Means and Methods for Diagnosing Heart Failure in a Subject

Abstract

The present invention relates to the field of diagnostic methods. Specifically, the present invention contemplates a method for diagnosing heart failure in a subject based on determining the amounts of at least three biomarkers. The invention also relates to tools for carrying out the aforementioned methods, such as diagnostic devices.

Claims

1. A method for diagnosing heart failure comprising the steps of: a. determining in a sample of a subject the amounts of at least three biomarkers, wherein said at least three biomarkers are: i. at least one triacylglyceride, at least one cholesterylester, and at least one phosphatidylcholine; ii. at least one triacylglyceride, at least one phosphatidylcholine, and at least one sphingomyelin; iii. at least one triacylglyceride, at least one cholesterylester, and at least one sphingomyelin; iv. at least one phosphatidylcholine, at least one cholesterylester, and at least one sphingomyelin; v. Cholesterylester C18:2, SSS and Cer(d17:1/24:0); vi. at least two sphingomyelins selected from the group consisting of SM2, SM3, SM5, SM18, SM23, SM24, and SM28, and at least one triacylglyceride selected from the group consisting of SOP2, SPP1 or PPO1; vii. at least two triacylglycerides selected from the group consisting of OSS2, SOP2, SPP1 and SSP2, and at least one sphingomyelin selected from the group consisting of SM23 and SM24; viii. SM18, SM24 and SM28; ix. the biomarkers of panel 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, or 199 of Table 2, or x. the biomarkers of panel 200, 201, 202, 203, 204, 205, or 206 of Table 2a, and b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed, wherein the at least one triacylglyceride biomarker in i., ii., and iii. is selected from the group consisting of SOP2, OSS2, SPP1, SSP2, PPO1 and PPP, the at least one cholesterylester biomarker in i., iii., and iv. is selected from the group consisting of cholesterylester C18:2 and cholesterylester C18:0, the at least one phosphatidylcholine biomarker in i., ii. and iv. is selected from the group consisting of PC4 and PC8, and the at least one sphingomyelin biomarker in ii., iii., and iv. is selected from the group consisting of SM18, SM24, SM23, SM21, SM28, SM5, SM3, SM29 and SM8.

2. The method of claim 1, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF).

3. The method of claims 1 and 2, wherein at least the amounts of the biomarkers of i., ii., and iii. of claim 1 are determined, and wherein the at least one triacylglyceride biomarker in i., ii., and iii. is selected from the group consisting of SOP2, OSS2, SSP2, PPO1 and PPP, in particular selected from the group consisting of SOP2, OSS2, SSP2, and PPO1, and the least one cholesterylester biomarker in i., and iii. is cholesterylester C18:2, and the least one phosphatidylcholine biomarker in i. and ii. is PC4, and the least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM18, SM24, SM23, SM28, SM5, and SM3.

4. The method of any one of claims 1 to 3, wherein at least the amounts of the biomarkers of i., ii., and iii. are determined, and wherein the at least one triacylglyceride biomarker in i., ii., and iii. is SOP2 and/or OSS2, and wherein the at least one cholesterylester biomarker in i., and iii. is cholesterylester C18:2, and wherein the at least one phosphatidylcholine biomarker in i. and ii. is PC4, and wherein the at least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM18, SM24, SM23, and SM3, in particular wherein at least the amounts of the biomarkers of i., ii., or iii are determined, and wherein the at least one triacylglyceride in i., ii., and iii. is SOP2 and/or OSS2, and wherein the at least one cholesterylester in i., and iii. is cholesterylester C18:2, and wherein the at least one phosphatidylcholine in i. and ii. is PC4, and wherein the at least one sphingomyelin in ii. and iii. is SM23.

5. The method of any one of claims 1 to 4, wherein at least the amounts of OSS2, PC4 and SM23 are determined (panel 1) or wherein at least the amounts of OSS2, cholesterylester C18:2 and SM23 are determined (panel 2, or panel 4).

6. The method of any one of claims 1 to 5, wherein at least the amounts of the biomarkers of iii. are determined, and wherein the at least one triacylglyceride biomarker is SOP2 and/or OSS2, and wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and wherein the at least one sphingomyelin biomarker is SM23.

7. The method of any one of claims 1 to 6, wherein at least the amounts of SOP2, OSS2, PC4, Cholesterylester C18:2, SM18, SM28, SM24, SSP2, and SM23 are determined (panel 3).

8. The method of any one of claims 2 to 7, wherein the subject does not show symptoms of heart failure.

9. The method of claim 8, wherein at least the amounts of the biomarkers of panel 7, 8, 9, 11, or 12 in Table 2 are determined.

10. The method of any of claims 2 to 9, wherein HFrEF is DCMP or ICMP.

11. The method of any one of claims 1 to 10, wherein the subject is a human subject, and/or wherein the sample is blood, serum or plasma.

12. The method of any one of claims 1 to 11, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS).

13. The method according to any one of claims 1 to 12, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%.

14. The method according to any one of claims 1 to 13, wherein the subject is overweight.

15. The method according to any one of claims 1 to 13, wherein the subject is older than 54 years of age.

16. The method according to any one of claims 1 to 13, wherein the subject is a female subject, older than 54 years of age, and has a body mass index of less than 25.0 kg/m.sup.2.

17. The method according to any one of claims 1 to 13, wherein the subject is younger than 61 years of age, and has a body mass index of more than 26.8 kg/m.sup.2.

18. The method according to any one of claims 1 to 17, wherein the amounts of OSS2, PC4 and SM23 (panel 1) are determined.

19. The method of any one of claims 1 to 18, further comprising the determination of the amount of NT-proBNP, BNP, ANP, or NT-proANP in step a).

20. A diagnostic device for carrying out the method according to any one of claims 1 to 19, comprising: a) an analysing unit comprising at least one detector for at least three biomarkers as set forth in any one of claims 1 to 9 and 18, wherein said analyzing unit is adapted for determining the amounts of the said biomarkers detected by the at least one detector, and, operatively linked thereto; b) an evaluation unit comprising a computer comprising tangibly embedded a computer program code for carrying out a comparison of the determined amounts of the at least three biomarkers, and reference amounts and a data base comprising said reference amounts for the said biomarkers, whereby it will be diagnosed whether a subject suffers from heart failure.

21. Use of at least three biomarkers as set forth in any one of claims 1 to 9 and 18 in a sample of a subject for diagnosing heart failure or for the preparation of a pharmaceutical and/or diagnostic composition for diagnosing heart failure.

Description

EMBODIMENTS/ITEMS OF THE PRESENT INVENTION

[0669] The definitions and explanations, given in the specification and/or the claims, preferably, apply mutatis mutandis to following preferred embodiments/items of the present invention. [0670] 1. A method for diagnosing heart failure comprising the steps of: [0671] a. determining in a sample of a subject the amounts of at least three biomarkers, wherein said at least three biomarkers are: [0672] i. at least one triacylglyceride biomarker, at least one cholesterylester biomarker, and at least one phosphatidylcholine biomarker; [0673] ii. at least one triacylglyceride biomarker, at least one phosphatidylcholine biomarker, and at least one sphingomyelin biomarker; [0674] iii. at least one triacylglyceride biomarker, at least one cholesterylester biomarker, and at least one sphingomyelin biomarker; [0675] iv. at least one phosphatidylcholine biomarker, at least one cholesterylester biomarker, and at least one sphingomyelin biomarker; [0676] v. Cholesterylester C18:2, SSS and Cer(d17:1/24:0); [0677] vi. at least two sphingomyelin biomarkers selected from the group consisting of SM2, SM3, SM5, SM18, SM23, SM24, and SM28, and at least one triacylglyceride biomarker selected from the group consisting of SOP2, SPP1 and PPO1, (or alternatively at least one triacylglyceride biomarker selected from the group consisting of SOP2, SPP1 and PPP); [0678] vii. at least two triacylglyceride biomarkers selected from the group consisting of OSS2, SOP2, SPP1 and SSP2, and at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24; [0679] viii. SM18, SM24 and SM28; or [0680] ix. the biomarkers of panel 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, or 199 of Table 2, [0681] x. the biomarkers of panel 200, 201, 202, 203, 204, 205, or 206 of Table 2a and [0682] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed, wherein the at least one triacylglyceride biomarker in i., ii., and iii. is selected from the group consisting of SOP2, OSS2, SPP1, SSP2, PPO1 and PPP, the at least one cholesterylester biomarker in i., iii., and iv. is selected from the group consisting of cholesterylester C18:2 and cholesterylester C18:0, the at least one phosphatidylcholine biomarker in i., ii. and iv. is selected from the group consisting of PC4 and PC8, and the at least one sphingomyelin biomarker in ii., iii., and iv. is selected from the group consisting of SM18, SM24, SM23, SM21, SM28, SM5, SM3, SM29 and SM8. [0683] 2. The method of embodiment 1, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF). [0684] 3. The method of embodiments 1 and 2, wherein at least the amounts of the biomarkers of i., ii., iii., vi, vii. ix or x. (in particular of i., ii., iii., vi., vii. or ix) of embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker in i., ii., and iii. is selected from the group consisting of SOP2, OSS2, SSP2, PPO1 and PPP, and/or (in particular “and”) the least one cholesterylester biomarker in i., and iii. is cholesterylester C18:2, and/or (in particular “and”) the least one phosphatidylcholine biomarker in i. and ii. is PC4, and/or (in particular “and”) the least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM18, SM24, SM23, SM28, SM5, and SM3. [0685] 4. The method of any one of embodiments 1 to 3, wherein at least the amounts of the biomarkers of panel 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56 in Table 2 are determined. [0686] 5. The method of any one of embodiments 1 to 4, wherein at least the amounts of the biomarkers of i., ii., iii, vi, ix or x. are determined, and wherein the at least one triacylglyceride biomarker in i., ii., and iii. is SOP2 and/or OSS2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker in i., and iii. is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one phosphatidylcholine biomarker in i. and ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM18, SM24, SM23, and SM3. [0687] 6. The method of any one of embodiments 1 to 5, wherein at least the amounts of the biomarkers of panel 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 in Table 2 are determined. [0688] 7. The method of any one of embodiments 1 to 6, wherein at least the amounts of the biomarkers of i., ii., iii, vi, ix or x. (in particular of i., ii, iii, or vi.) are determined, and wherein the at least one triacylglyceride biomarker in i., ii., and iii. is SOP2 and/or OSS2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker in i., and iii. is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one phosphatidylcholine biomarker in i. and ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is SM23. [0689] 8. The method of any one of embodiments 1 to 7, wherein at least the amounts of the biomarkers of panel 1, 2, 3 or 4 in Table 2 are determined. [0690] 9. The method of any one of embodiments 1 to 7, wherein at least the amounts of OSS2, PC4 and SM23 are determined, in particular wherein at least the amounts of OSS2, PC4 and SM23, and the amount of NT-proBNP or BNP are determined. [0691] 10. The method of any one of embodiments 1 to 7, wherein at least the amounts of OSS2, cholesterylester C18:2 and SM23 are determined. [0692] 11. The method of any one of embodiments 1 to 7, wherein at least the amounts of the biomarkers of iii. are determined, and wherein the at least one triacylglyceride biomarker is SOP2 and/or OSS2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker is SM23. [0693] 12. The method of any one of embodiments 1 to 11, wherein at least the amounts of SOP2, OSS2, PC4, Cholesterylester C18:2, SM18, SM28, SM24, SSP2, and SM23 are determined. [0694] 13. The method of any one of embodiments 2 to 12, in particular of embodiments 2 to 4, wherein the heart failure with reduced left ventricular ejection fraction is DCMP (dilated cardiomyopathy). [0695] 14. The method of embodiment 13, wherein at least the amounts of the biomarkers shown in i., ii., iii. or vii, in particular of in i., ii., or iii. are determined, and wherein the at least one triacylglyceride biomarker in i., ii. and iii. is selected from the group consisting of SOP2, OSS2, and SSP2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker in i. and iii. is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one phosphatidylcholine biomarker in i. and ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM24, SM23, SM28, and SM3. [0696] 15. The method of embodiments 13 and 14, wherein at least the amounts of the biomarkers of panel 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 in Table 2 are determined. [0697] 16. The method of any one of embodiments 13 to 15, in particular of embodiments 13 and 14, wherein at least the amounts of the biomarkers shown in ii. or iii. are determined, and wherein the at least one triacylglyceride biomarker in ii. and iii. is SOP2 and/or OSS2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker in iii. is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one phosphatidylcholine biomarker in ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is SM23 and/or SM24. [0698] 17. The method of any of embodiments 13 to 16, wherein at least the amounts of the biomarkers of panel 31, 32, 33, 34, 35 and 36 in Table 2 are determined. [0699] 18. The method of any one of embodiments 2 to 12, in particular of embodiments 2 to 4, wherein the heart failure with reduced left ventricular ejection fraction is ICMP (ischemic card iomyopathy). [0700] 19. The method of embodiment 18, wherein at least the amounts of the biomarkers shown in ii., iii. or vi, in particular in ii., or iii. are determined, and wherein the at least one triacylglyceride biomarker in ii. and iii. is SOP2 and/or OSS2 (in particular “and”), wherein the at least one cholesterylester biomarker in iii. is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one phosphatidylcholine biomarker in ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM18, SM24, and SM23. [0701] 20. The method of embodiments 18 and 19, wherein at least the amounts of the biomarkers of panel 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56 in Table 2 are determined. [0702] 21. The method of any one of embodiments 18 to 20, wherein at least the amounts of the biomarkers shown in iii. are determined, and wherein the at least one triacylglyceride biomarker is SOP2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker is SM18 and/or SM23. [0703] 22. The method of any one of embodiments 18 to 21, wherein at least the amounts of the biomarkers of panel 51, 52, 53, 54, 55 or 56 in Table 2 are determined. [0704] 23. The method of any one of embodiments 2 to 23, in particular of embodiments 2 to 4, wherein the HFrEF is asymptomatic (or wherein the subject does not show symptoms of heart failure). [0705] 24. The method of embodiment 23, and wherein at least the amounts of the biomarkers of, ii., iii. vi, vii., ix or x. (in particular of ii, iii, vi, vii, or ix.) are determined, and wherein the at least one triacylglyceride biomarker in ii., and iii. is selected from the group consisting of SOP2, OSS2, and PPO1, and/or (in particular “and”) wherein the at least one cholesterylester biomarker in iii. is cholesterylester C18:2, and/or (in particular “and”) the least one phosphatidylcholine biomarker in ii. is PC4, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker in ii. and iii. is selected from the group consisting of SM24 and SM23. [0706] 25. The method of embodiments 23 and 24, wherein at least the amounts of the biomarkers of panel 7, 8, 9, 10, 11, 12, 19, 20, 21, 22, 23, 24, 37, 38, 39, 40, 41 or 42 in Table 2 are determined. [0707] 26. The method of any one of embodiments 23 to 25, in particular of embodiments 23 and 24, wherein at least the amounts of the biomarkers of iii. or vi. (in particular of iii.) of embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker is SOP2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker is selected from the group consisting of SM24 and SM23. [0708] 27. The method of embodiment 26, wherein at least the amounts of the biomarkers of panel 7, 8, 9, 10, 11, or 12 in Table 2 are determined. [0709] 28. The method of any one of embodiments 13 to 17, in particular of any one of embodiments 13, 14 and 16, wherein the DCMP is asymptomatic (or wherein the subject does not show symptoms of heart failure). [0710] 29. The method of embodiment 28, wherein at least the amounts of the biomarkers of iii. in embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker is selected from the group consisting of SOP2 and OSS2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker is SM23. [0711] 30. The method of embodiments 28 or 29, wherein at least the amounts of the biomarkers of panel 19, 20, 21, 22, 23 or 24 in Table 2 are determined. [0712] 31. The method of embodiments 18 or 22, wherein the ICMP is asymptomatic (or wherein the subject does not show symptoms of heart failure). [0713] 32. The method of embodiment 31, wherein at least the amounts of the biomarkers of iii. or vi (in particular of iii.) are determined, and wherein the at least one triacylglyceride biomarker is SOP2, and/or (in particular “and”) wherein the at least one cholesterylester biomarker is cholesterylester C18:2, and/or (in particular “and”) wherein the at least one sphingomyelin biomarker is selected from the group consisting of SM24 and SM23. [0714] 33. The method of embodiments 31 or 32, wherein at least the amounts of the biomarkers of panel 37, 38, 39, 40, 41 or 42 in Table 2 are determined. [0715] 34. The method of embodiment 1, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF). [0716] 35. The method of embodiment 34, wherein at least the amounts of the biomarkers of ii., vi, or vii. of embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker in ii. is selected from the group consisting of SOP2, SSP2, SPP1 and PPO1, and/or (in particular “and”) the least one phosphatidylcholine biomarker in ii. is selected from the group consisting of PC4 and PC8, and/or (in particular “and”) the least one sphingomyelin biomarker in ii. is selected from the group consisting of SM18, SM24, SM23, SM28, SM5, and SM3. [0717] 36. The method of embodiment 35, wherein at least the amounts of the biomarkers of panel 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 or 102, in Table 2 are determined. [0718] 37. The method of embodiment 35 or 36, wherein at least the amounts of the biomarkers of ii. of embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker is selected from the group consisting of SSP2, SPP1 and PPO1, and/or (in particular “and”) the least one phosphatidylcholine biomarker is PC4, and/or (in particular “and”) the least one sphingomyelin biomarker is selected from the group consisting of SM24, SM5, and SM3. [0719] 38. The method of embodiment 37, wherein at least the amounts of the biomarkers of panel 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99 or 101 in Table 2 are determined. [0720] 39. The method of any one of embodiment 35 to 38, in particular of any one of embodiments 34 to 37, wherein at least the amounts of the biomarkers of ii. of embodiment 1 are determined, and wherein the at least one triacylglyceride biomarker is SSP2, and/or (in particular “and”) the least one phosphatidylcholine biomarker is PC4, and/or (in particular “and”) the least one sphingomyelin biomarker in ii. is selected from the group consisting of SM24 and SM5. [0721] 40. The method of embodiment 39, wherein at least the amounts of the biomarkers of panel 95, 97, 99 or 101 in Table 2 are determined. [0722] 41. The method of any one of embodiments 34 to 37, in particular of any one of embodiments 34 to 36, wherein the HFpEF is asymptomatic. [0723] 42. The method of embodiment 41, wherein in particular at least the amounts of the biomarkers of ii. or vii. (in particular of ii.) of embodiment 1 are determined and wherein the at least one triacylglyceride biomarker is selected from the group consisting of SPP1 and SSP2, and/or (in particular “and”) the least one phosphatidylcholine biomarker is PC4, and/or (in particular “and”) the least one sphingomyelin biomarker is selected from the group consisting of SM5 and SM3. [0724] 43. The method of embodiment 41 or 42, wherein at least the amounts of the biomarkers of panel 79, 80, 81, 82, 83, 84, 85 or 86 in Table 2 are determined. [0725] 44. The method of any one embodiments 41 to 43, wherein the at least one triacylglyceride biomarker in ii. is SPP1, and/or (in particular “and”) the least one phosphatidylcholine biomarker in ii. is PC4, and/or (in particular “and”) the least one sphingomyelin biomarker in ii. is SM5. [0726] 45. The method of any one of embodiments 41 to 44, wherein at least the amounts of the biomarkers of panel 79, 81, 83, or 85 in Table 2 are determined. [0727] 46. The method of any one of embodiments 1 to 45, wherein the subject is a human subject. [0728] 47. The method of any one of embodiments to 1 to 46, wherein the sample is blood, serum or plasma. [0729] 48. The method of any one of embodiments 1 to 47, wherein the method does not comprise the determination of NT-proBNP or BNP. [0730] 49. The method of any one of embodiments 1 to 47, further comprising determining the amount of NT-proBNP or BNP in a sample/the sample from the subject and comparing the amount of NT-proBNP or BNP to a reference. [0731] 50. The method of any one of embodiments 1 to 49, further comprising carrying out a correction for confounders. [0732] 51. The method of embodiment 50, wherein the confounders are age, BMI and/or gender, in particular age, BMI and gender. [0733] 52. The method of any one of embodiments 1 to 51, wherein in step b) a score is calculated based on the determined amounts of the at least three biomarkers, and wherein the reference is a reference score. [0734] 53. The method of any one of embodiments 1 to 52, wherein the reference or the reference score is from a subject or group of subjects known not to suffer from heart failure. [0735] 54. The method of embodiment 53, wherein a value for each of the at least three biomarkers, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the absence of heart failure. [0736] 55. The method of any one of embodiments 1 to 52, wherein the reference or the reference score is from a subject or group of subjects known to suffer from heart failure. [0737] 56. The method of any one of embodiment 55, wherein a value for each of the at least three biomarkers found, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the presence of the heart failure. [0738] 57. The method of any one of embodiments 1 to 56, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS). [0739] 58. The method of embodiment 57, wherein the mass spectrometry is LC-MS, in particular LC-MS/MS, or HPLC-MS, in particular HPLC-MS/MS. [0740] 59. The method of embodiments 57 and 58, wherein the mass spectrometry comprises an ionization step in which the at least three biomarkers are ionized [0741] 60. The method of embodiment 59, wherein the ionization step is carried out by electrospray ionization, in particular by positive ion mode electrospray ionization. [0742] 61. A diagnostic device for carrying out the method according to any one of embodiments 1 to [0743] 60, comprising: [0744] a) an analysing unit comprising at least one detector for the at least three biomarkers as set forth in any one of embodiments 1 to 45, wherein said analyzing unit is adapted for determining the amounts of the said biomarkers detected by the at least one detector, and, operatively linked thereto; [0745] b) an evaluation unit comprising a computer comprising tangibly embedded a computer program code for carrying out a comparison of the determined amounts of the at least three biomarkers, and reference amounts (or a reference score) and a data base comprising said reference amounts for the said biomarkers, whereby it will be diagnosed whether a subject suffers from heart failure. [0746] 62. Use of at least three biomarkers as set forth in any one of embodiments 1 to 45 in a sample of a subject for diagnosing heart failure or for the preparation of a pharmaceutical and/or diagnostic composition for diagnosing heart failure. [0747] 63. The method of any one of embodiments 2 to 33, the device of embodiment 61 or the use of embodiment 62, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [0748] 64. The method of any one of embodiments 1 to 33 or 63, the device of embodiment 61 or 63, or the use of embodiment 62 or 63, wherein the subject is overweight. [0749] 65. The method of any one of embodiments 1 to 33 or 63, the device of embodiment 61 or 63, or the use of embodiment 62 or 63, wherein the subject is older than 54 years of age. [0750] 66. The method of any one of embodiments 1 to 33 or 63, the device of embodiment 61 or 63, or the use of embodiment 62 or 63, wherein the subject is a female subject, older than 54 years of age, and has a body mass index of less than 25.0 kg/m.sup.2. [0751] 67. The method of any one of embodiments 1 to 33 or 63, the device of embodiment 61 or 63, or the use of embodiment 62 or 63, wherein the subject is younger than 61 years of age, and has a body mass index of more than 26.8 kg/m.sup.2.

