) 3.9E−03 Cer(d20:1/24:1)/PC 40:6 1.20 (1.06, 1.36) 3.9E−03 Cer(d20:1/24:1)/PC 40:5 1.20 (1.06, 1.36) 4.6E−03 Cer(d18:1/16:0)/PC 16:0/22:5 1.23 (1.06, 1.41) 4.7E−03 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.07 (1.02, 1.13) 5.0E−03 Cer(d18:1/20:0)/PC 38:7 1.07 (1.02, 1.13) 6.7E−03 Cer(d18:2/16:0)/PC 38:7 1.12 (1.03, 1.22) 6.8E−03 Cer(d18:1/22:0)/PC 38:7 1.21 (1.05, 1.39) 7.1E−03 Cer(d16:1/18:0)/PC 38:7 1.11 (1.03, 1.20) 8.9E−03

[0405] Table 18 presents examples of ceramide and phosphatidylcholine combinations which predict stroke in the population study cohort subjects.

TABLE-US-00018 TABLE 18 Hazard ratios (HR) and p-values of ceramide and phosphatidylcholine combinations in subjects who developed stroke during the follow- up. CV score (4 components) refers to the scoring system presented in Table 8 and CV score (3 components) to the scoring system presented in Table 9. 95% CI = 95% confidence interval. Stroke Lipid combination HR 95% CI p-value Cer(d18:1/20:0)/Cer(d18:2/24:0) 1.19 (1.12, 1.25) 4.5E−10 Cer(d18:1/22:0)/Cer(d18:2/24:0) 1.30 (1.19, 1.42) 6.2E−09 CV score (4 components) 1.32 (1.19, 1.47) 2.2E−07 CV score (3 components) 1.28 (1.15, 1.42) 3.3E−06 Cer(d20:1/24:1)/PC 40:8 1.15 (1.08, 1.23) 2.8E−05 Cer(d20:1/24:1)/PC 36:6 1.19 (1.09, 1.30) 1.0E−04 Cer(d20:1/22:0)/Cer(d18:2/24:0) 1.07 (1.03, 1.11) 1.0E−04 Cer(d18:1/24:1)/PC 40:8 1.20 (1.09, 1.31) 1.4E−04 Cer(d18:1/18:0)/PC 38:7 1.19 (1.09, 1.30) 2.2E−04 Cer(d20:1/24:1)/PC 38:7 1.17 (1.08, 1.28) 3.3E−04 Cer(d16:1/20:0)/Cer(d18:2/24:0) 1.11 (1.05, 1.18) 3.8E−04 Cer(d18:1/18:0)/PC 36:6 1.17 (1.07, 1.28) 4.3E−04 Cer(d20:1/24:1)/PC 35:4 1.09 (1.04, 1.14) 4.3E−04 Cer(d18:1/22:0)/PC 40:8 1.11 (1.04, 1.19) 1.1E−03 Cer(d18:1/16:0)/PC 36:6 1.17 (1.06, 1.29) 1.2E−03 Cer(d20:1/24:1)/PC 35:5 1.15 (1.06, 1.25) 1.2E−03 Cer(d18:1/24:1)/PC 38:7 1.18 (1.07, 1.30) 1.4E−03 Cer(d18:1/20:0)/PC 36:6 1.13 (1.05, 1.22) 1.4E−03 Cer(d18:2/16:0)/Cer(d18:2/24:0) 1.15 (1.05, 1.26) 1.6E−03 Cer(d18:1/18:0)/PC 16:0/22:5 1.16 (1.05, 1.27) 2.4E−03 Cer(d18:1/24:1)/PC 36:6 1.16 (1.05, 1.28) 2.5E−03 Cer(d18:2/18:0)/Cer(d18:2/24:0) 1.15 (1.05, 1.25) 2.7E−03 Cer(d20:1/24:1)/PC 40:6 1.14 (1.04, 1.26) 6.0E−03 Cer(d18:1/20:0)/PC 38:7 1.06 (1.02, 1.11) 7.4E−03 Cer(d18:1/16:0)/PC 16:0/22:5 1.10 (1.00, 1.21) 4.7E−02

[0406] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments described herein both in the Examples and in the body of the entire description. Such equivalents are considered to be within the scope of the present disclosure and are intended to be encompassed by the following claims or the items listed above.