[0752] Further Preferred Items of the Present Invention [0753] 1. A method for diagnosing heart failure comprising the steps of: [0754] a. determining in a sample of a subject the amounts of at least three biomarkers wherein said at least three biomarker are [0755] i. at least one sphingomyelin biomarker (SM) selected from the group consisting of SM18, SM21, SM23, SM24, SM28, SM3, SM5, SM2, SM9 and SM10, in particular at least one sphingomyelin (SM) biomarker selected from the group consisting of SM18, SM21, SM23, SM24, SM28, SM3 and SM5, [0756] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, PPO1, SOP2, SSP2 and SPP1, in particular at least one triacylglyceride biomarker selected from the group consisting of OSS2, PPO1, SOP2, and SSP2, and [0757] iii. at least one further biomarker selected from the group consisting of Cer(d16:1/24:0), Cer(d18:1/24:1), Cholesterylester C18:2, PC4, PC8, Cer(d18:2/24:0), Cer(d17:1/24:0) and glutamic acid 1, in particular at least one further biomarker selected from the group consisting of Cer(d16:1/24:0), Cer(d18:1/24:1), Cholesterylester C18:2, and PC4, [0758] and [0759] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0760] 2. The method of item 1, wherein at least the amounts of [0761] i. at least one sphingomyelin biomarker selected from the group consisting of SM28, SM23, SM21, and SM5, [0762] ii. SOP2 and/or OSS2, and [0763] iii. Cholesterylester C18:2 and/or PC4 are determined. [0764] 3. The method of item 1 or 2, wherein at least the amounts of [0765] i. at least one sphingomyelin biomarker selected from the group consisting of SM28, SM21, and SM5, in particular SM28, or at least one sphingomyelin biomarker selected from the group consisting of SM18, SM21, and SM5, in particular SM18, and [0766] ii. SOP2, and [0767] iii. PC4 are determined. [0768] 4. The method of any one of items 1 to 3, the heart failure is asymptomatic heart failure, and/or wherein the subject does not show symptoms of heart failure. [0769] 5. The method of item 4, wherein at least the amounts of [0770] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM2, SM23, SM24, SM28, SM3, and SM5, [0771] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, PPO1, SOP2, SSP2 and SPP1, and [0772] iii. at least one further biomarker selected from the group consisting of Cer(d16:1/24:0), Cholesterylester C18:2, PC4 and glutamic acid 1 are determined. [0773] 6. The method of items 4 and 5, wherein at least the amounts of [0774] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM2, and SM24, [0775] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, OSS2, and PPO1, and [0776] iii. Cholesterylester C18:2 and/or PC4, in particular Cholesterylester C18:2, are determined. [0777] 7. The method of any one of items 4 to 6, wherein at least the amounts of SM23 and/or SM2, in particular of SM23, of SOP2, and of PC4 are determined. [0778] 8. The method of any one of items 1 to 3, wherein the heart failure is symptomatic heart failure and/or wherein the subject shows symptoms of heart failure. [0779] 9. The method of item 8, wherein at least the amounts of [0780] i. at least one sphingomyelin biomarker selected from the group consisting of SM10, SM18, SM21, SM23, SM24, SM28, SM3 and SM9, [0781] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, PPO1, SOP2, SSP2 and SPP1, and [0782] iii. at least one further biomarker selected from the group consisting of Cer(d16:1/24:0), Cer(d18:1/24:1), Cer(d17:1/24:0), Cer (d18:2/24:0), Cholesterylester C18:2, PC4 and PC8 are determined. [0783] 10. The method of items 8 and 9, wherein at least the amounts of [0784] i. at least one sphingomyelin biomarker is selected from the group consisting of SM18, SM3, SM24, and SM23, in particular SM18, [0785] ii. SOP2 and/or OSS2, in particular SOP2, and [0786] iii. Cholesterylester C18:2 and/or PC4, in particular PC4, are determined. [0787] 11. The method of any one of items 8 to 10, wherein at least the amounts of SM18 and/or SM24, SOP2, and PC4 are determined. [0788] 12. The method of any one of items 1 to 11, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF). [0789] 13. The method of item 12, wherein at least the amounts of [0790] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM18, SM24, SM28, SM2 and SM3, in particular at least one sphingomyelin biomarker selected from the group consisting of SM23, SM18, SM24, and SM28, [0791] ii. OSS2 and/or SOP2, in particular OSS2, [0792] iii. Cholesterylester C18:2 and/or PC4 are determined. [0793] 14. The method of items 12 and 13, wherein at least the amounts of SM23, OSS2, and Cholesterylester C18:2 are determined. [0794] 15. The method of any one of items 12 to 14, wherein the HFrEF is asymptomatic HFrEF, and/or wherein the subject does not show symptoms of heart failure. [0795] 16. The method of item 15, wherein at least the amounts of [0796] i. at least one sphingomyelin biomarker selected from the group consisting of SM23 SM18, SM2, SM24 and SM28, [0797] ii. SOP2, and [0798] iii. Cholesterylester C18:2 are determined. [0799] 17. The method of items 15 and 16, wherein at least the amounts of SM23, SOP2, and Cholesterylester C18:2 are determined. [0800] 18. The method of any one of items 12 to 14, wherein the HFrEF is symptomatic HFrEF, and/or wherein the subject shows symptoms of heart failure. [0801] 19. The method of item 18, wherein at least the amounts of [0802] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM23, SM3 or at least one sphingomyelin biomarker selected from the group consisting of SM28, SM23 and SM3, [0803] ii. OSS2, and [0804] iii. Cholesterylester C18:2 and/or PC4 are determined. [0805] 20. The method of items 18 and 19, wherein at least the amounts of SM18 and/or SM28, of OSS2, and of Cholesterylester C18:2 are determined. [0806] 21. The method of any one of items 12 to 14, wherein the heart failure with reduced left ventricular ejection fraction is DCMP (dilated cardiomyopathy). [0807] 22. The method of item 21, wherein at least the amounts of [0808] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, SM28, and SM3, in particular at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, and SM28, [0809] ii. SOP2 and/or OSS2, and [0810] iii. Cholesterylester C18:2 and/or PC4 are determined. [0811] 23. The method of items 21 and 22, wherein at least the amounts of SM23, of SOP2, and of Cholesterylester C18:2 are determined. [0812] 24. The method of items 21 to 23, wherein the DCMP is asymptomatic DCMP, and/or wherein the subject does not show symptoms of heart failure. [0813] 25. The method of item 21, wherein at least the amounts of [0814] i. SM23, [0815] ii. OSS2 and/or SOP2, and [0816] iii. Cholesterylester C18:2 are determined. [0817] 26. The method of items 24 and 25, wherein at least the amounts of SM23, OSS2, and Cholesterylester C18:2 are determined. [0818] 27. The method of items 21 to 23, wherein the DCMP is symptomatic DCMP, and/or wherein the subject shows symptoms of heart failure. [0819] 28. The method of item 27, wherein at least the amounts of [0820] i. SM28 and/or SM3, [0821] ii. SOP2 and/or OSS2, and [0822] iii. PC4 are determined. [0823] 29. The method of items 27 and 28, wherein the at least the amounts of SM28, SOP2, and of PC4 are determined. [0824] 30. The method of any one of items 12 to 14, wherein the heart failure with reduced left ventricular ejection fraction is ICMP (ischemic cardiomyopathy). [0825] 31. The method of item 30, wherein at least the amounts of [0826] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, SM28 and SM18, in particular at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, and SM28, [0827] ii. SOP2, and [0828] iii. Cholesterylester C18:2 are determined. [0829] 32. The method of items 30 and 31, wherein at least the amounts of SM23, SOP2, and Cholesterylester C18:2 are determined. [0830] 33. The method of items 31 and 32, wherein the ICMP is symptomatic ICMP, and/or wherein the subject shows symptoms of heart failure. [0831] 34. The method of item 33, wherein at least the amounts of SM18, SOP2, and Cholesterylester C18:2 are determined. [0832] 35. A method for diagnosing asymptomatic heart failure comprising the steps of: [0833] a. determining in a sample of a subject the amounts of [0834] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM2, and SM24, [0835] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, OSS2, and PPO1, and [0836] iii. at least one further biomarker selected from Cholesterylester C18:2, PC4, and SM5, [0837] and [0838] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0839] 36. A method for diagnosing asymptomatic ICMP comprising the steps of: [0840] a. determining in a sample of a subject the amounts of at least three markers selected from the group consisting of SM24, SM5, SM23, SOP2 and PPO1, and [0841] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0842] 37. The method of items 36, wherein at least the amounts of [0843] i. SM24, SM5 and SOP2, or [0844] ii. SM23, SM5 and PPO1, are determined. [0845] 38. The method of any one of items 1 to 37, wherein the subject is a human subject. [0846] 39. The method of any one of items to 1 to 38, wherein the sample is blood, serum or plasma. [0847] 40. The method of any one of items 1 to 39, wherein the method does not comprise the determination of NT-proBNP or BNP. [0848] 41. The method of any one of items 1 to 39, further comprising determining the amount of NT-proBNP or BNP in a sample/the sample from the subject and comparing the amount of NT-proBNP or BNP to a reference. [0849] 42. The method of any one of items 1 to 41, further comprising carrying out a correction for confounders. [0850] 43. The method of item 42, wherein the confounders are age, BMI and/or gender, in particular age, BMI and gender. [0851] 44. The method of any one of items 1 to 43, wherein in step b) a score is calculated based on the determined amounts of the at least three biomarkers, and wherein the reference is a reference score. [0852] 45. The method of any one of items 1 to 44, wherein the reference or the reference score is from a subject or group of subjects known not to suffer from heart failure. [0853] 46. The method of item 45, wherein a value for each of the at least three biomarkers, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the absence of heart failure. [0854] 47. The method of any one of items 1 to 44, wherein the reference or the reference score is from a subject or group of subjects known to suffer from heart failure. [0855] 48. The method of any one of item 47, wherein a value for each of the at least three biomarkers found, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the presence of the heart failure. [0856] 49. The method of any one of items 1 to 48, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS). [0857] 50. The method of item 49, wherein the mass spectrometry is LC-MS, in particular LCMS/MS, or HPLC-MS, in particular HPLC-MS/MS. [0858] 51. The method of items 49 and 50, wherein the mass spectrometry comprises an ionization step in which the at least three biomarkers are ionized [0859] 52. The method of item 51, wherein the ionization step is carried out by electrospray ionization, in particular by positive ion mode electrospray ionization. [0860] 53. A diagnostic device for carrying out the method according to any one of items 1 to 52, comprising: [0861] a) an analysing unit comprising at least one detector for the at least three biomarkers as set forth in any one of items 1 to 37, wherein said analyzing unit is adapted for determining the amounts of the said biomarkers detected by the at least one detector, and, operatively linked thereto; [0862] b) an evaluation unit comprising a computer comprising tangibly embedded a computer program code for carrying out a comparison of the determined amounts of the at least three biomarkers, and reference amounts (or a reference score) and a data base comprising said reference amounts for the said biomarkers, whereby it will be diagnosed whether a subject suffers from heart failure. [0863] 54. Use of at least three biomarkers as set forth in any one of items 1 to 37 in a sample of a subject for diagnosing heart failure or for the preparation of a pharmaceutical and/or diagnostic composition for diagnosing heart failure. [0864] 55. The method of any one of items 2 to 52, the device of embodiment 53 or the use of embodiment [0865] 54, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [0866] 56. A composition comprising the at least three biomarkers as set forth in any one of items 1 to 27. [0867] 57. A calibration solution comprising the composition of item 56. [0868] 58. A calibration sample, comprising the composition of item 56 and delipidized serum or delipidized plasma.

Further Preferred Embodiments of the Present Invention

[0869] 1. A method for diagnosing heart failure comprising the steps of: [0870] a. determining in a sample of a subject the amounts, preferably, the amounts of at least three biomarkers, wherein said at least three biomarkers are [0871] i. at least one sphingomyelin (SM) biomarker selected from the group consisting of SM18, SM23, SM24, SM3, SM5, SM2, and SM28, and in particular at least one sphingomyelin (SM) biomarker selected from the group consisting of SM18, SM23, SM24, SM3, and SM5, [0872] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, SOP2, SSP2 and PPO1, in particular at least one triacylglyceride biomarker selected from the group consisting of OSS2 and SOP2, and [0873] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, and [0874] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0875] 2. The method of embodiment 1, wherein at least the amounts of [0876] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM23, SM24, SM3, and SM5, [0877] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2 and SOP2, and [0878] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0879] 3. The method of embodiment 1 or 2, wherein at least the amounts of [0880] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM3, and SM5, in particular SM18, and [0881] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2 and SOP2, in particular SOP2, and [0882] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, in particular PC4 are determined. [0883] 4. The method of any one of embodiments 1 to 3, the heart failure is asymptomatic heart failure, and/or wherein the subject does not show symptoms of heart failure. [0884] 5. The method of embodiment 4, wherein at least the amounts of [0885] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM2, SM23, SM24, SM28, and SM5, [0886] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, PPO1, SOP2, and SSP2, and [0887] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0888] 6. The method of embodiments 4 and 5, wherein at least the amounts of [0889] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, SM18, and SM2, in particular SM23, [0890] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, OSS2, and PPO1, in particular SOP2, and [0891] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, in particular Cholesterylester C18:2, are determined [0892] 7. The method of any one of embodiments 4 to 6, wherein at least the amounts of [0893] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM18, and SM2, in particular SM23, [0894] ii. SOP2, and [0895] iii. Cholesterylester C18:2 and/or PC4, in particular Cholesterylester C18:2, are determined. [0896] 8. The method of any one of embodiments 1 to 3, wherein the heart failure is symptomatic heart failure, and/or wherein the subject shows symptoms of heart failure. [0897] 9. The method of embodiment 8, wherein at least the amounts of [0898] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM23, SM24, SM28, and SM3, [0899] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2 and SOP2, and [0900] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0901] 10. The method of embodiments 8 and 9, wherein at least the amounts of [0902] i. SM18, [0903] ii. SOP2, and [0904] iii. Cholesterylester C18:2, are determined. [0905] 11. The method of any one of embodiments 8 to 10, wherein at least the amounts of SM18 and/or SM24, in particular SM18, of SOP2, and of PC4 are determined. [0906] 12. The method of any one of embodiments 1 to 11, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF). [0907] 13. The method of embodiment 12, wherein at least the amounts of [0908] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM18, SM3, SM24, SM 28 in particular at least one sphingomyelin selected from the group consisting of SM23 and SM18, [0909] ii. at least one triacylglyceride biomarker selected from the group consisting of OSS2, SOP2 and PPO1, in particular OSS2, and [0910] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0911] 14. The method of embodiments 12 and 13, wherein at least the amounts of SM23, OSS2, and Cholesterylester C18:2 are determined. [0912] 15. The method of any one of embodiments 12 to 14, wherein the HFrEF is asymptomatic HFrEF, and/or wherein the subject does not show symptoms of heart failure. [0913] 16. The method of embodiment 15, wherein at least the amounts of [0914] i. at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24, in particular SM23, [0915] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, and OSS2, in particular SOP2, and [0916] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, in particular Cholesterylester C18:2 are determined. [0917] 17. The method of embodiments 15 and 16, wherein at least the amounts of SM23, SOP2, and Cholesterylester C18:2 are determined. [0918] 18. The method of any one of embodiments 12 to 14, wherein the HFrEF is symptomatic HFrEF, and/or wherein the subject shows symptoms of heart failure. [0919] 19. The method of embodiment 18, wherein at least the amounts of [0920] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM23, SM3, SM28 and SM24, in particular at least one sphingomyelin selected from the group consisting of SM18, SM23 and SM3, [0921] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and OSS2, and [0922] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0923] 20. The method of embodiments 18 and 19, wherein at least the amounts of SM18, of OSS2, and of Cholesterylester C18:2 are determined. [0924] 21. The method of any one of embodiments 12 to 14, wherein the heart failure with reduced left ventricular ejection fraction is DCMP (dilated cardiomyopathy). [0925] 22. The method of embodiment 21, wherein at least the amounts of [0926] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, SM3 and SM28, in particular at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24, [0927] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, and OSS2, and [0928] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0929] 23. The method of embodiments 21 and 22, wherein at least the amounts of SM23, of SOP2, and of Cholesterylester C18:2 are determined. [0930] 24. The method of embodiments 21 to 23, wherein the DCMP is asymptomatic DCMP, and/or wherein the subject does not show symptoms of heart failure. [0931] 25. The method of embodiment 21, wherein at least the amounts of [0932] i. at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24, [0933] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and OSS2, and [0934] iii. Cholesterylester C18:2 are determined. [0935] 26. The method of embodiments 24 and 25, wherein at least the amounts of SM23, OSS2, and Cholesterylester C18:2 are determined. [0936] 27. The method of embodiments 21 to 23, wherein the DCMP is symptomatic DCMP, and/or wherein the subject shows symptoms of heart failure. [0937] 28. The method of embodiment 27, wherein at least the amounts of [0938] i. at least one sphingomyelin biomarker selected from the group consisting of SM3, SM24 and SM28, [0939] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and OSS2, and [0940] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4 are determined. [0941] 29. The method of embodiments 27 and 28, wherein the at least the amounts of SM3, OSS2, and of PC4 are determined. [0942] 30. The method of any one of embodiments 12 to 14, wherein the heart failure with reduced left ventricular ejection fraction is ICMP (ischemic cardiomyopathy). [0943] 31. The method of embodiment 30, wherein at least the amounts of [0944] i. at least one sphingomyelin biomarker selected from the group consisting of SM18, SM23, and SM24, in particular at least one sphingomyelin biomarker selected from the group consisting of SM18 and SM23, [0945] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and PPO1, in particular SOP2, and [0946] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, in particular Cholesterylester C18:2 are determined. [0947] 32. The method of embodiments 30 and 31, wherein at least the amounts of SM18, SOP2, and Cholesterylester C18:2 are determined. [0948] 33. The method of embodiments 31 and 32, wherein the ICMP is asymptomatic ICMP, and/or wherein the subject does not show symptoms of heart failure. [0949] 34. The method of embodiment 33, wherein [0950] i. at least one sphingomyelin biomarker selected from the group consisting of SM24 and SM23, [0951] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and PPO1, and [0952] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and PC4, in particular Cholesterylester C18:2 are determined. [0953] 35. The method of embodiment 33, wherein at least the amounts of SM24, SOP2, and Cholesterylester C18:2 are determined. [0954] 36. The method of embodiments 31 and 32, wherein the ICMP is symptomatic ICMP, and/or wherein the subject shows symptoms of heart failure. [0955] 37. The method of embodiment 33, wherein at least the amounts of SM18, SOP2, and Cholesterylester C18:2 are determined. [0956] 38. A method for diagnosing asymptomatic heart failure comprising the steps of: [0957] a. determining in a sample of a subject the amounts of [0958] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM24, SM18, and SM2, in particular SM23, [0959] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, OSS2, and PPO1, in particular SOP2, and [0960] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2, PC4, SM5 and SSP2, in particular Cholesterylester C18:2, and [0961] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0962] 39. A method for diagnosing asymptomatic heart failure comprising the steps of: [0963] a. determining in a sample of a subject the amounts of [0964] i. at least one sphingomyelin biomarker selected from the group consisting of SM23, SM18, and SM2, in particular SM23, [0965] ii. SOP2, and [0966] iii. at least one further biomarker selected from the group consisting of SM5, Cholesterylester C18:2 PC4, in particular SM5, and [0967] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0968] 40. A method for diagnosing asymptomatic HFrEF comprising the steps of: [0969] a. determining in a sample of a subject the amounts of [0970] i. at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24, [0971] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2, and OSS2, in particular SOP2, and [0972] iii. at least one further biomarker selected from the group consisting of Cholesterylester C18:2 and SM28, in particular Cholesterylester C18:2, and [0973] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0974] 41. A method for diagnosing asymptomatic DCMP comprising the steps of: [0975] a. determining in a sample of a subject the amounts of [0976] i. at least one sphingomyelin biomarker selected from the group consisting of SM23 and SM24, in particular SM23, [0977] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and OSS2, in particular OSS2 and [0978] iii. Cholesterylester C18:2 and SSP2, in particular Cholesterylester C18:2, and [0979] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0980] 42. A method for diagnosing asymptomatic ICMP comprising the steps of: [0981] a. determining in a sample of a subject the amounts of [0982] i. at least one sphingomyelin biomarker selected from the group consisting of SM24 and SM23, in particular SM24, [0983] ii. at least one triacylglyceride biomarker selected from the group consisting of SOP2 and PPO1, in particular SOP2, and [0984] iii. at least one further biomarker selected from the group consisting of SM5, Cholesterylester C18:2 and PC4, in particular Cholesterylester C18:2, in particular SM5, or in particular PC4, and [0985] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [0986] 43. The method of any one of embodiments 1 to 42, wherein the subject is a human subject. [0987] 44. The method of any one of embodiments to 1 to 43, wherein the sample is blood, serum or plasma. [0988] 45. The method of any one of embodiments 1 to 44, wherein the method does not comprise the determination of NT-proBNP or BNP. [0989] 46. The method of any one of embodiments 1 to 44, further comprising determining the amount of NT-proBNP or BNP in a sample/the sample from the subject and comparing the amount of NT-proBNP or BNP to a reference. [0990] 47. The method of any one of embodiments 1 to 46, further comprising carrying out a correction for confounders. [0991] 48. The method of embodiment 47, wherein the confounders are age, BMI and gender. [0992] 49. The method of any one of embodiments 1 to 48, wherein in step b) a score is calculated based on the determined amounts of the at least three biomarkers, and wherein the reference is a reference score. [0993] 50. The method of any one of embodiments 1 to 49, wherein the reference or the reference score is from a subject or group of subjects known not to suffer from heart failure. [0994] 51. The method of embodiment 50, wherein a value for each of the at least three biomarkers, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the absence of heart failure. [0995] 52. The method of any one of embodiments 1 to 49, wherein the reference or the reference score is from a subject or group of subjects known to suffer from heart failure. [0996] 53. The method of any one of embodiment 52, wherein a value for each of the at least three biomarkers found, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the presence of the heart failure. [0997] 54. The method of any one of embodiments 1 to 53, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS). [0998] 55. The method of embodiment 54, wherein the mass spectrometry is LC-MS, in particular LC-MS/MS, or HPLC-MS, in particular HPLC-MS/MS. [0999] 56. The method of embodiments 54 and 55, wherein the mass spectrometry comprises an ionization step in which the at least three biomarkers are ionized [1000] 57. The method of embodiment 56, wherein the ionization step is carried out by electrospray ionization, in particular by positive ion mode electrospray ionization. [1001] 58. A diagnostic device for carrying out the method according to any one of embodiments 1 to [1002] 57, comprising: [1003] a) an analysing unit comprising at least one detector for the at least three biomarkers as set forth in any one of embodiments 1 to 42, wherein said analyzing unit is adapted for determining the amounts of the said biomarkers detected by the at least one detector, and, operatively linked thereto; [1004] b) an evaluation unit comprising a computer comprising tangibly embedded a computer program code for carrying out a comparison of the determined amounts of the at least three biomarkers, and reference amounts (or a reference score) and a data base comprising said reference amounts for the said biomarkers, whereby it will be diagnosed whether a subject suffers from heart failure. [1005] 59. Use of at least three biomarkers as set forth in any one of embodiments 1 to 42 in a sample of a subject for diagnosing heart failure or for the preparation of a pharmaceutical and/or diagnostic composition for diagnosing heart failure. [1006] 60. The method of any one of embodiments 2 to 57, the device of embodiment 58 or the use of embodiment 59, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [1007] 61. A composition comprising the at least three biomarkers as set forth in any one of embodiments 1 to 42. [1008] 62. A calibration solution comprising the composition of embodiment 61. [1009] 63. A calibration sample comprising the composition of embodiment 61 and delipidized serum or delipidized plasma.

[1010] Items for Panel 1

[1011] In a preferred embodiment, the amounts of the biomarkers in panel 1 are determined. The heart failure to be diagnosed may be classified as NYHA class I or II. Preferably, the determination is carried out for the diagnosis of HFrEF, in particular for the diagnosis of HFrEF with a left ventricular ejection fraction of lower than 50% but larger than 35%. Further, it is envisaged that the subject does not show symptoms of heart failure.

[1012] In addition, it is envisaged to determine the amount of NT-proBNP in addition of the at least three biomarkers. Preferably, a correction for confounders (in particular age, BMI and gender) is not carried out.

[1013] With respect to panel 1, the following items are preferred. The definitions and explanations, given in the specification above, preferably, apply mutatis mutandis to following preferred items of the present invention. [1014] 1. A method for diagnosing heart failure comprising the steps of: [1015] a. determining in a sample of a subject the amounts of the SM23, OSS2 and PC4, and [1016] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed [1017] 2. The method of item 1, wherein the subject does not show symptoms of heart failure. [1018] 3. The method of item 1, wherein the subject shows symptoms of heart failure. [1019] 4. The method of any one of item 1 to 3, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF), in particular wherein said HFrEF is asymptomatic HFrEF. [1020] 5. The method of item 4, wherein said heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF) is dilatative cardiomyopathy (DCMP), in particular wherein said DCMP is asymptomatic DCMP. [1021] 6. The method of item 4, wherein said heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF) is ischemic cardiomyopathy (ICMP), in particular wherein said ICMP is asymptomatic ICMP. [1022] 7. The method of any one of items 2 to 6, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [1023] 8. The method of any one of items 1 to 7, wherein the subject is a human subject. [1024] 9. The method of any one of items to 1 to 8, wherein the sample is blood, serum or plasma. [1025] 10. The method of any one of items 1 to 9, wherein the method does not comprise the determination of NT-proBNP or BNP. [1026] 11. The method of any one of items 1 to 9, further comprising determining the amount of NT-proBNP or BNP in a sample/the sample from the subject and comparing the amount of NT-proBNP or BNP to a reference. [1027] 12. The method of any one of items 1 to 11, further comprising carrying out a correction for confounders. [1028] 13. The method of item 12, wherein the confounders are age, BMI and/or gender, in particular age, BMI and gender. [1029] 14. The method of item 1 to 11, wherein no correction for confounders is carried out. [1030] 15. The method of item 14, wherein no correction for confounders age, BMI and gender is carried out. [1031] 16. The method of any one of items 1 to 15, wherein in step b) a score is calculated based on the determined amounts of the at least three biomarkers, wherein the reference is a reference score, and wherein the score is compared to the reference score. [1032] 17. The method of any one of items 1 to 16, wherein the reference or the reference score is from a subject or group of subjects known not to suffer from heart failure. [1033] 18. The method of item 17, wherein a value for each of the at least three biomarkers, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the absence of heart failure. [1034] 19. The method of any one of items 1 to 16, wherein the reference or the reference score is from a subject or group of subjects known to suffer from heart failure. [1035] 20. The method of any one of item 19, wherein a value for each of the at least three biomarkers found, or a score in the test sample being essentially identical as compared to the reference or reference score is indicative for the presence of the heart failure. [1036] 21. The method of any one of items 1 to 20, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS). [1037] 22. The method of item 21, wherein the mass spectrometry is LC-MS, in particular LCMS/MS, or HPLC-MS, in particular HPLC-MS/MS. [1038] 23. The method of items 22 and 23, wherein the mass spectrometry comprises an ionization step in which the at least three biomarkers are ionized. [1039] 24. The method of item 24, wherein the ionization step is carried out by electrospray ionization, in particular by positive ion mode electrospray ionization. [1040] 25. The method of any one of items 1 to 24, wherein the subject is overweight. [1041] 26. The method of any one of items 2 to 33 or 63, wherein the subject is younger than 61 years of age, and has a body mass index of more than 26.8 kg/m.sup.2. [1042] 27. The method of any one of items 1 to 24, wherein the subject is older than 54 years of age. [1043] 28. The method of any one of items 1 to 24, wherein the subject is a female subject, older than 54 years of age, and has a body mass index of less than 25.0 kg/m.sup.2. [1044] 29. The method of items 1 to 28, wherein OSS2 is TAG(C18:1, C18:0, C18:0). [1045] 30. The method of items 1 to 29, wherein Phosphatidylcholine (C16:0 C18:2). [1046] 31. The method of any one of items 1 to 30, wherein SM23 is Sphingomyelin(d18:1/23:1), ii) Sphingomyelin(d18:2/23:0), iii) Sphingomyelin(d17:1/24:1), or iv) a combination of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0) and Sphingomyelin(d17:1/24:1). [1047] 32. The method of any one of items 31, wherein the amount of SM23 is determined by i) determining the amount of the amount of Sphingomyelin(d18:1/23:1), the amount of Sphingomyelin (d17:1/24:1), or, in particular, the combined amount of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1). [1048] 33. The method of any one of items 1 to 33, wherein the amount of SM23 is determined by determining the combined amount of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1). [1049] 34. A method for diagnosing HFrEF comprising the steps of: [1050] a. determining in a blood, serum or plasma sample of a subject who does not show symptoms of heart failure the amounts of the biomarkers SM23, OSS2 and PC4 and optionally the amount of NT-proBNP, and [1051] b. comparing the amounts as determined in step a. to a reference, whereby heart failure is to be diagnosed. [1052] 35. A method for diagnosing HFrEF comprising the steps of: [1053] a) determining in a blood, serum or plasma sample of a subject who does not show symptoms of heart failure the amounts of the biomarkers SM23, OSS2 and PC4, and optionally the amount of BNP or NT-proBNP; and [1054] b1) calculating a score based on the determined amounts of the biomarkers and, if determined, on the amount of BNP or NT-proBNP, and [1055] b2) comparing the, thus, calculated score to a reference score, whereby heart failure is to be diagnosed. [1056] 36. The method of items 34 or 35, wherein no correction for confounders, in particular no correction for the confounders age, BMI and gender is carried out. [1057] 37. The method of any of items 34 to 36, wherein the subject is a subject as defined in items 25 to 28. [1058] 38. The method of any one of items 34 to 37, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [1059] 39. A diagnostic device for carrying out the method according to any one of items 1 to 38, comprising: [1060] a) an analysing unit comprising at least one detector for the biomarkers SM23, OSS2 and PC4, wherein said analyzing unit is adapted for determining the amounts of the said biomarkers detected by the at least one detector, and, operatively linked thereto; [1061] b) an evaluation unit comprising a computer comprising tangibly embedded a computer program code for carrying out a comparison of the determined amounts of the biomarkers, and reference amounts and a data base comprising said reference amounts for the said biomarkers, whereby it will be diagnosed whether a subject suffers from heart failure. [1062] 40. Use of SM23, OSS2 and PC4 in a sample of a subject for diagnosing heart failure or for the preparation of a pharmaceutical and/or diagnostic composition for diagnosing heart failure. [1063] 41. Use according to item 40, wherein the heart failure is a heart failure as set forth in any one of items 4 to 7. [1064] 42. Use according to item 40 or 41, wherein the subject is a subject as defined in any one of items 25 to 28. [1065] 43. Use according to any one of items 40 to 42, wherein the subject does not show symptoms of heart failure. [1066] 44. A composition comprising PC4, OSS2 and SM 27, or comprising PC4, OSS2 and SM23. [1067] 45. A calibration solution comprising the composition of embodiment 44. [1068] 46. A calibration sample comprising the composition of embodiment 44 and delipidized serum or delipidized plasma.

[1069] Further preferred embodiments for panel 1: [1070] 1. A diagnostic test for diagnosing heart failure in a subject comprising: [1071] a. one or more prepared blood, serum or plasma samples obtained from a human subject, wherein the prepared sample was processed for the detection of lipid biomarkers; [1072] b. one or more analysing units for detecting the biomarkers of at least one biomarker panel,

[1073] wherein the biomarker panel comprises detecting the amounts of at least one triacylglyceride, at least one phosphatidylcholine, and at least one sphingomyelin;

[1074] wherein the at least one sphingomyelin comprises SM23 and the at least one triacylglycerides comprises OSS2 and the at least one phosphatidylcholine comprises PC4; and

[1075] further wherein SM23 comprises the sum amounts of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1); [1076] c. one or more databases containing patient medical record information, wherein the medical record information comprises the subject's BNP test results, and further wherein the BNP test result comprises the amount of at least one of the following brain natriuretic peptide (BNP), amino-terminal pro-brain natriuretic peptide (NT-proBNP), ANP (atrial natriuretic peptide) or NT-proANP (N-terminus of the prohormone brain natriuretic peptide) in a blood, serum, or plasma sample from a subject; [1077] d. an evaluation unit comprising a computer comprising a program for [1078] i. calculating a score value for a subject based on the amounts of (b) and (c); and [1079] ii. comparing that score value of step (i) to a reference value, whereby heart failure in a subject is to be diagnosed. [1080] 2. The diagnostic test of embodiment 1, wherein the diagnostic test is used to diagnose heart failure with reduced left ventricular ejection fraction (HFrEF) in a subject. [1081] 3. The diagnostic test of embodiment 2, wherein HFrEF is DCMP or ICMP. [1082] 4. The diagnostic test of embodiment 2, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [1083] 5. The diagnostic test of embodiment 1, wherein the amounts of the biomarkers in the at least one biomarker panel are determined by mass spectrometry (MS). [1084] 6. The diagnostic test of embodiment 1, wherein the test is used on a subject who does not show symptoms of heart failure. [1085] 7. The diagnostic test of embodiment 1, wherein the test is used on a subject who is overweight. [1086] 8. The diagnostic test of embodiment 1, wherein the test is used on a subject who is older than 54 years of age. [1087] 9. The diagnostic test of embodiment 1, wherein the test is used on a subject who is a female subject, older than 54 years of age, and has a body mass index of less than 25.0 kg/m.sup.2. [1088] 10. The diagnostic test of embodiment 1, wherein the test is used on a subject who is younger than 61 years of age, and has a body mass index of more than 26.8 kg/m.sup.2. [1089] 11. A method for diagnosing heart failure comprising the steps of: [1090] a. obtaining at least one blood, plasma, or serum sample from a human subject [1091] b. processing the at least one sample for HPLC-MS/MS analysis, wherein the at least one sample is combined with an extraction solvent to create a combined sample, wherein the extraction solvent separates the lipids in the combined sample from the proteins in the combined sample, and further wherein the combined sample undergoes centrifugation to remove the proteins from the sample and to create the processed sample for HPLC-MS/MS analysis; [1092] c. using HPLC-MS/MS analysis to determine in the at least one processed sample of the subject the amounts of biomarkers in at least one biomarker panel, wherein the at least one biomarker panel comprises at least three biomarkers and further wherein the at least three biomarkers comprise: [1093] i. at least one triacylglyceride, at least one phosphatidylcholine, and at least one sphingomyelin, wherein the at least one sphingomyelin comprises SM23 and the at least one triacylglycerides comprises OSS2 and the at least one phosphatidylcholine biomarker comprises PC4 and further wherein SM23 comprises the sum amounts of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1); [1094] d. obtaining the subject's BNP test results by using one or more of the following methods: [1095] i. determining the amount of one or more of the following proteins in the sample: NT-proBNP, BNP, ANP, or NT-proANP wherein the amount of the one or more proteins is determined using an antibody test, and/or [1096] ii. determining the amount of one or more of the following proteins in the sample: NT-proBNP, BNP, ANP, or NT-proANP wherein the amount of the one or more proteins is derived from the subject's medical record and/or stored in an electronic database; [1097] e. calculating a score value for a subject based on the amounts determined in steps (c) and (d); and [1098] f. comparing that score value of step (e) to a reference value, whereby heart failure in a subject is to be diagnosed. [1099] 12. The method of embodiment 11, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF). [1100] 13. The method of any of embodiment 12, wherein HFrEF is DCMP or ICMP. [1101] 14. The method of embodiment 12, wherein the HFrEF is heart failure with a left ventricular ejection fraction of lower than 50% but larger than 35%. [1102] 15. The method of any one of embodiment 11, wherein the sample is a plasma sample. [1103] 16. The method of embodiment 11, wherein the amounts of the at least three biomarkers are determined by mass spectrometry (MS). [1104] 17. The method of embodiment 11, wherein the subject does not show symptoms of heart failure. [1105] 18. The method of embodiment 11, wherein the subject is overweight. [1106] 19. The method of embodiment 11, wherein the subject is older than 54 years of age. [1107] 20. The method of embodiment 11, wherein the subject is a female subject, older than 54 years of age, and has a body mass index of less than 25.0 kg/m.sup.2. [1108] 21. The method of embodiment 11, wherein the subject is younger than 61 years of age, and has a body mass index of more than 26.8 kg/m.sup.2. [1109] 22. The method of embodiment 11, wherein the reference is a commercially available lipid standard reference. [1110] 23. A method of diagnosing asymptomatic and/or early stage HFrEF in a human subject comprising: [1111] a. obtaining at least one plasma sample from a patient; [1112] b. processing the at least one sample for HPLC-MS/MS analysis, wherein the at least one sample is combined with an extraction solvent to create a combined sample, wherein the extraction solvent separates the lipids in the combined sample from the proteins in the combined sample, and further wherein the combined sample undergoes centrifugation to remove the proteins from the sample and to create the processed sample for HPLC-MS/MS analysis; [1113] c. using a biomarker panel and an LC-MS/MS test to determine the amounts of at least three biomarkers wherein the at least three biomarkers comprise: [1114] i. at least one triacylglyceride, at least one phosphatidylcholine, and at least one sphingomyelin, wherein the at least one sphingomyelin comprises SM23 and the at least one triacylglycerides comprises OSS2 and the at least one phosphatidylcholine biomarker comprises PC4;

[1115] and further wherein SM23 comprises the sum amounts of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1); [1116] d. obtaining the amount of NT-proBNP protein found in a subject wherein the amount of the protein is obtained by one or more of the following methods: [1117] i. determining the amount of NT-proBNP in the sample taken from the subject wherein the amount of the one or more proteins is determined using an antibody test, and/or [1118] ii. determining the amount of NT-proBNP wherein the amount of the protein is derived from the subject's medical record and/or stored in an electronic database; [1119] e. calculating a score value for a subject based on the amounts determined in steps (c) and (d); and [1120] f. comparing that score value of step (e) to a reference value, whereby asymptomatic and/or early stage HFrEF in a subject is to be diagnosed. [1121] 24. The method of embodiment 23, wherein the reference value is a cut-off value determined from one or more subjects known to suffer from heart failure and from one or more subjects known not to suffer from heart failure. [1122] 25. A method for diagnosing heart failure in a patient currently undergoing therapy for heart failure comprising the steps of: [1123] a. obtaining at least one blood, plasma, or serum sample from a human subject currently undergoing therapy for heart failure; [1124] b. processing the at least one sample for HPLC-MS/MS analysis, wherein the at least one sample is combined with an extraction solvent to create a combined sample, wherein the extraction solvent separates the lipids in the combined sample from the proteins in the combined sample, and further wherein the combined sample undergoes centrifugation to remove the proteins from the sample and to create the processed sample for HPLC-MS/MS analysis; [1125] c. determining in the at least one processed sample of a subject the amounts of biomarkers in at least one biomarker panel, wherein the at least one biomarker panel comprises at least three biomarkers and further wherein the at least three biomarkers comprise: [1126] i. at least one triacylglyceride, at least one phosphatidylcholine, and at least one sphingomyelin, wherein the at least one sphingomyelin comprises SM23 and the at least one triacylglycerides comprises OSS2 and the at least one phosphatidylcholine biomarker comprises PC4 and further wherein SM23 comprises the sum amounts of Sphingomyelin(d18:1/23:1), Sphingomyelin(d18:2/23:0), and Sphingomyelin(d17:1/24:1); [1127] d. obtaining the subject's BNP test results by using one or more of the following methods: [1128] i. determining the amount of one or more of the following proteins in the sample: NT-proBNP, BNP, ANP, or NT-proANP wherein the amount of the one or more proteins is determined using an antibody test, and/or [1129] ii. determining the amount of one or more of the following proteins in the sample: NT-proBNP, BNP, ANP, or NT-proANP wherein the amount of the one or more proteins is derived from the subject's medical record and/or stored in an electronic database; [1130] e. calculating a score value for a subject based on the amounts determined in steps (c) and (d); and [1131] f. comparing that score value of step (e) to a reference value, whereby heart failure in a subject is to be diagnosed; and [1132] g. determining whether the current heart failure therapy is effective for the subject based on the diagnosis obtained in step (f).

[1133] The Figures show:

[1134] FIG. 1: Flow Diagram of LCMS method applied in the studies underlying the present invention EXAMPLES

[1135] FIG. 2: Effect of medication with diuretics and/or statins on the prediction probabilities of HF patients calculated using Panel 1 including NT-proBNP (A) or on the levels of NT-proBNP (B). Values on the ordinate were transformed using the logit function (A) or were log-transformed (B) to achieve normal distribution. Case numbers are indicated below the boxes.

[1136] The following Examples shall illustrate the invention. They shall, however, not be construed as limiting the scope of the invention.

Example 1: Study Design for the Diagnosis of CHF Subtypes with Reduced Ejection Fraction (HFrEF) Composed of DCMP (Dilated Cardiomyopathy) and ICMP (Ischemic Cardiomyopathy) and Heart Failure with Preserved Ejection Fraction (HFpEF)

[1137] A multicentric study with three clinical centers and in total 843 subjects was conducted. The study comprised 194 male and female DCMP, 183 male and female ICMP and 210 male and female HFpEF patients as well as 256 male and female healthy controls in an age range from 35-75 and a BMI range from 20-35 kg/m.sup.2. NYHA (New York Heart Association) scores of the patients ranged from I to III. Patients and controls were matched for age, gender and BMI. For all patients and controls, a blood sample was collected. Plasma was prepared by centrifugation, and samples were stored at −80° C. until measurements were performed.

[1138] Three subgroups of CHF (DCMP, ICMP and HFpEF) were defined on the basis of echocardiography and hemodynamic criteria: [1139] a) Subgroup DCMP: is hemodynamically defined as a systolic pump failure with cardic dilation (echocardiographic enhancement of the left ventricular end diastolic diameter>55 mm and a restricted left ventricular ejection fraction (LVEF) of <50%) without the presence of >50% stenosis [1140] b) Subgroup ICMP: is hemodynamically defined as systolic pump failure due to a coronary insufficiency (>50% coronary stenosis and LVEF of <50%) [1141] c) Subgroup heart failure with preserved ejection fraction (HFpEF): concentric heart hypertrophy (echocardiography: cardiac septum>12 mm and posterior myocardial wall>11 mm) and with a diastolic heart failure (non or mildly impaired pump function with LVEF of ≧50%) without a cardiac septum thickness>18 mm.

[1142] NYHA IV patients were excluded as well as patients suffering from apoplex, patients who had myocardial infarction within the last 4 months before testing, patients with altered medications within the last 4 weeks before testing as well as patients who suffered from acute or chronic inflammatory diseases and malignant tumours.

Example 2: Determination of Metabolites

[1143] Significantly altered metabolites in CHF vs healthy respectively HFrEF vs healthy patients have been identified. Metabolites have been selected according to their accessibility with a one-shot LC-MS/MS measurement with a simplified preanalytical process (see analytical method description, below).

[1144] In an iterative process in which in-silico performance of metabolite combinations and assay optimization steps have been performed, an LC-MS/MS method for the analysis of CHF was established. This method is capable to analyze all of the biomarkers as listed in Table 1, where the biomarkers are characterized by the combination of retention time and multiple reaction monitoring (MRM) transitions, and further potential lipid metabolites.

[1145] Each biomarker may contain more than one analyte, whereby the analytes contained in the same biomarker have the same total number of carbon atoms and the same total number of double bonds.

Example 3: Analytical Method

[1146] Human plasma samples were prepared and subjected to HPLC-MS/MS analysis as described in the following:

[1147] 10 μl plasma were mixed with 1500 μl extraction solvent containing methanol/dichloromethane (in a ratio of 2:1, v/v) and 10 μl internal standard mixture in a 2 ml safelock microcentrifuge tube (Eppendorf, Germany). The internal standard solution consisted of 25.65 μg/ml lysophosphatidylcholine (LPC) C17:0, 0.386 μg/ml ceramide (Cer) d18:1117:0, 41.28 μg/ml phosphatidylcholine (PC) C19:0 C19:0 (as PC5 listed in Table 8), 22.51 μg/ml cholesteryl heptadecanoate (CE C17:0), and 5.26 μg/ml glyceryl triheptadecanoate (MMM) in extraction solvent. Lipid standards were purchased from Avanti Polar Lipids, CA, U.S.A., Larodan Fine Chemicals, Sweden, Sigma-Aldrich, MO, U.S.A., or Tokyo Chemical Industry, Japan.

[1148] Ultrapure water (Milli-Q water system, Millipore) and analytical grade chemicals were used for extraction, dilution or as LC solvents. Quality control and reference sample were prepared from commercially available human plasma (RECIPE Chemicals+Instruments GmbH). Delipidized plasma (Plasma, Human, Defibrinated, Delipidized, 2× Charcoal treated, Highly Purified; USBio) was used for the preparation of calibrators and blanks.

[1149] After thoroughly mixing at 20° C. for 5 min, the precipitated proteins were removed by centrifugation for 10 min. An aliquot of the liquid supernatant was transferred to an appropriate glass vial and stored at −20° C. until analysis by LC-MS/MS. This sample preparation method uses protein precipitation as the only purification step to capture all lipids of interest (PC, SM, Cer, CE, TAG), so that a more comprehensive and complex extraction of lipids (as described e.g. by Folch, or Bligh & Dyer) was not necessary. The HPLC-MS/MS systems consisted of an Agilent 1100 LC system (Agilent Technologies, Waldbronn, Germany) coupled to an ABSciex™ API 4000 triple quadrupole mass spectrometer (ABSCIEX, Toronto, Canada). HPLC analysis was performed at 55° C. on commercially available reversed phase separation columns with C18 stationary phases (Ascentis® Express C18 column (5 cm×2.1 mm, 2.7 μm, Phenomenex, Germany).

[1150] Up to 5 μL of the crude extract were injected and separated by gradient elution using a mixture of solvents consisting of methanol, water, formic acid, 2-propanol and 2-methoxy-2-methylpropan: [1151] Solvent A: 400 g methanol, 400 g water, 1 g formic acid [1152] Solvent B: 400 g tert-butyl methyl ether (tBME), 200 g 2-propanol, 100 g methanol, 1 g formic acid

[1153] Details of the elution gradient are given in Table 7.

[1154] Mass spectrometry was carried out by electrospray ionization in positive ion mode using multiple-reaction-monitoring (MRM). The source parameters were: nebulizer gas, 50; heater gas, 60; curtain gas, 25; CAD gas, 4; ion spray voltage, 5500 V; temperature, 400° C.; pause between mass ranges, 5 ms; resolution Q1 and Q3, unit. The MRM settings are given in Table 8. To enhance the ionization efficiency in the electrospray process for some lipids (CE, TAG), ammonium formate buffer dissolved in methanol (Solvent C: 200 g methanol, 30 g 0.1M ammonium formate solution in water) was added post column during the elution time of CE and TAG (see FIG. 1). The method is intended to be compatible with e.g. the ABSciex™ 3200MD benchtop LCMS/MS system.

[1155] Furthermore, as some highly abundant lipids are out of the dynamic range of the MS detector, MS parameters—like collision energy—were changed for said highly abundant lipids to get lower signal intensities due to lower fragmentation efficiencies.

[1156] Using electrospray isonization (ESI), PC 8 and several SMs with equal numbers of carbons and double bonds were detected together (as to say without separation of said species), since these isobaric species were not separated chromatographically. Chromatography was required to detect the low-concentrated ceramides and to separate phosphatidiyl cholines and sphingomyelins from each other, because the C13-impact of PC to SM or SM to PC disturbs the metabolite performance (in the sense of measurability).

[1157] Quantitative results for all compounds were achieved by using the corresponding reference compounds, except for sphingomyelines, for which no commercial reference compounds were available. Sphingomyelines were quantified by adding commercially available sphingomyeline standards with a different chain length than the target metabolites assuming that the detector response is the same. The proof of concept was carried out on SM(d18:1/16:0), SM(d18:1/24:1) and PC C18:0 C18:2. The PC C18:0 C18:2 was included to show that the positive ion formation on the phosphocholine side via electrospray is not only independent on the fatty acid composition, but also independent of the phosphocholine species (sphingosine or glycerol backbone). A relative standard deviation (% RSD) of 20 could be achieved by intercalibrating the standards with each other.

[1158] The calibration solutions were prepared in delipidized plasma (commercially available) to simulate a matrix as close as possible to real plasma.

[1159] Positive and negative controls were prepared by lyophilization different amounts of commercially available plasma to meet the positive and negative cutoffs for all down regulated metabolites. For the triacylglycerides (TAG) the corresponding TAG was added into the plasma before the lyophilisation process but avoiding the protein to precipitate. The lyophilisated samples were stored in the freezer till sample preparation.

[1160] Quality control samples were prepared by extracting commercially available plasma with extraction solvent. Several aliquots of these extracts were stored in the freezer and used for the daily quality control of the instrument performance and sample preparation.

[1161] Plasma samples were analyzed in randomized analytical sequence design. Following comprehensive analytical validation steps, the resulting peak areas were divided by the peak areas of an internal standard with similar analytical behavior to reduce analytical variation. The resulting ratios were log 10-transformed to achieve normal distribution.

TABLE-US-00001 TABLE 1 Biomarkers used for panel composition and their analytical characteristics. Transition Retention (parent/fragment) Time Biomarker Analyte 1 Analyte 2 Analyte 3 Group (Da) (min) Cer(d16:1/24:0) Cer(d16:1/24:0) Ceramide 622.6/236.2 2.83 Cer(d17:1/24:0) Cer(d17:1/24:0) Ceramide 636.6/250.2 2.95 Cer(d18:1/23:0) Cer(d18:1/23:0) Ceramide 636.5/264.2 2.95 Cer(d18:1/24:1) Cer(d18:1/24:1) Ceramide 648.6/264.2 2.83 Cer(d18:2/24:0) Cer(d18:2/24:0) Ceramide 648.6/262.2 2.9 CE C18:0 CE C18:0 Cholester- 670.7/369.3 4.72 ylester CE C18:2 CE C18:2 Cholester- 666.7/369.3 4.47 ylester Glutamic acid Glutamic acid amino acid 148.0/84.1 0.23 PC4 PC (C16:0 C18:2) Phosphati- 758.6/184.1 1.72 dylcholine PC8 PC (C18:0 C18:2) PC (C18:1 C18:1) Phosphati- 786.6/184.1 1.88 dylcholine SM10 SM(d18:1/18:0) SM(d16:1/20:0) Sphingo- 731.5/184.1 1.7 myeline SM18 SM(d18:1/21:0) SM(d16:1/23:0) SM(d17:1/22:0) Sphingo- 773.5/184.1 1.97 myeline SM2 SM(d18:1/14:0) SM(d16:1/16:0) Sphingo- 675.5/184.1 1.47 myeline SM21 SM(d17:1/23:0) SM(d18:1/22:0) SM(d16:1/24:0) Sphingo- 787.5/184.1 2.05 myeline SM23 SM(d18:1/23:1) SM(d18:2/23:0) SM(d17:1/24:1) Sphingo- 799.5/184.1 2.02 myeline SM24 SM(d18:1/23:0) SM(d17:1/24:0) Sphingo- 801.5/184.1 2.16 myeline SM28 SM(d18:1/24:0) Sphingo- 815.5/184.1 2.27 myeline SM29 SM(d18:2/17:0) Sphingo- 715.5/184.1 1.57 myeline SM3 SM(d17:1/16:0) Sphingo- 689.5/184.1 1.52 myeline SM5 SM(d18:1/16:0) SM(d16:1/18:0) Sphingo- 703.5/184.1 1.57 myeline SM8 SM(d18:2/18:1) Sphingo- 727.5/184.1 1.55 myeline SM9 SM(d18:1/18:1) SM(d18:2/18:0) Sphingo- 729.5/184.1 1.62 myeline OSS2 TAG C18:1 C18:0 Triacyl- 906.9/605.4 4.87 C18:0 glyceride PPO1 TAG C16:0 C16:0 Triacyl- 850.8/577.5 4.64 C18:1 glyceride PPP TAG C16:0 C16:0 Triacyl- 824.8/551.5 4.61 C16:0 glyceride SOP2 TAG C18:0 C18:1 Triacyl- 878.9/577.6 4.76 C16:0 glyceride SPP1 TAG C18:0 C16:0 Triacyl- 852.9/579.6 4.74 C16:0 glyceride SSP2 TAG C18:0 C18:0 Triacyl- 880.9/579.6 4.85 C16:0 glyceride SSS TAG C18:0 C18:0 Triacyl- 908.9/607.6 4.96 C18:0 glyceride

Example 4: Data Analysis and Statistical Evaluation

[1162] For each biomarker listed in Table 1, the direction of change in CHF patients relative to healthy control subjects was calculated by ANOVA (see Tables 1A and 1B). The direction ‘Up’ means that the levels of the biomarker are higher in CHF patients than in healthy control subjects, the direction ‘Down’ means that the levels of the biomarker are lower in CHF patients than in healthy control subjects. The direction of change was found to be the same for all CHF patients compared to healthy control subjects taken together [ANOVA model: CHF+CENTER+(GENDER+AGE+BMI)̂2], for HFpEF patients compared to healthy control subjects, and for HFrEF patients compared to healthy control subjects [CHF_SUBGROUP+CENTER+(GENDER+AGE+BMI)̂2].

TABLE-US-00002 TABLE 1A Results of the ANOVA analysis as described above regarding the different biomarkers from Table 1. CHF_ALL HFpEF HFrEF p < p- p < p- p < p- Biomarker Direction 0.05 Ratio Value Direction 0.05 Ratio Value Direction 0.05 Ratio Value Cer(d16:1/24:0) Down Yes 0.76 3.08E−09 Down Yes 0.84 1.74E−03 Down Yes 0.72 2.72E−11 Cer(d17:1/24:0) Down Yes 0.78 1.88E−09 Down Yes 0.82 7.38E−05 Down Yes 0.76 4.17E−10 Cer(d18:1/23:0) Down Yes 0.86 2.22E−06 Down Yes 0.87 1.62E−04 Down Yes 0.86 6.23E−06 Cer(d18:1/24:1) Down No 0.98 5.77E−01 Down No 0.97 4.07E−01 Down No 0.99 7.62E−01 Cer(d18:2/24:0) Down Yes 0.86 4.78E−05 Down Yes 0.90 1.24E−02 Down Yes 0.85 1.53E−05 CE C18:0 Down No 0.94 1.55E−01 Down No 0.99 8.34E−01 Down No 0.92 5.65E−02 CE C18:2 Down Yes 0.87 1.21E−13 Down Yes 0.92 1.31E−04 Down Yes 0.85 2.72E−17 Glutamic acid Down No 0.93 1.31E−01 Down Yes 0.89 3.62E−02 Down No 0.96 3.62E−01 OSS2 Up Yes 1.75 2.67E−11 Up Yes 1.54 2.03E−05 Up Yes 1.87 2.13E−12 PC4 Down Yes 0.90 1.31E−08 Down Yes 0.92 1.09E−04 Down Yes 0.89 5.37E−09 PC8 Down Yes 0.92 6.89E−05 Down Yes 0.93 4.44E−03 Down Yes 0.92 6.56E−05 PPO1 Up Yes 1.49 1.29E−07 Up Yes 1.35 1.16E−03 Up Yes 1.57 1.81E−08 PPP Up Yes 1.61 1.16E−06 Up Yes 1.46 1.39E−03 Up Yes 1.70 4.38E−07 SM10 Down Yes 0.95 2.18E−02 Down No 0.96 8.57E−02 Down Yes 0.95 2.44E−02 SM18 Down Yes 0.79 1.41E−18 Down Yes 0.84 8.68E−08 Down Yes 0.76 1.55E−21 SM2 Down Yes 0.81 3.77E−13 Down Yes 0.85 3.14E−06 Down Yes 0.79 1.83E−14 SM21 Down Yes 0.84 4.51E−15 Down Yes 0.89 1.22E−05 Down Yes 0.81 2.54E−18 SM23 Down Yes 0.83 2.44E−15 Down Yes 0.88 1.70E−06 Down Yes 0.81 1.07E−17 SM24 Down Yes 0.81 2.42E−17 Down Yes 0.86 5.47E−07 Down Yes 0.78 1.92E−20 SM28 Down Yes 0.83 1.22E−13 Down Yes 0.90 2.92E−04 Down Yes 0.79 8.08E−18 SM29 Down Yes 0.86 4.18E−07 Down Yes 0.88 3.22E−04 Down Yes 0.85 3.49E−07 SM3 Down Yes 0.81 4.76E−14 Down Yes 0.83 8.12E−08 Down Yes 0.79 2.51E−14 SM5 Down Yes 0.89 1.94E−10 Down Yes 0.90 2.20E−06 Down Yes 0.88 3.05E−10 SM8 Down Yes 0.87 5.27E−07 Down Yes 0.89 2.50E−04 Down Yes 0.87 5.99E−07 SM9 Down No 0.97 2.21E−01 Down No 0.98 4.67E−01 Down No 0.97 1.89E−01 SOP2 Up Yes 1.70 7.93E−11 Up Yes 1.50 3.73E−05 Up Yes 1.81 6.21E−12 SPP1 Up Yes 1.75 3.54E−09 Up Yes 1.59 5.96E−05 Up Yes 1.85 1.32E−09 SSP2 Up Yes 1.64 2.51E−09 Up Yes 1.50 6.41E−05 Up Yes 1.73 7.37E−10 SSS Up Yes 1.27 1.11E−04 Up Yes 1.22 1.06E−02 Up Yes 1.31 6.26E−05

TABLE-US-00003 TABLE 1B Results of the ANOVA analysis for CHF subgroups ICMP and DCMP as described above regarding the different biomarkers from Table 1. Only the biomarkers from Panel 1 in Table 2 are listed. ICMP DCMP p < p- p < p- Biomarker Direction 0.05 Ratio Value Direction 0.05 Ratio Value OSS2 Up Yes 1.77 5.01E−08 Up Yes 1.96 2.85E−11 PC4 Down Yes 0.86 1.52E−10 Down Yes 0.92 9.52E−05 SM23 Down Yes 0.78 6.64E−19 Down Yes 0.84 3.67E−10

[1163] The data of the study described in Example 1 were utilized for the evaluation of the diagnostic power for the classification of CHF subgroups compared with controls in combination with the peptide NT-proBNP. Metabolite data were corrected for confounding factors or uncorrected metabolite data were used. The ANOVA model for correction for confounders comprised the factors age, BMI, gender and CHF subgroup (ANOVA model: CHF_SUBGROUP+(GENDER+AGE+BMI)̂2; correction factors: GENDER, AGE and BMI). CHF patients were subdivided based on CHF subtype [HFpEF, DCMP, ICMP, or alternatively the joined DCMP+ICMP group named HFrEF (heart failure with reduced ejection fraction) and a measure for the severity of the disease. Two different measures for the severity of the disease were used: NYHA class and LVEF. To this end, CHF patients were subdivided into those having no or only mild symptoms (NYHA class I and early stages of NYHA class II; sometimes referred to as ‘asymptomatic’) and those having more severe symptoms (NYHA classes II and III, sometimes referred to as ‘symptomatic’). Alternatively, CHF patient were subdivided into those with severely reduced LVEF (LVEF<35%) and those with mildly reduced or non-reduced LVEV (LVEF≧35). The latter subgroup comprises HFrEF patient with 35%≦LVEF<50% as well as all HFpEF patients (LVEF≧50%).

[1164] A total set of about 850 samples was split into a training or identification set (also referred to as “ID Data” set; about 66% of the samples) and a testing set (also referred to as “VD Data” set; about 33% of the samples). The split was done group-wise, with groups being defined by the combination of gender, type of heart failure and NYHA levels.

[1165] The total sample numbers and compositions were as follows:

TABLE-US-00004 ID Data Set: VD Data Set: CHF: 374 samples CHF: 205 samples CHF, NYHA I-I/II: 169 samples CHF, NYHA I-I/II: 93 samples CHF, NYHA II-III: 205 samples CHF, NYHA II-III: 112 samples CHF, LVEF ≧ 35%: 275 samples* CHF, LVEF ≧ 35: 145 samples HFpEF: 134 samples HFpEF: 74 samples ICMP: 118 samples ICMP: 65 samples ICMP, NYHA I-I/II: 44 samples ICMP, NYHA I-I/II: 24 samples ICMP, NYHA II-III: 74 samples ICMP, NYHA II-III: 41 samples DCMP: 122 samples DCMP: 66 samples DCMP, NYHA I-I/II: 46 samples DCMP, NYHA I-I/II: 25 samples DCMP, NYHA II-III: 76 samples DCMP, NYHA II-III: 41 samples HFrEF: 240 samples HFrEF: 131 samples HFrEF, NYHA I-I/II: 90 samples HFrEF, NYHA I-I/II: 49 samples HFrEF, NYHA II-III: 150 samples HFrEF, NYHA II-III: 82 samples HFrEF, 35% ≦ LVEF < 50%: 141 samples* HFrEF, 35% ≦ LVEF < 50%: 71 samples HFrEF, LVEF < 35%: 98 samples* HFrEF, LVEF < 35%: 60 samples Controls: 167 samples Controls: 87 samples** *One CHF patient with missing LVEF measurement was not included in these subgroups **3 controls were subsequently excluded due to HF-related medication; re-analysis showed no significant changes with regard to the diagnostic performance of the biomarker combinations

Example 5

[1166] In Table 2 biomarker panels according to the present invention are listed. In column 1 the respective panel number is given, in column 2 the composition of each panel, in column 3 the number of non-proteinic biomarker is given, in column 4 the CHF subgroup, in column 5 it is indicated if the panel is a so-called “saturated panel” or not, in column 6 it is indicated whether NT-proBNP was determined in addition, in column 7 it is indicated whether an ANOVA correction for confounders age, BMI and gender have been performed, and in column 8 the AUC-value is given.

[1167] Prediction probabilities for each patient were calculated with a logistic regression model fitted using the elastic net algorithm as implemented in the R package glmnet (Zou, H. and Hastie, T., 2003: Regression shrinkage and selection via the elastic net, with applications to microarrays. Journal of the Royal Statistical Society: Series B, 67, 301-320; Friedman, J., Hastie, T., and Tibshirani, R, 2010: Regularization Paths for Generalized Linear Models via Coordinate Descent. J. Stat. Softw. 33). The fitting was performed on the data from the ID cohort. The L1 and the L2 penalties were given equal weight. Log-transformed peak area ratios were centered and scaled to unit variance before the analysis. The prediction probability was calculated using the formula

[00003] $p = \frac{1}{1 + e^{- (w_{0} + {.Math.}_{i = 1}^{n} .Math. w_{i} .Math. {\hat{x}}_{i})}},$

[1168] with the feature {circumflex over (x)}.sub.i, being

[00004] ${\hat{x}}_{i} = \frac{x_{i} - m_{i}}{s_{i}}$

[1169] wherein x.sub.i are the log-transformed peak area ratios (or concentrations, e.g. of NT-proBNP, if taken into account) and m.sub.i, s.sub.i are feature specific scaling factors and w.sub.i are the coefficients of the model [w.sub.0, intercept; w.sub.1, coefficient for NT-proBNP (where applicable); w.sub.2 . . . w.sub.n, coefficients for the features; n, number of lipid biomarkers in the panel, +BNP or NT-proBNP, if determined or taken into account].

[1170] The coefficients for Panel 1+NT-proBNP are: w.sub.0=0.7602899 (Intercept), w.sub.1=1.5745605 (NT-proBNP), w.sub.2=−0.7158906 (SM23), w.sub.3=0.6762354 (OSS2), w.sub.4=−0.4594183 (PC4), n=4. The respective scaling factors are m.sub.1=2.2023800, m.sub.2=−0.5379916, m.sub.3=−2.1316954, m.sub.4=0.8736775 and s.sub.1=0.6364517, s.sub.2=0.1159420, s.sub.3=0.3863649, s.sub.4=0.0834807. NT-proBNP was measured in the unit pg/ml.

[1171] A sample with a prediction probability larger than the cutoff of the respective panel is said to be tested positive, and a sample with a prediction probability smaller than or equal to the cutoff is said to be tested negative. The sensitivity is the fraction of HF patients in the respective subgroup that are tested positive, while the specificity is the fraction of healthy control subjects that are tested negative.

[1172] The cutoff values were first determined to maximize the Youden index for the detection of HFrEF. The resulting cutoff for Panel 1+NT-proBNP was defined to be 0. 587, for Panel 3 to be 0.522, and for Panel 4 to be 0.574, resulting in the sensitivities and specificities for Panels 1, 3, and 4 as shown in Table 6.

[1173] Alternatively, the cutoff values can be determined to achieve the same specificity for the detection of HFrEF in the ID dataset when using the biomarker panel as when using NT-proBNP alone. According to this requirement, the cutoff for Panel 1+NT-proBNP was alternatively defined to be 0.738. Using this alternative cutoff for Panel 1+NT-proBNP, the sensitivity is 61.0% for the detection of CHF, 80.2% for the detection of HFrEF, and 67.6% for the detection of HFrEF with only mildly reduced LVEF (35%≦LVEF<50%). The specificity of Panel 1+NT-proBNP using the alternative cutoff is 97.7%.

[1174] Prevalence of HF in the Medicare-eligible population of the US was 9-12% between 1994 and 2003, about half of which is affected by HFrEF [Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Drazner, M. H., Fonarow, G. C., Geraci, S. A., Horwich, T., Januzzi, J. L., Johnson, M. R., Kasper, E. K., Levy, W. C., Masoudi, F. A., McBride, P. E., McMurray, J. J. V., Mitchell, J. E., Peterson, P. N., Riegel, B., Sam, F., Stevenson, L. W., Tang, W. H. W., Tsai, E. J., Wilkoff, B. L., 2013. 2013 ACCF/AHA Guideline for the Management of Heart Failure. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 128, e240-e327; Curtis L H, Whellan D J, Hammill B G, et al, 2008. Incidence and prevalence of heart failure in elderly persons, 1994-2003. Arch Intern Med 168, 418-424. doi:10.1001/archinternmed.2007.80].

[1175] Assuming, based on the literature cited above, a prevalence of 10% for CHF and 5% for HFrEF, the resulting positive predictive value (PPV) is 74.7% for CHF and 64.7% for HFrEF. The resulting negative predictive value (NPV) is 95.8% for CHF and 98.9% for HFrEF, as shown in Table 6A. Principally, the diagnostic performance of NT-proBNP could be remarkably increased; e.g for the subgroups CHF and HFrEF, a Net Reclassification Index (NRI=Sensitivity [Test A]−Sensitivity [Test B]+Specificity [Test A]−Specificity [Test B]) of 6.4% and 8.8% was observed, respectively. The NRI for asymptomatic ICMP even reached 10.3%. Thus, the panels of the present invention especially improved diagnostic performance of HFrEF and/or asymptomatic forms of heart failure.

[1176] The term “saturated panel” preferably indicates that the addition of a further suitable cardiac marker from Table 1 to the respective panel does not result in a noticeable improvement of the AUC value.

Example 6: Validation of Performance in Testing Set

[1177] The performance of a combination of biomarkers identified in the training data when applied to the validation data was assessed by the Area Under the Curve (AUC) of a receiver operating curve, which was modelled with the binormal model.

[1178] The biomarker combinations/panels 103-199 (Table 2) are shown with their calculated performances in different CHF subgroups in the tables below.

Example 7: Influence of Medication on Performance in Testing Set

[1179] The effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitors and diuretics on the HF prediction probabilities for HFrEF patients calculated using Panel 1 including NT-proBNP is shown in FIG. 2. Since patients receiving diuretics have on average a lower LVEF than patients not receiving diuretics (not shown), the prediction probabilities were plotted separately for patients with mildly (35% LVEF 50%; top panel) or strongly reduced LVEF (LVEF<35%; bottom panel). HFrEF patients receiving neither diuretics nor statins have a slightly lower prediction probability than patients receiving either or both of these medications (four right-most columns in FIG. 2), resulting in a lower sensitivity in patients with mildly reduced LVEF which receive neither diuretics nor statins (35%≦LVEF≦50%; Table 9). The effect is less obvious when comparing the partially overlapping groups including all patients receiving statins or diuretics (Table 9; three left-most columns in FIG. 2)

Example 8: Influence of Clinical Parameters on Performance in the Whole Patient Cohort

[1180] The influence of clinical parameters on the performance of Panel 1 in comparison with NT-proBNP was assessed by investigating the characteristics of patients which are classified differently using either Panel 1 including NT-proBNP or NT-proBNP alone. In the whole patient cohort, 30 healthy controls were correctly classified as negative using Panel 1 including NT-proBNP, but wrongly classified as positive using NT-proBNP alone. These subjects were significantly older (median 62.5 years versus 53.5 years; p=0.0036 before and p<0.05 after FDR (False Discovery Rate) correction), had a significantly lower BMI (median 23.0 kg/m.sup.2 versus 24.8 kg/m.sup.2; p=0.0197 before and p<0.1 after FDR correction), and comprised a significantly higher proportion of females (24 out of 30 versus 107 out of 216; p=0.0033 before and p<0.05 after FDR correction) than the remaining 216 healthy controls in the cohort.

[1181] In the whole patient cohort, 27 HFrEF patients were correctly classified as positive using Panel 1 including NT-proBNP, but wrongly classified as negative using NT-proBNP alone. These subjects were significantly younger (median 55.0 years versus 61.0 years; p=0.0218 before and p<0.1 after FDR correction), had a significantly higher BMI (median 29.9 kg/m.sup.2 versus 26.8 kg/m.sup.2; p=0.0037 before and p<0.05 after FDR correction), had significantly lower high-sensitivity cardiac troponin T (hs-cTnT values; median 4.0 ng/l versus 7.0 ng/l; p=0.0238 before and p<0.1 after FDR correction), had a significantly larger LVEF (median 45.0% versus 35.0%; p=0.0003 before and p<0.01 after FDR correction), had a significantly lower left ventricular end-diastolic dimension (LVEDD; median 50.0 mm versus 55.0 mm; p=0.0020 before and p<0.05 after FDR correction), had a significantly higher septal wall thickness (13.0 mm versus 11.0 mm; p=0.0017 before and p<0.05 after FDR correction), had a significantly higher posterior wall thickness (12.0 mm versus 11.0 mm; p=0.0008 before and p<0.05 after FDR correction), and comprised a significantly higher proportion of patients suffering from Diabetes mellitus (11 out of 27 versus 68 out of 347; p=0.0189 before and p<0.1 after FDR correction) than the remaining 347 HFrEF patients in the cohort.

Example 9: Further Refinement of the Method of Example 3 for the Determination of Panel 1

[1182] An improved quantification of triglycerides, phosphatidylcholines, and sphingomyelins can be achieved using the calibration standards 1,3-distearoyl-2-oleoylglycerol (TAG C18:0 C18:1 C18:0; available from LGC Standards, U.K.), phosphatidylcholine C16:0 C18:2 (available from Avanti Polar Lipids, CA, U.S.A.), and sphingomyeline d18:1/24:1 (available from Avanti Polar Lipids, CA, U.S.A.). The calibration standards are dissolved in the range of 1 to 5 mg/ml solutions using methanol/dichloromethane (2:1, v/v) or dichloromethane as solvent.

[1183] The method is intended to be compatible with e.g. the ABSciex™ 3200 MD benchtop LC-MS/MS system.

Example 10: Further Biomarker Panel, Determined with a Combined/Targeted Lipid Analysis Approach

[1184] Using a combination of the method described herein with a method for targeted lipid analysis as e.g. disclosed in Example 1 of WO2013079594, which is suitable for detection of e.g the single metabolite species (also referred to as analytes) represented within the biomarkers from Table 1, or a method for targeted lipid analysis as e.g. disclosed in WO2013079594 alone, further metabolite panels with a good performance for the diagnosis of HFrEF can be identified. One such combination of 6 metabolites is shown in Table 10 (Panel No. 300).

[1185] When combined with the value for NT-proBNP, this panel (Panel No. 300) shows estimated AUC-values of up to 0.988 (Subgroup: HFrEF with LVEF<35%), 0.937 ((Subgroup: HFrEF with LVEF between 35% and 50%), 0.942 (Subgroup: HFrEF asymptomatic), 0.969 (Subgroup: HFrEF symptomatic), 0.959 (Subgroup: HFrEF total) 0.979 (ICMP total), or 0.936 (DCMP total).

Example 11: Analytical Method for the Absolute Quantification of SM23, PC 4, CE C18:2, and OSS2

[1186] Human plasma samples were prepared and subjected to HPLC-MS/MS analysis as described in the following:

[1187] 10 μl plasma were mixed with 1500 μl extraction solvent containing methanol/dichloromethane (in a ratio of 2:1, v/v) and 10 μl internal standard mixture in a 2 ml safelock microcentrifuge tube (Eppendorf, Germany). The internal standard contained 41.28 μg/ml phosphatidylcholine (PC) C19:0 C19:0 (as PC5 listed in Table 8 in extraction solvent. This Lipid standard was purchased from Avanti Polar Lipids, CA, U.S.A.

[1188] Ultrapure water (Milli-Q water system, Millipore) and analytical grade chemicals were used for extraction, dilution or as LC solvents. Quality control and reference sample were prepared from commercially available human plasma (RECIPE Chemicals+Instruments GmbH). Delipidized plasma (Plasma, Human, Defibrinated, Delipidized, 2× Charcoal treated, Highly Purified; USBio) was used for the preparation of calibrators and blanks.

[1189] After thoroughly mixing at 20° C. for 5 min, the precipitated proteins were removed by centrifugation for 10 min. An aliquot of the liquid supernatant was transferred to an appropriate glass vial and stored at −20° C. until analysis by LC-MS/MS. This sample preparation method uses protein precipitation as the only purification step to capture all lipids of interest (PC4, SM23, OSS2, CE C18:2). The HPLC-MS/MS systems consisted of an Agilent 1100 LC system (Agilent Technologies, Waldbronn, Germany) coupled to an ABSciex™ API 4000 triple quadrupole mass spectrometer (ABSCIEX, Toronto, Canada). HPLC analysis was performed at 55° C. on commercially available reversed phase separation columns with C18 stationary phases (Ascentis® Express C18 column (5 cm×2.1 mm, 2.7 μm, Phenomenex, Germany).

[1190] Up to 5 μL of the crude extract were injected and separated by gradient elution using a mixture of solvents consisting of methanol, water, formic acid, 2-propanol and 2-methoxy-2-methylpropan: [1191] Solvent A: 400 g methanol, 400 g water, 1 g formic acid [1192] Solvent B: 400 g tert-butyl methyl ether (tBME), 200 g 2-propanol, 100 g methanol, 1 g formic acid Details of the elution gradient are given in Table 7.

[1193] Mass spectrometry was carried out by electrospray ionization in positive ion mode using multiple-reaction-monitoring (MRM). The source parameters were: nebulizer gas, 50; heater gas, 60; curtain gas, 25; CAD gas, 4; ion spray voltage, 5500 V; temperature, 400° C.; pause between mass ranges, 5 ms; resolution Q1 and Q3, unit. The MRM settings are given in Table 12. To enhance the ionization efficiency in the electrospray process for OSS2, ammonium formate buffer dissolved in methanol (Solvent C: 200 g methanol, 100 g 0.1M ammonium formate solution in water) was added post column during the elution time of OSS2 (see FIG. 1). The eluation conditions etc. are given in Table 7 except for the flow rate of Solvent C which was increased in this Example 11 to 300 μl/min during the elution times from 3.30 min to 5.30 min.

[1194] The method is intended to be compatible with e.g. the ABSciex™ 3200 MD benchtop LC-MS/MS system.

[1195] The above mentioned internal standard PC5 was added to all samples at a known concentration. As a consequence, the determination of the respective peak area in the MS measurement makes it possible to calculate a correction factor in said samples; this correction factor may be used in order to correct the peak area of the biomarkers to be determined for variations of the devices, inherent system errors, or the like.

[1196] For each biomarker determined as peak area, the area ratio of the biomarker peak area to the internal standard peak area was determined.

[1197] The respective retention times and standards for peak area ratio calculations are shown in Table 12a. Quantitative results for SM23, PC4, CE C18:2, and OSS2 were achieved by using a calibration procedure with a calibration solution as described in the following (Example 12).

Example 12: Preparation of Calibration Samples

[1198] In order to generate calibration curves for the absolute quantification of SM23, PC4, CE C18:2, and OSS2, calibration solutions comprising known amounts of SM27 (Sphingomyelin (d18:1/24:1) for the quantification of SM23, purchased from Avanti Lipids), PC 4, and OSS2 were prepared in MeOH/CH2Cl2 (2/1, v/v).

[1199] For the subsequent generation of calibration samples, calibration solutions containing the respective concentrations of SM27, PC4, CE C18:2, and OSS2 in MeOH/CH2Cl2 (2/1) as shown in Table 13 (respective ratios are given in Table 13a) were prepared.

[1200] From each of these calibration solutions, 50 μl were added to a mixture of 10 μl delipidized plasma (commercially available) and 750 μl MeOH/CH2Cl2 (2/1). 10 μl internal standard were added, as described above, and further 700 μl MeOH/CH2Cl2 (2/1) were added in order to achieve a final calibration sample volume of 1520 μl.

[1201] The resulting 7 calibration samples were then treated the same way as the actual plasma samples for biomarker determination.

Example 13: Calculation of the Absolute Concentrations of SM23, PC 4, CE C18:2, and OSS2 in the Patient Samples

[1202] The absolute concentrations of SM23, PC4, CE C18:2, and OSS2 in any given sample can be determined by comparing the peak area ratios in the sample to the respective peak area ratios in a calibration sample or the calibration curve resulting from the respective peak area ratios of the respective set of calibration samples containing known amounts of SM23, PC4, CE C18:2, and OSS2.

[1203] As described above, SM27 was used in the calibration samples for the quantification of SM23.

[1204] Using the analytical method described in Example 11 and the calibration samples described in Example 12, above, absolute quantification of SM23, PC4, CE C18:2, and OSS2 was carried out with an additional step involving an ultrapool sample consisting of commercially available human plasma, which was mixed well and split into a sufficient number of aliquots. Aliquots of the ultrapool sample were included with the patient samples measured on each day of the analysis. To calculate absolute concentrations, the peak area ratios of SM23, PC4, CE C18:2, and OSS2 in each patient sample (as described above) where first divided by the median of the respective peak area ratios in the aliquots of the ultrapool sample measured on the same day of the analysis as said patient sample, and then multiplied by the known concentrations of SM23, PC4, CE C18:2, and OSS2, respectively, in the ultrapool sample.

[1205] A small number of samples which had been included in the calculation of the results shown in Examples 1 to 10 were now excluded for technical reasons. Concentrations of SM23, PC4, CE C18:2, and OSS2 in the ultrapool sample had previously been determined by comparing their peak area ratios to a calibration curve obtained from calibration samples as described in Example 12, above.

[1206] Since 50 μl of each calibration standard, but only 10 μl plasma of each patient sample were used, a multiplication factor of five was applied in order to receive the actual concentration ranges from the patient samples.

[1207] The resulting concentrations of SM23, PC4, CE C18:2, and OSS2 as determined for control samples and samples of the selected CHF subgroups HFrEF and HFpEF are shown in Table 14.

Example 14: Absolute Quantification of SM23, PC 4, and OSS2 (Panel 1)—Absolute Quantification of SM23, CE C18:2, and OSS2 (Panel 2)

[1208] The same procedure as described in Examples 11 to 13 was applied for the absolute quantification of SM23, PC 4, and OSS2 (Panel 1), however without determining CE C18:2. Also the same procedure as described in Examples 11 to 13 can be applied for the absolute quantification for absolute quantification of SM23, CE C18:2, and OSS2 (Panel 2), however without determining PC4. The respective information concerning MS-settings, standards for quantification etc. is given in Tables 12, 12a, 13 and 13b (Panel 2) or 13c (Panel 1).

Example 15: Performance Calculation for Different Subgroups Using Absolute Concentrations for SM23, PC4, and OSS2 (Panel 1+NT-proBNP)

[1209] Using absolute concentrations of the metabolite biomarkers, prediction probabilities and performance statistics where calculated for Panel 1+NT-proBNP as described in Example 5 without ANOVA correction. The scaling factors for the metabolite biomarkers measured in the unit μg/dl were m.sub.2=3.106761 (SM23), m.sub.3=2.12519 (OSS2), m.sub.4=4.583751 (PC4) and s.sub.2=0.123062, s.sub.3=0.3926955, s.sub.4=0.0892658. The scaling factors m.sub.1 and s.sub.i for NT-proBNP and the weights w.sub.0, w.sub.1, w2, w3, and w4, were the same as in Example 5. The cut-off was determined for a “matched sensitivity” in the subgroup HFrEF as described in Example 5, above, to be 0.743.

[1210] To enable a direct comparison between the performance statistics calculated using absolute concentrations versus peak area ratios, the performance calculations based on peak area ratios as previously conducted and described in Examples 1 to 10 were also repeated, excluding the same few samples which were excluded from the calculation of absolute concentrations (see Example 13).

[1211] In the testing (“VD”) data set, the AUC for CHF was 0.915 using absolute concentrations compared to 0.917 using peak area ratios. Sensitivity (62.3%) and specificity (97.6%) for CHF at said cutoff value were unchanged. The AUC (0.969) and specificity (97.6%) for HFrEF were unchanged. Sensitivity for HFrEF was 80.9% using absolute concentrations compared to 80.2% using peak area ratios. The AUC for HFrEF asymptomatic was 0.953 using absolute concentrations compared to 0.954 using peak area ratios. Sensitivity (73.5%) and specificity (97.6%) for HFrEF asymptomatic at said cutoff value were unchanged. The AUC for HFrEF LVEF 35% to 50% was 0.946 using absolute concentrations compared to 0.948 using peak area ratios. The sensitivity for HFrEF LVEF 35% to 50% was 69.0% using absolute concentrations compared to 67.6% using peak area ratios. The specificity (97.6%) for HFrEF LVEF 35% to 50% was unchanged. The performance statistics for Panel 1+NT-proBNP calculated using absolute concentrations for the metabolite biomarkers were thus essentially identical to those calculated using peak area ratios.

TABLE-US-00005 TABLE 2 Multimarker panel compositions and their respective Area under the curve (AUC) values of receiver operating characteristic (ROC) analysis calculated for different CHF subgroups including or excluding NT-proBNP, with or without ANOVA correction for confounders age, BMI and gender. No. of Panel Panel Composition Biomar “Saturated” With NT- With AUC Number (Biomarkers) markers Subgroup Panel proBNP ANOVA Estimate 1 SM23; OSS2; PC4 3 HFrEF yes yes no 0.968 2 OSS2; SM23; CE C18:2 3 HFrEF yes yes yes 0.955 3 SOP2; OSS2; PC4; CE C18:2; SM18; 9 HFrEF yes no no 0.89 SM28; SM24; SSP2; SM23 4 OSS2; CE C18:2; SM23 3 HFrEF no no no 0.876 5 SOP2; OSS2; SM18; CE C18:2; SM24; 8 HFrEF yes no yes 0.864 SM28; Cer(d16:1/24:0); PC4 6 SM18; OSS2; CE C18:2 3 HFrEF no no yes 0.851 7 SM23; SOP2; CE C18:2 3 HFrEF asymptomatic yes yes no 0.952 8 SM23; SOP2; CE C18:2 3 HFrEF asymptomatic yes yes yes 0.934 9 SOP2; SM24; SSP2; SM23; CE C18:2; 8 HFrEF asymptomatic yes no no 0.86 SM28; SM18; PC4 10 SM23; SOP2; SM28 3 HFrEF asymptomatic no no no 0.855 11 SM24; SOP2; CE C18:2; SM28; SSP2; 9 HFrEF asymptomatic yes no yes 0.815 SM18; OSS2; SM2; Cer(d16:1/24:0) 12 SM24; SOP2; CE C18:2 3 HFrEF asymptomatic no no yes 0.805 13 OSS2; PC4; SM23 3 HFrEF symptomatic yes yes no 0.978 14 OSS2; CE C18:2; SM3 3 HFrEF symptomatic yes yes yes 0.967 15 SM18; SM28; PC4; OSS2; SOP2; 8 HFrEF symptomatic yes no no 0.905 CE C18:2; PPO1; SM10 16 CE C18:2; SOP2; SM18 3 HFrEF symptomatic no no no 0.89 17 SM18; OSS2; SOP2; CE C18:2; PC4; 10 HFrEF symptomatic yes no yes 0.882 SPP1; SM24; Cer(d16:1/24:0); SM28; SM21 18 SM18; CE C18:2; OSS2 3 HFrEF symptomatic no no yes 0.867 19 SM23; SOP2; CE C18:2 3 DCMP asymptomatic yes yes no 0.929 20 OSS2; SM23; CE C18:2 3 DCMP asymptomatic yes yes yes 0.91 21 CE C18:2; OSS2; SM23; SM24; SSP2 5 DCMP asymptomatic yes no no 0.803 22 OSS2; SM23; CE C18:2 3 DCMP asymptomatic no no no 0.799 23 SM23; CE C18:2; OSS2; SSP2; SM24 5 DCMP asymptomatic yes no yes 0.738 24 SM24; SSP2; OSS2 3 DCMP asymptomatic no no yes 0.728 25 SOP2; PC4; SM3 3 DCMP symptomatic yes yes no 0.977 26 OSS2; PC4; SM3 3 DCMP symptomatic yes yes yes 0.966 27 SSP2; PPO1; SM18; CE C18:2; OSS2; 8 DCMP symptomatic yes no no 0.87 SOP2; PC4; SM28 28 SOP2; SM28; PC4 3 DCMP symptomatic no no no 0.851 29 Cer(d16:1/24:0); SM28; PC4; SM24; 8 DCMP symptomatic yes no yes 0.846 CE C18:2; SPP1; OSS2; SOP2 30 OSS2; CE C18:2; SM24 3 DCMP symptomatic no no yes 0.824 31 SOP2; SM23; PC4 3 DCMP yes yes no 0.959 32 OSS2; CE C18:2; SM23 3 DCMP yes yes yes 0.946 33 SM24; SOP2; OSS2; CE C18:2; SSP2; 7 DCMP yes no no 0.845 PC4; SM28 34 SOP2; SM24; PC4 3 DCMP no no no 0.833 35 OSS2; CE C18:2; SOP2; SM18; SM24; 8 DCMP yes no yes 0.815 SSP2; SM28; PC4 36 OSS2; SM24; CE C18:2 3 DCMP no no yes 0.803 37 SM5; PPO1; SM23 3 ICMP asymptomatic yes yes no 0.98 38 SM5; SOP2; SM24 3 ICMP asymptomatic yes yes yes 0.966 39 SSP2; CE C18:2; SM18; SM23; 10 ICMP asymptomatic yes no no 0.897 Cer(d16:1/24:0); PC4; SOP2; PPO1; SM28; SM24 40 SM24; SOP2; PC4 3 ICMP asymptomatic no no no 0.884 41 PC4; SM5; CE C18:2; SM2; PPO1; 9 ICMP asymptomatic yes no yes 0.866 SOP2; SM28; Cer(d16:1/24:0); SM24 42 SM24; CE C18:2; SOP2 3 ICMP asymptomatic no no yes 0.834 43 Cer(d18:1/24:1); SOP2; CE C18:2; 4 ICMP symptomatic yes yes no 0.98 SM18 44 SM18; CE C18:2; SOP2 3 ICMP symptomatic no yes no 0.978 45 SOP2; SM24; CE C18:2; SM18 4 ICMP symptomatic yes yes yes 0.967 46 SM18; CE C18:2; SOP2 3 ICMP symptomatic no yes yes 0.965 47 SSP2; PC4; Cer(d18:1/24:1); 8 ICMP symptomatic yes no no 0.937 SM28; SM24; SOP2; CE C18:2; SM18 48 SM18; CE C18:2; SOP2 3 ICMP symptomatic no no no 0.93 49 SM28; CE C18:2; SOP2; SM18 4 ICMP symptomatic yes no yes 0.913 50 SM18; CE C18:2; SOP2 3 ICMP symptomatic no no yes 0.909 51 SM23; CE C18:2; SOP2 3 ICMP yes yes no 0.977 52 SM23; CE C18:2; SOP2 3 ICMP yes yes yes 0.965 53 SOP2; SM24; CE C18:2; SM18; PC4; 10 ICMP yes no no 0.924 SM28; PPO1; Cer(d16:1/24:0); OSS2; Cer(d18:1/24:1) 54 SM18; CE C18:2; SOP2 3 ICMP no no no 0.915 55 SOP2; SM18; SM24; CE C18:2; 8 ICMP yes no yes 0.902 Cer(d16:1/24:0); SM28; OSS2; PC4 56 SM18; CE C18:2; SOP2 3 ICMP no no yes 0.892 57 SOP2; SM23; PC4 3 CHF asymptomatic yes yes no 0.875 58 SOP2; SSP2; SM5; SPP1; SM2; 9 CHF asymptomatic yes yes yes 0.844 SM3; PC4; CE C18:2; Glutamic acid 59 SOP2; SM5; SM2 3 CHF asymptomatic no yes yes 0.84 60 SOP2; SM23; SSP2; SM24; CE C18:2; 7 CHF asymptomatic yes no no 0.797 PC4; OSS2 61 SOP2; SM23; CE C18:2 3 CHF asymptomatic no no no 0.791 62 SOP2; SSP2; SM2; CE C18:2; SM24; 9 CHF asymptomatic yes no yes 0.759 OSS2; SM18; PC4; SM28 63 SOP2; SM18; CE C18:2 3 CHF asymptomatic no no yes 0.742 64 SOP2; PC4; OSS2; Cer(d18:1/24:1); 8 CHF symptomatic yes yes no 0.953 SM24; PC8; SM21; Cer(d17:1/24:0) 65 SOP2; PC4; SM24 3 CHF symptomatic no yes no 0.952 66 SOP2; SM18; PC4; SM21 4 CHF symptomatic yes yes yes 0.931 67 SOP2; SM18; PC4 3 CHF symptomatic no yes yes 0.93 68 SOP2; PC4; SM28; SM18; 7 CHF symptomatic yes no no 0.874 Cer(d18:1/24:1); Cer(d18:2/24:0); SM9 69 SOP2; PC4; SM18 3 CHF symptomatic no no no 0.854 70 PC4; SOP2; SM18; SM24; OSS2; 10 CHF symptomatic yes no yes 0.853 SPP1; SM21; Cer(d16:1/24:0); SM28; CE C18:2 71 SM18; SOP2; PC4 3 CHF symptomatic no no yes 0.837 72 SOP2; PC4; SM5 3 CHF yes yes no 0.919 73 SOP2; SM3; PC4; SM21 4 CHF yes yes yes 0.893 74 SOP2; SM3; PC4 3 CHF no yes yes 0.889 75 SOP2; SM18; PC4; SM28; OSS2; 7 CHF yes no no 0.844 SSP2; CE C18:2 76 SOP2; SM18; PC4 3 CHF no no no 0.834 77 SOP2; OSS2; SM18; SM24; PC4; 8 CHF yes no yes 0.816 CE C18:2; Cer(d16:1/24:0); SM28 78 OSS2; SM18; CE C18:2 3 CHF no no yes 0.806 79 SPP1; SOP2; SM5; PC4; SM3; SSP2 6 HFpEF asymptomatic yes yes no 0.788 80 SPP1; SM5; PC4 3 HFpEF asymptomatic no yes no 0.782 81 SPP1; SM3; SM5; SSP2; PC4; 9 HFpEF asymptomatic yes yes yes 0.739 Glutamic acid; CE C18:0; OSS2; SOP2 82 SPP1; SM3; SM5 3 HFpEF asymptomatic no yes yes 0.723 83 SPP1; SOP2; SSP2; PC4; SM23; SM5; 8 HFpEF asymptomatic yes no no 0.727 SM3; CE C18:2 84 SPP1; SM23; SOP2 3 HFpEF asymptomatic no no no 0.717 85 SM3; SPP1; SSP2; SM5; SOP2; PC4 6 HFpEF asymptomatic yes no yes 0.692 86 SPP1; SM3; SM5 3 HFpEF asymptomatic no no yes 0.664 87 SOP2; Cer(d18:1/24:1); PC8; 9 HFpEF symptomatic yes yes no 0.882 PPO1; Cer(d18:1/23:0); PC4; SM24; SM28; SM9 88 SOP2; PC4; SM24 3 HFpEF symptomatic no yes no 0.87 89 Cer(d18:1/23:0); SM24; SOP2; 9 HFpEF symptomatic yes yes yes 0.828 Cer(d18:1/24:1); PC4; PPO1; PC8; SSS; SM18 90 SM24; SOP2; PC4 3 HFpEF symptomatic no yes yes 0.81 91 PC4; SM28; SM24; Cer(d18:1/24:1); 10 HFpEF symptomatic yes no no 0.808 PC8; SOP2; SM9; PPO1; SM21; SSP2 92 PC4; SM28; SOP2 3 HFpEF symptomatic no no no 0.748 93 SM24; PC4; SM18; SOP2; SM21; SPP1; 8 HFpEF symptomatic yes no yes 0.767 Cer(d18:1/23:0); SSP2 94 SM24; SM18; SOP2 3 HFpEF symptomatic no no yes 0.746 95 SOP2; PC8; SPP1; PC4; SSP2; PPO1; 9 HFpEF yes yes no 0.824 SM5; SM18; Cer(d17:1/24:0) 96 SOP2; PC8; SM5 3 HFpEF no yes no 0.821 97 SPP1; PC4; SM3; SOP2; SSP2; 9 HFpEF yes yes yes 0.771 Cer(d18:1/23:0); SM24; SM5; Glutamic acid 98 SPP1; SM3; PC4 3 HFpEF no yes yes 0.763 99 SOP2; PC4; SPP1; PC8; SSP2; SM28; 10 HFpEF yes no no 0.759 SM24; PPO1; SM18; Cer(d17:1/24:0) 100 SOP2; PC4; SM24 3 HFpEF no no no 0.743 101 PC4; SPP1; SM24; SSP2; SM3; SOP2; 10 HFpEF yes no yes 0.726 SM18; Glutamic acid; Cer(d17:1/24:0); Cer(d18:1/23:0) 102 SPP1; SM18; PC4 3 HFpEF no no yes 0.705 103 CE C18:2; SSS; Cer(d17:1/24:0) 3 (all) (na) (na) (na) (see Table 3) 104 PC4; SOP2; CE C18:2 3 (all) (na) (na) (na) (see Tables 4A-D) 105 CE C18:2; PC4; SM29; SOP2 4 (all) (na) (na) (na) (see Tables 4A-D) 106 CE C18:2; PC8; SM29; SSP2 4 (all) (na) (na) (na) (see Tables 4A-D) 107 CE C18:2; PC4; SM8; SSP2 4 (all) (na) (na) (na) (see Tables 4A-D) 108 CE C18:2; PC8; SM8; SSP2 4 (all) (na) (na) (na) (see Tables 4A-D) 109 CE C18:2; PC4; SM29; PPO1 4 (all) (na) (na) (na) (see Tables 4A-D) 110 CE C18:2; PC8; SM29; PPO1 4 (all) (na) (na) (na) (see Tables 4A-D) 111 CE C18:2; PC4; SM8; PPO1 4 (all) (na) (na) (na) (see Tables 4A-D) 112 CE C18:2; PC8; SM8; PPO1 4 (all) (na) (na) (na) (see Tables 4A-D) 113 CE C18:2; PC4; SM29; PPP 4 (all) (na) (na) (na) (see Tables 4A-D) 114 CE C18:2; PC8; SM29; PPP 4 (all) (na) (na) (na) (see Tables 4A-D) 115 CE C18:2; PC4; SM8; PPP 4 (all) (na) (na) (na) (see Tables 4A-D) 116 CE C18:2; PC8; SM29; SOP2 4 (all) (na) (na) (na) (see Tables 4A-D) 117 CE C18:2; PC8; SM8; PPP 4 (all) (na) (na) (na) (see Tables 4A-D) 118 CE C18:2; PC4; SM8; SOP2 4 (all) (na) (na) (na) (see Tables 4A-D) 119 CE C18:2; PC8; SM8; SOP2 4 (all) (na) (na) (na) (see Tables 4A-D) 120 CE C18:2; PC4; SM29; SPP1 4 (all) (na) (na) (na) (see Tables 4A-D) 121 CE C18:2; PC8; SM29; SPP1 4 (all) (na) (na) (na) (see Tables 4A-D) 122 CE C18:2; PC4; SM8; SPP1 4 (all) (na) (na) (na) (see Tables 4A-D) 123 CE C18:2; PC8; SM8; SPP1 4 (all) (na) (na) (na) (see Tables 4A-D) 124 CE C18:2; PC4; SM29; SSP2 4 (all) (na) (na) (na) (see Tables 4A-D) 125 PC4; SOP2; CE C18:2; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 126 PC4; SOP2; CE C18:0; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 127 PC4; SOP2; CE C18:2; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 128 PC4; SOP2; CE C18:0; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 129 PC4; SOP2; CE C18:2; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 130 PC4; SOP2; CE C18:0; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 131 PC4; SOP2; CE C18:2; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 132 PC4; SOP2; CE C18:0; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 133 SOP2; CE C18:0; SM18; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 134 SOP2; CE C18:2; SM21; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 135 SOP2; CE C18:0; SM21; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 136 SOP2; CE C18:2; SM23; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 137 SOP2; CE C18:0; SM23; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 138 SOP2; CE C18:2; SM24; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 139 SOP2; CE C18:0; SM24; PC4; SPP1 5 (all) (na) (na) (na) (see Tables 4A-D) 140 SOP2; CE C18:2; SM18; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 141 SOP2; CE C18:0; SM18; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 142 SOP2; CE C18:2; SM21; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 143 SOP2; CE C18:0; SM21; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 144 SOP2; CE C18:2; SM23; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 145 SOP2; CE C18:0; SM23; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 146 SOP2; CE C18:2; SM24; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 147 SOP2; CE C18:0; SM24; PC4; SSP2 5 (all) (na) (na) (na) (see Tables 4A-D) 148 SOP2; CE C18:2; SM18; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 149 SOP2; CE C18:0; SM18; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 150 SOP2; CE C18:2; SM21; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 151 SOP2; CE C18:0; SM21; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 152 SOP2; CE C18:2; SM23; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 153 SOP2; CE C18:0; SM23; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 154 SOP2; CE C18:2; SM24; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 155 SOP2; CE C18:0; SM24; PC4; PPO1 5 (all) (na) (na) (na) (see Tables 4A-D) 156 SOP2; CE C18:2; SM18; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 157 SOP2; CE C18:0; SM18; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 158 SOP2; CE C18:2; SM21; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 159 SOP2; CE C18:0; SM21; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 160 SOP2; CE C18:2; SM23; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 161 SOP2; CE C18:0; SM23; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 162 SOP2; CE C18:2; SM24; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 163 SOP2; CE C18:0; SM24; PC4; PPP 5 (all) (na) (na) (na) (see Tables 4A-D) 164 SOP2; CE C18:2; SM18; PC4; 5 (all) (na) (na) (na) (see SPP1 Tables 4A-D) 165 PC4; PPP; CE C18:0; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 166 PC4; SPP1; CE C18:2; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 167 PC4; SSP2; CE C18:2; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 168 PC4; PPO1; CE C18:2; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 169 PC4; PPP; CE C18:2; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 170 PC4; SPP1; CE C18:0; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 171 PC4; SSP2; CE C18:0; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 172 PC4; PPO1; CE C18:0; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 173 PC4; SPP1; CE C18:2; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 174 PC4; PPP; CE C18:0; SM21 4 (all) (na) (na) (na) (see Tables 4A-D) 175 PC4; SPP1; CE C18:2; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 176 PC4; SSP2; CE C18:2; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 177 PC4; PPO1; CE C18:2; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 178 PC4; PPP; CE C18:2; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 179 PC4; SPP1; CE C18:0; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 180 PC4; SSP2; CE C18:0; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 181 PC4; PPO1; CE C18:0; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 182 PC4; SSP2; CE C18:2; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 183 PC4; PPP; CE C18:0; SM23 4 (all) (na) (na) (na) (see Tables 4A-D) 184 PC4; SPP1; CE C18:2; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 185 PC4; SSP2; CE C18:2; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 186 PC4; PPO1; CE C18:2; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 187 PC4; PPP; CE C18:2; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 188 PC4; SPP1; CE C18:0; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 189 PC4; SSP2; CE C18:0; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 190 PC4; PPO1; CE C18:0; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 191 PC4; PPO1; CE C18:2; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 192 PC4; PPP; CE C18:0; SM24 4 (all) (na) (na) (na) (see Tables 4A-D) 193 PC4; PPP; CE C18:2; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 194 PC4; SPP1; CE C18:0; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 195 PC4; SSP2; CE C18:0; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 196 PC4; PPO1; CE C18:0; SM18 4 (all) (na) (na) (na) (see Tables 4A-D) 197 PC4; SOP2; CE C18:2; SM28 4 (all) (na) (na) (na) (see Tables 4A-D) 198 PC4; SOP2; CE C18:0; SM28 4 (all) (na) (na) (na) (see Tables 4A-D) 199 SM18; SM24; SM28 3 (all) (na) (na) (na) (see Tables 4A-D)

TABLE-US-00006 TABLE 2a Further multimarker panel compositions for diagnosis of different CHF subgroups. No. of With Panel Panel Composition Bio- Sub- NT- AUC Number (Biomarkers) markers group proBNP Estimate 200 OSS2; SM23; CE 4 (all) (na) (see Table 5a) C18:2; PC4 201 CE C18:2; SM18; 3 (all) (na) (see Table 5a) SSS 202 CE C18:2; PC8; 6 (all) YES (see Table 5a) SM18; SM2; SM24; SSS 203 CE C18:2; SM18; 5 (all) NO (see Table 5a) SM21; SM24; SSS 204 SM24; CE C18:2; 3 (all) (na) (see Table 5a) SM2 205 SM2; SSS; CE 3 (all) (na) (see Table 5a) C18:2 206 SM24; SSS; CE 3 (all) (na) (see Table 5a) C18:2

TABLE-US-00007 TABLE 3 Performance of Panel Number 103 in different CHF subgroups, including or excluding NT-proBNP, with or without ANOVA correction for confounders age, BMI and gender. Panel With NT- With AUC Number proBNP ANOVA Subgroup estimate 103 yes no DCMP asymptomatic 0.903 103 yes yes DCMP asymptomatic 0.896 103 no no DCMP asymptomatic 0.729 103 no yes DCMP asymptomatic 0.667 103 yes no DCMP symptomatic 0.961 103 yes yes DCMP symptomatic 0.954 103 no no DCMP symptomatic 0.805 103 no yes DCMP symptomatic 0.791 103 yes no DCMP 0.942 103 yes yes DCMP 0.937 103 no no DCMP 0.795 103 no yes DCMP 0.771 103 yes no HFrEF asymptomatic 0.93 103 yes yes HFrEF asymptomatic 0.925 103 no no HFrEF asymptomatic 0.796 103 no yes HFrEF asymptomatic 0.768 103 yes no HFrEF symptomatic 0.969 103 yes yes HFrEF symptomatic 0.96 103 no no HFrEF symptomatic 0.855 103 no yes HFrEF symptomatic 0.838 103 yes no HFrEF 0.956 103 yes yes HFrEF 0.949 103 no no HFrEF 0.84 103 no yes HFrEF 0.818 103 yes no ICMP asymptomatic 0.951 103 yes yes ICMP asymptomatic 0.947 103 no no ICMP asymptomatic 0.838 103 no yes ICMP asymptomatic 0.815 103 yes no ICMP symptomatic 0.973 103 yes yes ICMP symptomatic 0.963 103 no no ICMP symptomatic 0.891 103 no yes ICMP symptomatic 0.871 103 yes no ICMP 0.967 103 yes yes ICMP 0.959 103 no no ICMP 0.878 103 no yes ICMP 0.858 103 yes no CHF asymptomatic 0.844 103 yes yes CHF asymptomatic 0.825 103 no no CHF asymptomatic 0.747 103 no yes CHF asymptomatic 0.717 103 yes no CHF symptomatic 0.938 103 yes yes CHF symptomatic 0.921 103 no no CHF symptomatic 0.822 103 no yes CHF symptomatic 0.812 103 yes no CHF 0.898 103 yes yes CHF 0.88 103 no no CHF 0.79 103 no yes CHF 0.772 103 yes no HFpEF asymptomatic 0.718 103 yes yes HFpEF asymptomatic 0.668 103 no no HFpEF asymptomatic 0.634 103 no yes HFpEF asymptomatic 0.592 103 yes no HFpEF symptomatic 0.835 103 yes yes HFpEF symptomatic 0.794 103 no no HFpEF symptomatic 0.658 103 no yes HFpEF symptomatic 0.697 103 yes no HFpEF 0.78 103 yes yes HFpEF 0.743 103 no no HFpEF 0.689 103 no yes HFpEF 0.679

TABLE-US-00008 TABLE 4A AUC values for Panel Number 104 to 199 without NT-proBNP and without ANOVA correction in different CHF subgoups CHF CHF DCMP DCMP HFpEF HFpEF HFrEF HFrEF ICMP ICMP Panel asymp- symp- asymp- symp- asymp- symp- asymp- symp- asymp- symp- Number CHF tomatic tomatic DCMP tomatic tomatic HFpEF tomatic tomatic HFrEF tomatic tomatic ICMP tomatic tomatic 104 0.829 0.794 0.857 0.835 0.785 0.857 0.751 0.736 0.758 0.870 0.835 0.886 0.902 0.881 0.907 105 0.828 0.793 0.855 0.833 0.786 0.856 0.749 0.731 0.756 0.870 0.835 0.885 0.904 0.880 0.911 106 0.821 0.791 0.844 0.828 0.799 0.842 0.746 0.728 0.738 0.862 0.832 0.874 0.895 0.873 0.900 107 0.825 0.795 0.850 0.834 0.799 0.850 0.743 0.731 0.742 0.867 0.837 0.881 0.895 0.875 0.899 108 0.821 0.792 0.845 0.827 0.802 0.840 0.746 0.728 0.743 0.862 0.834 0.874 0.892 0.874 0.894 109 0.817 0.776 0.850 0.815 0.744 0.847 0.741 0.707 0.753 0.858 0.817 0.876 0.896 0.873 0.902 110 0.808 0.769 0.838 0.806 0.749 0.831 0.736 0.699 0.743 0.848 0.812 0.863 0.889 0.865 0.895 111 0.818 0.780 0.851 0.815 0.760 0.845 0.741 0.710 0.754 0.859 0.821 0.876 0.894 0.874 0.897 112 0.808 0.774 0.838 0.808 0.766 0.830 0.736 0.703 0.742 0.850 0.817 0.864 0.887 0.867 0.889 113 0.807 0.770 0.837 0.803 0.730 0.833 0.733 0.706 0.734 0.847 0.807 0.864 0.886 0.862 0.893 114 0.796 0.761 0.824 0.794 0.734 0.816 0.726 0.696 0.721 0.836 0.800 0.851 0.878 0.852 0.885 115 0.807 0.773 0.838 0.803 0.743 0.831 0.733 0.710 0.736 0.847 0.811 0.864 0.883 0.863 0.886 116 0.824 0.789 0.849 0.826 0.788 0.845 0.752 0.729 0.754 0.863 0.831 0.877 0.900 0.878 0.905 117 0.796 0.765 0.824 0.795 0.747 0.815 0.725 0.700 0.722 0.837 0.806 0.850 0.875 0.855 0.877 118 0.829 0.795 0.856 0.833 0.794 0.855 0.749 0.733 0.756 0.870 0.837 0.885 0.902 0.881 0.906 119 0.824 0.791 0.849 0.826 0.796 0.844 0.751 0.729 0.754 0.864 0.834 0.877 0.898 0.879 0.900 120 0.820 0.785 0.847 0.820 0.759 0.849 0.748 0.736 0.741 0.859 0.819 0.877 0.894 0.868 0.902 121 0.811 0.778 0.837 0.810 0.760 0.834 0.746 0.729 0.734 0.849 0.813 0.865 0.888 0.863 0.894 122 0.820 0.787 0.848 0.820 0.768 0.847 0.748 0.736 0.742 0.859 0.821 0.876 0.891 0.869 0.895 123 0.811 0.780 0.837 0.810 0.771 0.832 0.745 0.729 0.735 0.850 0.816 0.865 0.885 0.864 0.888 124 0.825 0.794 0.849 0.834 0.797 0.852 0.743 0.732 0.740 0.867 0.835 0.881 0.898 0.875 0.905 125 0.840 0.805 0.867 0.845 0.810 0.861 0.751 0.736 0.752 0.888 0.856 0.901 0.929 0.902 0.936 126 0.841 0.807 0.868 0.846 0.807 0.863 0.754 0.737 0.761 0.886 0.856 0.901 0.928 0.905 0.929 127 0.841 0.798 0.876 0.847 0.790 0.869 0.753 0.733 0.775 0.887 0.849 0.903 0.923 0.901 0.927 128 0.843 0.800 0.879 0.850 0.791 0.874 0.756 0.733 0.775 0.889 0.852 0.906 0.925 0.905 0.927 129 0.835 0.806 0.859 0.845 0.825 0.858 0.748 0.734 0.748 0.884 0.859 0.894 0.919 0.899 0.922 130 0.835 0.807 0.859 0.846 0.822 0.858 0.750 0.735 0.758 0.882 0.860 0.893 0.917 0.902 0.915 131 0.843 0.806 0.873 0.851 0.827 0.865 0.753 0.733 0.764 0.891 0.867 0.902 0.929 0.911 0.931 132 0.845 0.810 0.875 0.855 0.830 0.870 0.757 0.734 0.767 0.892 0.870 0.904 0.930 0.914 0.928 133 0.839 0.806 0.867 0.844 0.801 0.863 0.754 0.742 0.758 0.885 0.853 0.900 0.926 0.901 0.928 134 0.839 0.795 0.874 0.843 0.782 0.868 0.753 0.735 0.772 0.885 0.846 0.901 0.921 0.897 0.925 135 0.841 0.797 0.876 0.846 0.782 0.873 0.755 0.735 0.772 0.886 0.848 0.904 0.923 0.900 0.924 136 0.833 0.804 0.857 0.843 0.818 0.857 0.748 0.737 0.745 0.882 0.857 0.893 0.917 0.896 0.921 137 0.833 0.806 0.857 0.843 0.816 0.858 0.750 0.739 0.755 0.880 0.857 0.891 0.915 0.898 0.913 138 0.842 0.805 0.871 0.849 0.821 0.865 0.753 0.737 0.761 0.890 0.865 0.901 0.928 0.907 0.930 139 0.844 0.808 0.874 0.852 0.823 0.869 0.757 0.738 0.764 0.890 0.867 0.903 0.928 0.911 0.926 140 0.841 0.808 0.867 0.849 0.816 0.863 0.750 0.736 0.752 0.889 0.858 0.902 0.928 0.900 0.935 141 0.841 0.809 0.868 0.849 0.812 0.864 0.753 0.737 0.758 0.887 0.858 0.901 0.926 0.903 0.928 142 0.841 0.800 0.874 0.848 0.795 0.868 0.752 0.735 0.773 0.887 0.851 0.902 0.922 0.900 0.926 143 0.843 0.801 0.877 0.850 0.793 0.873 0.754 0.734 0.772 0.888 0.853 0.905 0.924 0.903 0.925 144 0.835 0.808 0.858 0.848 0.829 0.859 0.747 0.734 0.748 0.885 0.861 0.895 0.918 0.898 0.921 145 0.835 0.808 0.858 0.847 0.825 0.858 0.749 0.735 0.756 0.882 0.861 0.892 0.915 0.900 0.913 146 0.844 0.808 0.872 0.853 0.831 0.866 0.752 0.734 0.761 0.892 0.868 0.902 0.928 0.909 0.930 147 0.845 0.810 0.874 0.855 0.831 0.869 0.755 0.734 0.764 0.892 0.870 0.903 0.928 0.912 0.926 148 0.838 0.802 0.867 0.842 0.805 0.860 0.749 0.732 0.753 0.886 0.853 0.899 0.928 0.900 0.935 149 0.839 0.804 0.867 0.842 0.802 0.862 0.752 0.734 0.762 0.885 0.853 0.899 0.926 0.903 0.927 150 0.839 0.794 0.875 0.843 0.785 0.868 0.751 0.729 0.777 0.885 0.846 0.901 0.922 0.899 0.926 151 0.841 0.796 0.878 0.846 0.785 0.873 0.754 0.728 0.777 0.887 0.848 0.904 0.924 0.902 0.925 152 0.833 0.803 0.858 0.842 0.820 0.857 0.746 0.730 0.748 0.882 0.857 0.893 0.918 0.897 0.921 153 0.833 0.804 0.858 0.842 0.817 0.857 0.748 0.732 0.759 0.880 0.857 0.891 0.915 0.899 0.913 154 0.842 0.804 0.872 0.848 0.822 0.865 0.752 0.727 0.767 0.890 0.865 0.901 0.928 0.910 0.930 155 0.844 0.806 0.875 0.851 0.824 0.869 0.755 0.729 0.770 0.891 0.867 0.902 0.928 0.913 0.926 156 0.838 0.803 0.866 0.842 0.805 0.859 0.748 0.732 0.749 0.886 0.853 0.899 0.927 0.898 0.935 157 0.839 0.805 0.866 0.843 0.801 0.861 0.751 0.734 0.758 0.884 0.853 0.899 0.925 0.900 0.927 158 0.838 0.795 0.874 0.843 0.784 0.866 0.750 0.729 0.772 0.885 0.846 0.900 0.921 0.896 0.925 159 0.841 0.797 0.876 0.846 0.785 0.872 0.753 0.729 0.772 0.886 0.848 0.903 0.923 0.900 0.925 160 0.833 0.803 0.857 0.842 0.820 0.855 0.745 0.730 0.744 0.882 0.857 0.893 0.917 0.895 0.921 161 0.833 0.804 0.857 0.842 0.817 0.855 0.747 0.731 0.755 0.880 0.857 0.891 0.915 0.897 0.913 162 0.841 0.804 0.871 0.848 0.822 0.863 0.751 0.729 0.761 0.890 0.865 0.900 0.927 0.907 0.929 163 0.843 0.807 0.873 0.851 0.824 0.867 0.754 0.728 0.764 0.890 0.867 0.902 0.927 0.910 0.926 164 0.839 0.804 0.866 0.843 0.803 0.861 0.751 0.739 0.749 0.886 0.853 0.900 0.928 0.898 0.935 165 0.824 0.791 0.855 0.822 0.766 0.842 0.742 0.720 0.743 0.869 0.835 0.886 0.916 0.891 0.918 166 0.831 0.789 0.866 0.833 0.763 0.860 0.751 0.737 0.763 0.874 0.833 0.892 0.912 0.888 0.916 167 0.834 0.797 0.865 0.843 0.795 0.858 0.745 0.733 0.757 0.881 0.847 0.894 0.914 0.893 0.918 168 0.829 0.780 0.870 0.828 0.753 0.859 0.745 0.708 0.777 0.875 0.831 0.893 0.916 0.894 0.918 169 0.818 0.774 0.856 0.817 0.738 0.845 0.737 0.709 0.757 0.863 0.821 0.880 0.904 0.882 0.906 170 0.834 0.792 0.869 0.836 0.758 0.865 0.754 0.738 0.763 0.876 0.834 0.896 0.913 0.892 0.915 171 0.836 0.797 0.868 0.843 0.790 0.861 0.748 0.731 0.758 0.880 0.847 0.894 0.913 0.896 0.914 172 0.831 0.781 0.873 0.830 0.743 0.865 0.749 0.708 0.778 0.875 0.831 0.895 0.916 0.897 0.916 173 0.834 0.800 0.861 0.836 0.790 0.855 0.751 0.741 0.742 0.880 0.845 0.896 0.924 0.893 0.932 174 0.820 0.776 0.859 0.819 0.726 0.851 0.740 0.710 0.758 0.863 0.821 0.883 0.903 0.885 0.903 175 0.829 0.801 0.852 0.837 0.810 0.852 0.747 0.739 0.736 0.877 0.850 0.889 0.913 0.891 0.916 176 0.831 0.806 0.853 0.847 0.831 0.853 0.742 0.732 0.735 0.882 0.859 0.891 0.914 0.895 0.918 177 0.826 0.793 0.855 0.830 0.801 0.849 0.741 0.712 0.748 0.875 0.847 0.887 0.914 0.895 0.916 178 0.818 0.789 0.844 0.824 0.792 0.838 0.734 0.711 0.729 0.868 0.841 0.880 0.907 0.887 0.910 179 0.829 0.804 0.853 0.838 0.808 0.853 0.750 0.742 0.743 0.875 0.851 0.888 0.910 0.894 0.909 180 0.830 0.807 0.851 0.844 0.826 0.850 0.744 0.732 0.742 0.877 0.858 0.886 0.909 0.895 0.906 181 0.825 0.794 0.853 0.829 0.792 0.849 0.743 0.713 0.759 0.871 0.846 0.883 0.909 0.896 0.905 182 0.837 0.806 0.862 0.847 0.818 0.857 0.745 0.733 0.741 0.886 0.856 0.898 0.925 0.896 0.933 183 0.818 0.791 0.844 0.824 0.788 0.838 0.737 0.718 0.736 0.864 0.841 0.877 0.903 0.888 0.900 184 0.837 0.801 0.866 0.841 0.809 0.859 0.753 0.739 0.755 0.883 0.857 0.895 0.922 0.902 0.924 185 0.838 0.805 0.865 0.850 0.830 0.858 0.746 0.732 0.748 0.887 0.864 0.896 0.921 0.903 0.924 186 0.834 0.793 0.869 0.835 0.800 0.857 0.747 0.709 0.768 0.882 0.855 0.894 0.924 0.908 0.925 187 0.826 0.788 0.858 0.827 0.794 0.846 0.740 0.709 0.750 0.873 0.848 0.885 0.916 0.898 0.917 188 0.839 0.805 0.869 0.845 0.813 0.864 0.756 0.741 0.758 0.884 0.859 0.898 0.922 0.906 0.920 189 0.839 0.807 0.867 0.851 0.829 0.859 0.749 0.731 0.751 0.886 0.866 0.895 0.919 0.905 0.917 190 0.836 0.796 0.871 0.838 0.802 0.861 0.751 0.711 0.772 0.882 0.857 0.895 0.923 0.911 0.919 191 0.831 0.792 0.863 0.828 0.777 0.851 0.744 0.712 0.753 0.878 0.842 0.893 0.925 0.898 0.931 192 0.828 0.792 0.861 0.831 0.797 0.850 0.744 0.714 0.753 0.873 0.850 0.886 0.915 0.902 0.911 193 0.824 0.788 0.854 0.821 0.770 0.841 0.738 0.717 0.737 0.871 0.836 0.887 0.919 0.889 0.927 194 0.835 0.804 0.863 0.838 0.788 0.858 0.754 0.744 0.748 0.879 0.845 0.896 0.922 0.897 0.925 195 0.836 0.807 0.862 0.846 0.811 0.856 0.748 0.734 0.746 0.883 0.855 0.896 0.920 0.897 0.923 196 0.830 0.793 0.863 0.827 0.770 0.852 0.747 0.715 0.762 0.875 0.840 0.891 0.921 0.900 0.921 197 0.839 0.796 0.875 0.845 0.784 0.870 0.753 0.734 0.781 0.883 0.844 0.900 0.917 0.896 0.920 198 0.841 0.797 0.878 0.848 0.784 0.876 0.756 0.733 0.781 0.885 0.847 0.903 0.919 0.900 0.920 199 0.766 0.731 0.804 0.756 0.694 0.767 0.665 0.580 0.688 0.819 0.799 0.831 0.889 0.877 0.887

TABLE-US-00009 TABLE 4B AUC values for Panel Number 104 to 199 with NT-proBNP and without ANOVA correction in different CHF subgroups Panel CHF CHF DCMP DCMP HFpEF Number CHF asymptomatic symptomatic DCMP asymptomatic symptomatic HFpEF asymptomatic 104 0.919 0.873 0.955 0.959 0.920 0.980 0.827 0.790 105 0.919 0.875 0.955 0.959 0.924 0.979 0.826 0.788 106 0.916 0.873 0.951 0.956 0.926 0.974 0.826 0.786 107 0.916 0.874 0.952 0.959 0.926 0.978 0.820 0.787 108 0.915 0.873 0.951 0.956 0.926 0.974 0.826 0.787 109 0.914 0.866 0.952 0.951 0.911 0.974 0.822 0.776 110 0.910 0.864 0.948 0.947 0.911 0.968 0.822 0.772 111 0.913 0.868 0.952 0.951 0.912 0.974 0.823 0.780 112 0.910 0.866 0.948 0.947 0.912 0.968 0.823 0.777 113 0.911 0.866 0.948 0.950 0.911 0.973 0.821 0.778 114 0.907 0.862 0.944 0.946 0.912 0.967 0.819 0.771 115 0.910 0.866 0.948 0.950 0.911 0.973 0.821 0.779 116 0.918 0.874 0.953 0.955 0.924 0.974 0.832 0.789 117 0.906 0.864 0.944 0.946 0.912 0.967 0.819 0.774 118 0.919 0.876 0.955 0.958 0.924 0.979 0.827 0.790 119 0.918 0.875 0.953 0.955 0.924 0.974 0.832 0.790 120 0.916 0.872 0.951 0.955 0.915 0.977 0.828 0.794 121 0.913 0.870 0.948 0.951 0.915 0.971 0.831 0.792 122 0.915 0.872 0.951 0.954 0.914 0.977 0.828 0.794 123 0.912 0.871 0.948 0.950 0.915 0.971 0.831 0.792 124 0.917 0.873 0.952 0.960 0.926 0.979 0.820 0.786 125 0.921 0.877 0.956 0.958 0.927 0.978 0.828 0.792 126 0.922 0.879 0.957 0.959 0.927 0.978 0.830 0.795 127 0.919 0.872 0.956 0.957 0.918 0.978 0.827 0.787 128 0.921 0.873 0.957 0.958 0.916 0.979 0.829 0.790 129 0.922 0.883 0.955 0.961 0.941 0.978 0.827 0.793 130 0.923 0.886 0.956 0.963 0.941 0.979 0.829 0.796 131 0.921 0.876 0.956 0.959 0.931 0.978 0.828 0.788 132 0.923 0.878 0.957 0.960 0.932 0.978 0.829 0.790 133 0.921 0.878 0.956 0.959 0.924 0.978 0.831 0.799 134 0.918 0.871 0.956 0.957 0.915 0.978 0.828 0.791 135 0.920 0.872 0.956 0.957 0.913 0.979 0.830 0.793 136 0.921 0.883 0.955 0.961 0.939 0.978 0.829 0.798 137 0.923 0.885 0.955 0.962 0.939 0.979 0.831 0.800 138 0.921 0.876 0.956 0.958 0.928 0.978 0.829 0.792 139 0.922 0.878 0.957 0.959 0.929 0.978 0.831 0.795 140 0.921 0.877 0.956 0.960 0.930 0.979 0.827 0.792 141 0.922 0.879 0.956 0.961 0.929 0.979 0.829 0.795 142 0.919 0.872 0.956 0.959 0.921 0.979 0.826 0.789 143 0.920 0.873 0.957 0.959 0.918 0.979 0.828 0.791 144 0.922 0.883 0.955 0.963 0.942 0.979 0.826 0.793 145 0.923 0.886 0.956 0.964 0.943 0.980 0.828 0.795 146 0.921 0.876 0.956 0.960 0.933 0.979 0.826 0.789 147 0.923 0.879 0.957 0.961 0.934 0.979 0.829 0.791 148 0.920 0.875 0.955 0.957 0.925 0.978 0.827 0.790 149 0.921 0.877 0.956 0.959 0.925 0.978 0.829 0.792 150 0.918 0.870 0.956 0.957 0.916 0.978 0.826 0.784 151 0.919 0.871 0.957 0.958 0.914 0.978 0.828 0.787 152 0.921 0.882 0.955 0.961 0.939 0.978 0.827 0.791 153 0.922 0.884 0.956 0.962 0.940 0.979 0.829 0.793 154 0.920 0.875 0.956 0.958 0.929 0.977 0.827 0.786 155 0.922 0.877 0.957 0.959 0.930 0.978 0.829 0.788 156 0.920 0.875 0.955 0.957 0.925 0.978 0.827 0.790 157 0.921 0.877 0.956 0.958 0.925 0.978 0.829 0.793 158 0.918 0.870 0.956 0.957 0.916 0.978 0.826 0.785 159 0.919 0.871 0.956 0.957 0.913 0.978 0.828 0.788 160 0.921 0.882 0.954 0.961 0.939 0.978 0.827 0.791 161 0.922 0.884 0.955 0.962 0.939 0.978 0.829 0.794 162 0.920 0.875 0.956 0.958 0.929 0.977 0.827 0.786 163 0.922 0.877 0.957 0.959 0.930 0.978 0.829 0.789 164 0.920 0.876 0.955 0.957 0.925 0.978 0.830 0.796 165 0.915 0.871 0.952 0.952 0.917 0.973 0.825 0.787 166 0.915 0.868 0.953 0.954 0.908 0.977 0.828 0.793 167 0.916 0.870 0.953 0.959 0.921 0.978 0.820 0.786 168 0.913 0.862 0.953 0.949 0.903 0.974 0.822 0.774 169 0.910 0.861 0.950 0.949 0.903 0.973 0.820 0.777 170 0.917 0.870 0.954 0.954 0.905 0.977 0.830 0.796 171 0.917 0.870 0.954 0.958 0.917 0.978 0.821 0.787 172 0.914 0.862 0.954 0.949 0.898 0.974 0.824 0.776 173 0.918 0.875 0.953 0.955 0.920 0.977 0.830 0.798 174 0.911 0.862 0.950 0.949 0.899 0.973 0.822 0.779 175 0.920 0.883 0.952 0.959 0.936 0.977 0.830 0.800 176 0.920 0.882 0.953 0.962 0.943 0.978 0.821 0.790 177 0.917 0.877 0.952 0.955 0.932 0.974 0.824 0.783 178 0.916 0.877 0.950 0.955 0.934 0.974 0.823 0.786 179 0.921 0.885 0.954 0.961 0.937 0.978 0.832 0.803 180 0.921 0.884 0.953 0.964 0.943 0.979 0.823 0.792 181 0.918 0.879 0.953 0.956 0.932 0.975 0.827 0.787 182 0.919 0.875 0.954 0.959 0.930 0.978 0.822 0.789 183 0.917 0.880 0.951 0.957 0.935 0.974 0.825 0.790 184 0.919 0.874 0.954 0.955 0.924 0.976 0.830 0.794 185 0.918 0.874 0.954 0.959 0.932 0.978 0.821 0.785 186 0.916 0.868 0.954 0.950 0.919 0.973 0.824 0.776 187 0.914 0.868 0.951 0.950 0.921 0.972 0.822 0.778 188 0.920 0.876 0.955 0.956 0.925 0.977 0.831 0.797 189 0.920 0.875 0.954 0.960 0.933 0.978 0.823 0.787 190 0.917 0.870 0.955 0.952 0.920 0.973 0.826 0.779 191 0.916 0.869 0.953 0.950 0.915 0.973 0.824 0.780 192 0.915 0.870 0.952 0.952 0.922 0.973 0.824 0.782 193 0.914 0.869 0.951 0.950 0.917 0.973 0.823 0.783 194 0.920 0.877 0.954 0.956 0.920 0.977 0.832 0.801 195 0.920 0.877 0.954 0.960 0.929 0.978 0.824 0.791 196 0.917 0.870 0.954 0.951 0.914 0.973 0.826 0.784 197 0.918 0.871 0.955 0.957 0.917 0.978 0.826 0.788 198 0.919 0.871 0.956 0.958 0.915 0.978 0.828 0.790 199 0.884 0.830 0.929 0.924 0.894 0.944 0.764 0.707 Panel HFpEF HFrEF HFrEF ICMP ICMP Number symptomatic HFrEF asymptomatic symptomatic ICMP asymptomatic symptomatic 104 0.872 0.966 0.942 0.979 0.972 0.961 0.975 105 0.870 0.967 0.946 0.979 0.976 0.965 0.978 106 0.866 0.965 0.943 0.976 0.974 0.961 0.977 107 0.858 0.965 0.943 0.978 0.971 0.960 0.974 108 0.867 0.964 0.942 0.976 0.972 0.961 0.974 109 0.870 0.962 0.939 0.976 0.973 0.962 0.975 110 0.873 0.960 0.938 0.973 0.972 0.961 0.975 111 0.870 0.962 0.939 0.975 0.971 0.962 0.973 112 0.873 0.960 0.938 0.972 0.970 0.962 0.972 113 0.862 0.961 0.937 0.974 0.970 0.959 0.973 114 0.864 0.958 0.936 0.971 0.970 0.958 0.973 115 0.862 0.959 0.936 0.973 0.968 0.959 0.970 116 0.879 0.965 0.945 0.977 0.975 0.965 0.978 117 0.864 0.957 0.935 0.970 0.967 0.958 0.969 118 0.870 0.966 0.945 0.979 0.974 0.965 0.976 119 0.879 0.965 0.945 0.976 0.974 0.966 0.975 120 0.864 0.964 0.940 0.977 0.972 0.960 0.975 121 0.869 0.961 0.938 0.974 0.972 0.960 0.974 122 0.864 0.962 0.939 0.976 0.970 0.960 0.972 123 0.870 0.960 0.938 0.973 0.969 0.960 0.971 124 0.858 0.966 0.943 0.978 0.973 0.960 0.977 125 0.869 0.969 0.947 0.980 0.980 0.965 0.984 126 0.870 0.969 0.947 0.981 0.980 0.972 0.983 127 0.873 0.966 0.942 0.979 0.976 0.966 0.979 128 0.873 0.967 0.944 0.980 0.977 0.972 0.979 129 0.867 0.971 0.957 0.980 0.980 0.973 0.981 130 0.869 0.972 0.957 0.981 0.981 0.976 0.981 131 0.871 0.969 0.951 0.980 0.980 0.971 0.982 132 0.871 0.970 0.951 0.980 0.981 0.975 0.982 133 0.869 0.968 0.946 0.980 0.980 0.971 0.983 134 0.871 0.966 0.941 0.979 0.976 0.965 0.978 135 0.871 0.966 0.942 0.979 0.977 0.971 0.978 136 0.866 0.970 0.956 0.980 0.980 0.972 0.981 137 0.867 0.971 0.956 0.981 0.980 0.975 0.981 138 0.869 0.968 0.950 0.979 0.980 0.970 0.981 139 0.870 0.969 0.950 0.980 0.980 0.974 0.981 140 0.868 0.969 0.947 0.980 0.979 0.964 0.984 141 0.869 0.969 0.947 0.981 0.980 0.971 0.983 142 0.871 0.967 0.942 0.979 0.976 0.965 0.978 143 0.871 0.967 0.944 0.980 0.977 0.971 0.979 144 0.866 0.971 0.956 0.980 0.980 0.972 0.981 145 0.867 0.972 0.956 0.981 0.980 0.975 0.981 146 0.869 0.969 0.951 0.980 0.980 0.970 0.982 147 0.870 0.970 0.951 0.980 0.980 0.975 0.982 148 0.870 0.968 0.946 0.980 0.979 0.964 0.984 149 0.872 0.969 0.946 0.980 0.980 0.971 0.983 150 0.874 0.966 0.941 0.979 0.976 0.965 0.978 151 0.875 0.967 0.943 0.979 0.977 0.971 0.978 152 0.868 0.971 0.956 0.980 0.980 0.972 0.981 153 0.870 0.971 0.956 0.981 0.980 0.976 0.981 154 0.872 0.969 0.950 0.979 0.980 0.971 0.982 155 0.873 0.969 0.950 0.980 0.980 0.975 0.982 156 0.867 0.968 0.946 0.980 0.979 0.964 0.984 157 0.869 0.968 0.946 0.980 0.980 0.970 0.983 158 0.871 0.966 0.941 0.979 0.976 0.965 0.978 159 0.871 0.967 0.942 0.979 0.977 0.970 0.978 160 0.865 0.971 0.956 0.980 0.980 0.972 0.981 161 0.867 0.971 0.956 0.981 0.980 0.975 0.981 162 0.869 0.969 0.950 0.979 0.980 0.970 0.982 163 0.870 0.969 0.950 0.980 0.980 0.974 0.982 164 0.868 0.968 0.946 0.980 0.979 0.964 0.984 165 0.863 0.963 0.938 0.976 0.976 0.962 0.980 166 0.867 0.962 0.935 0.976 0.972 0.961 0.975 167 0.860 0.965 0.940 0.978 0.973 0.961 0.977 168 0.874 0.961 0.934 0.975 0.973 0.964 0.975 169 0.865 0.959 0.932 0.973 0.970 0.959 0.972 170 0.867 0.963 0.935 0.977 0.972 0.964 0.975 171 0.861 0.965 0.939 0.978 0.973 0.965 0.976 172 0.875 0.961 0.933 0.976 0.974 0.967 0.975 173 0.864 0.966 0.942 0.978 0.978 0.961 0.982 174 0.866 0.959 0.930 0.974 0.970 0.961 0.972 175 0.861 0.969 0.953 0.979 0.978 0.970 0.979 176 0.855 0.970 0.955 0.980 0.979 0.969 0.981 177 0.868 0.967 0.952 0.978 0.979 0.972 0.980 178 0.859 0.967 0.951 0.977 0.977 0.970 0.978 179 0.863 0.969 0.953 0.980 0.978 0.972 0.979 180 0.857 0.971 0.955 0.980 0.978 0.970 0.980 181 0.870 0.968 0.952 0.978 0.978 0.973 0.979 182 0.858 0.968 0.945 0.979 0.978 0.961 0.983 183 0.861 0.967 0.951 0.978 0.977 0.970 0.978 184 0.865 0.966 0.946 0.978 0.978 0.967 0.979 185 0.858 0.968 0.948 0.979 0.978 0.966 0.980 186 0.872 0.965 0.945 0.976 0.979 0.970 0.980 187 0.864 0.963 0.943 0.975 0.976 0.967 0.978 188 0.866 0.966 0.946 0.978 0.978 0.970 0.979 189 0.860 0.968 0.948 0.979 0.978 0.967 0.980 190 0.873 0.965 0.945 0.977 0.978 0.974 0.979 191 0.870 0.964 0.941 0.977 0.978 0.963 0.982 192 0.864 0.964 0.944 0.976 0.976 0.969 0.977 193 0.862 0.963 0.939 0.976 0.976 0.960 0.981 194 0.865 0.966 0.941 0.979 0.977 0.965 0.982 195 0.860 0.968 0.944 0.980 0.977 0.964 0.982 196 0.871 0.964 0.939 0.977 0.977 0.967 0.981 197 0.872 0.965 0.941 0.978 0.974 0.963 0.976 198 0.872 0.966 0.943 0.979 0.976 0.972 0.977 199 0.819 0.947 0.920 0.962 0.971 0.951 0.977

TABLE-US-00010 TABLE 4C AUC values for Panel Number 104 to 199 without NT-proBNP and with ANOVA correction for age, BMI and gender in different CHF sub-groups Panel CHF CHF DCMP DCMP HFpEF Number CHF asymptomatic symptomatic DCMP asymptomatic symptomatic HFpEF asymptomatic 104 0.787 0.740 0.822 0.798 0.723 0.830 0.703 0.662 105 0.788 0.739 0.822 0.797 0.720 0.828 0.704 0.657 106 0.782 0.739 0.813 0.796 0.726 0.819 0.703 0.664 107 0.788 0.744 0.820 0.798 0.720 0.826 0.708 0.669 108 0.782 0.740 0.812 0.795 0.725 0.819 0.702 0.662 109 0.772 0.718 0.812 0.776 0.657 0.816 0.687 0.619 110 0.763 0.714 0.799 0.774 0.667 0.806 0.675 0.610 111 0.772 0.719 0.812 0.776 0.657 0.816 0.687 0.619 112 0.764 0.715 0.798 0.774 0.667 0.806 0.675 0.614 113 0.766 0.715 0.804 0.766 0.633 0.806 0.689 0.627 114 0.756 0.710 0.790 0.764 0.642 0.795 0.675 0.613 115 0.766 0.716 0.803 0.765 0.633 0.805 0.688 0.629 116 0.780 0.734 0.812 0.793 0.720 0.820 0.697 0.650 117 0.756 0.711 0.789 0.763 0.644 0.794 0.674 0.616 118 0.787 0.739 0.821 0.796 0.717 0.828 0.703 0.658 119 0.780 0.735 0.812 0.793 0.720 0.820 0.697 0.650 120 0.781 0.733 0.817 0.784 0.674 0.824 0.710 0.671 121 0.771 0.726 0.804 0.780 0.679 0.812 0.698 0.659 122 0.781 0.733 0.816 0.783 0.673 0.823 0.708 0.672 123 0.771 0.727 0.803 0.779 0.678 0.811 0.698 0.658 124 0.789 0.744 0.822 0.799 0.725 0.827 0.709 0.671 125 0.809 0.757 0.850 0.813 0.745 0.839 0.719 0.665 126 0.810 0.758 0.851 0.812 0.741 0.841 0.723 0.669 127 0.805 0.746 0.852 0.813 0.727 0.846 0.713 0.659 128 0.807 0.747 0.855 0.815 0.720 0.852 0.716 0.660 129 0.800 0.751 0.835 0.810 0.755 0.834 0.710 0.659 130 0.799 0.751 0.835 0.809 0.744 0.834 0.713 0.661 131 0.812 0.756 0.856 0.819 0.761 0.844 0.723 0.658 132 0.815 0.759 0.860 0.822 0.763 0.849 0.727 0.664 133 0.810 0.757 0.851 0.810 0.730 0.842 0.727 0.681 134 0.803 0.744 0.851 0.809 0.720 0.846 0.716 0.669 135 0.805 0.744 0.854 0.812 0.711 0.852 0.719 0.668 136 0.799 0.750 0.835 0.808 0.749 0.835 0.714 0.670 137 0.799 0.750 0.835 0.806 0.737 0.835 0.718 0.673 138 0.812 0.755 0.857 0.816 0.755 0.845 0.727 0.672 139 0.814 0.758 0.860 0.819 0.755 0.850 0.731 0.674 140 0.812 0.761 0.852 0.817 0.754 0.842 0.723 0.676 141 0.812 0.761 0.852 0.815 0.746 0.843 0.726 0.678 142 0.806 0.749 0.852 0.814 0.734 0.846 0.716 0.669 143 0.808 0.749 0.855 0.815 0.721 0.851 0.719 0.668 144 0.802 0.755 0.836 0.813 0.759 0.837 0.713 0.670 145 0.801 0.754 0.836 0.810 0.750 0.835 0.717 0.670 146 0.814 0.759 0.857 0.821 0.764 0.845 0.725 0.671 147 0.816 0.762 0.860 0.822 0.763 0.850 0.729 0.672 148 0.808 0.755 0.849 0.810 0.743 0.837 0.718 0.664 149 0.809 0.756 0.850 0.809 0.739 0.839 0.721 0.668 150 0.803 0.744 0.851 0.810 0.725 0.845 0.712 0.658 151 0.805 0.745 0.854 0.812 0.719 0.851 0.715 0.658 152 0.798 0.749 0.834 0.808 0.753 0.833 0.708 0.657 153 0.798 0.749 0.834 0.806 0.742 0.833 0.712 0.661 154 0.811 0.754 0.856 0.816 0.759 0.843 0.721 0.656 155 0.814 0.757 0.859 0.818 0.760 0.848 0.725 0.662 156 0.808 0.755 0.849 0.810 0.745 0.837 0.717 0.660 157 0.808 0.756 0.850 0.809 0.737 0.839 0.721 0.665 158 0.803 0.744 0.851 0.810 0.727 0.844 0.711 0.654 159 0.805 0.745 0.853 0.813 0.717 0.850 0.714 0.656 160 0.798 0.749 0.834 0.808 0.751 0.832 0.708 0.655 161 0.798 0.749 0.834 0.806 0.740 0.832 0.712 0.659 162 0.811 0.755 0.855 0.816 0.757 0.842 0.721 0.654 163 0.813 0.757 0.858 0.818 0.757 0.848 0.725 0.659 164 0.809 0.756 0.850 0.811 0.738 0.840 0.724 0.677 165 0.795 0.739 0.840 0.785 0.673 0.820 0.714 0.656 166 0.797 0.739 0.845 0.798 0.681 0.838 0.717 0.670 167 0.802 0.749 0.846 0.809 0.735 0.836 0.715 0.669 168 0.788 0.724 0.842 0.790 0.669 0.833 0.695 0.618 169 0.782 0.721 0.833 0.780 0.645 0.821 0.697 0.631 170 0.799 0.740 0.849 0.800 0.667 0.845 0.721 0.673 171 0.803 0.748 0.848 0.807 0.715 0.838 0.719 0.670 172 0.789 0.722 0.844 0.791 0.649 0.839 0.700 0.625 173 0.806 0.753 0.849 0.803 0.718 0.835 0.726 0.681 174 0.783 0.721 0.836 0.781 0.627 0.828 0.702 0.638 175 0.796 0.747 0.833 0.801 0.726 0.831 0.717 0.675 176 0.801 0.755 0.834 0.812 0.759 0.832 0.714 0.672 177 0.787 0.733 0.827 0.792 0.713 0.823 0.695 0.626 178 0.783 0.732 0.822 0.785 0.703 0.815 0.698 0.637 179 0.797 0.749 0.834 0.801 0.716 0.832 0.721 0.678 180 0.799 0.754 0.833 0.807 0.749 0.828 0.718 0.672 181 0.785 0.731 0.826 0.788 0.695 0.822 0.700 0.634 182 0.811 0.761 0.850 0.816 0.756 0.837 0.724 0.677 183 0.783 0.732 0.822 0.782 0.677 0.815 0.704 0.648 184 0.808 0.752 0.854 0.808 0.734 0.840 0.730 0.676 185 0.811 0.759 0.853 0.817 0.763 0.838 0.726 0.673 186 0.799 0.738 0.848 0.799 0.724 0.833 0.708 0.625 187 0.795 0.736 0.843 0.791 0.710 0.824 0.711 0.638 188 0.811 0.757 0.857 0.811 0.735 0.846 0.734 0.678 189 0.812 0.761 0.855 0.816 0.759 0.840 0.730 0.672 190 0.801 0.740 0.851 0.800 0.723 0.838 0.714 0.633 191 0.797 0.739 0.842 0.793 0.703 0.826 0.705 0.635 192 0.797 0.740 0.846 0.793 0.709 0.830 0.717 0.649 193 0.794 0.738 0.839 0.787 0.693 0.819 0.709 0.646 194 0.808 0.756 0.850 0.803 0.709 0.838 0.730 0.684 195 0.810 0.762 0.850 0.812 0.745 0.836 0.727 0.680 196 0.796 0.738 0.842 0.789 0.685 0.826 0.709 0.641 197 0.799 0.743 0.843 0.810 0.723 0.843 0.704 0.658 198 0.800 0.743 0.846 0.811 0.714 0.849 0.708 0.655 199 0.754 0.702 0.801 0.739 0.646 0.757 0.672 0.558 Panel HFpEF HFrEF HFrEF ICMP ICMP Number symptomatic HFrEF asymptomatic symptomatic ICMP asymptomatic symptomatic 104 0.717 0.831 0.788 0.853 0.862 0.836 0.867 105 0.720 0.831 0.785 0.853 0.865 0.833 0.874 106 0.700 0.825 0.782 0.845 0.857 0.822 0.868 107 0.705 0.830 0.785 0.851 0.857 0.828 0.861 108 0.688 0.824 0.783 0.844 0.852 0.821 0.858 109 0.710 0.817 0.766 0.841 0.855 0.824 0.863 110 0.678 0.811 0.764 0.832 0.848 0.812 0.859 111 0.693 0.817 0.766 0.841 0.851 0.823 0.853 112 0.667 0.810 0.764 0.831 0.844 0.811 0.848 113 0.704 0.806 0.754 0.832 0.847 0.814 0.855 114 0.673 0.800 0.752 0.822 0.839 0.801 0.852 115 0.692 0.806 0.754 0.831 0.842 0.810 0.843 116 0.703 0.825 0.782 0.845 0.859 0.826 0.870 117 0.657 0.800 0.753 0.821 0.834 0.800 0.839 118 0.711 0.831 0.785 0.852 0.861 0.831 0.864 119 0.695 0.824 0.782 0.844 0.855 0.825 0.859 120 0.718 0.820 0.767 0.846 0.856 0.821 0.866 121 0.695 0.812 0.764 0.836 0.848 0.810 0.861 122 0.710 0.819 0.767 0.845 0.851 0.816 0.855 123 0.683 0.812 0.764 0.835 0.843 0.809 0.849 124 0.715 0.830 0.785 0.852 0.862 0.829 0.872 125 0.756 0.858 0.813 0.880 0.906 0.863 0.919 126 0.759 0.855 0.810 0.880 0.904 0.866 0.912 127 0.766 0.853 0.806 0.876 0.892 0.863 0.896 128 0.763 0.855 0.806 0.880 0.894 0.867 0.896 129 0.724 0.848 0.807 0.868 0.885 0.851 0.892 130 0.728 0.845 0.804 0.866 0.882 0.852 0.885 131 0.777 0.860 0.823 0.880 0.903 0.873 0.908 132 0.776 0.861 0.824 0.882 0.904 0.877 0.906 133 0.760 0.854 0.806 0.880 0.902 0.862 0.912 134 0.765 0.851 0.803 0.875 0.890 0.859 0.895 135 0.762 0.853 0.803 0.878 0.892 0.863 0.894 136 0.725 0.847 0.805 0.868 0.884 0.846 0.892 137 0.729 0.843 0.801 0.866 0.881 0.848 0.885 138 0.778 0.859 0.820 0.879 0.902 0.869 0.907 139 0.777 0.860 0.821 0.882 0.902 0.873 0.905 140 0.757 0.860 0.814 0.882 0.905 0.861 0.919 141 0.759 0.857 0.810 0.881 0.903 0.864 0.912 142 0.765 0.854 0.806 0.877 0.891 0.862 0.896 143 0.762 0.855 0.806 0.880 0.893 0.866 0.895 144 0.724 0.850 0.808 0.870 0.885 0.849 0.893 145 0.727 0.846 0.804 0.867 0.881 0.850 0.885 146 0.776 0.861 0.822 0.881 0.902 0.871 0.908 147 0.776 0.862 0.823 0.883 0.903 0.875 0.905 148 0.754 0.857 0.810 0.878 0.904 0.860 0.918 149 0.757 0.854 0.807 0.878 0.902 0.862 0.911 150 0.764 0.852 0.803 0.875 0.891 0.859 0.895 151 0.761 0.853 0.803 0.878 0.892 0.863 0.894 152 0.722 0.847 0.805 0.867 0.884 0.847 0.892 153 0.726 0.843 0.801 0.864 0.880 0.848 0.884 154 0.775 0.859 0.820 0.878 0.902 0.870 0.907 155 0.775 0.860 0.821 0.881 0.902 0.874 0.904 156 0.755 0.857 0.811 0.878 0.904 0.859 0.918 157 0.758 0.854 0.808 0.878 0.902 0.861 0.911 158 0.764 0.852 0.804 0.875 0.890 0.859 0.895 159 0.761 0.853 0.805 0.878 0.892 0.862 0.894 160 0.722 0.847 0.806 0.867 0.884 0.846 0.892 161 0.726 0.843 0.802 0.864 0.880 0.847 0.884 162 0.775 0.859 0.821 0.878 0.901 0.868 0.907 163 0.775 0.860 0.822 0.880 0.902 0.872 0.904 164 0.758 0.857 0.810 0.879 0.904 0.859 0.918 165 0.754 0.837 0.783 0.866 0.892 0.850 0.903 166 0.763 0.840 0.787 0.868 0.881 0.850 0.886 167 0.759 0.849 0.803 0.870 0.885 0.857 0.890 168 0.757 0.838 0.785 0.864 0.882 0.854 0.885 169 0.751 0.827 0.774 0.853 0.871 0.844 0.874 170 0.760 0.841 0.787 0.871 0.882 0.854 0.885 171 0.758 0.847 0.801 0.869 0.883 0.858 0.885 172 0.756 0.837 0.782 0.866 0.881 0.857 0.881 173 0.758 0.851 0.800 0.877 0.902 0.854 0.917 174 0.751 0.826 0.771 0.855 0.870 0.846 0.870 175 0.724 0.841 0.794 0.865 0.880 0.841 0.888 176 0.721 0.848 0.806 0.868 0.882 0.847 0.891 177 0.716 0.837 0.790 0.858 0.878 0.844 0.885 178 0.714 0.830 0.782 0.853 0.873 0.836 0.881 179 0.730 0.838 0.791 0.864 0.877 0.842 0.882 180 0.725 0.841 0.800 0.863 0.876 0.844 0.881 181 0.722 0.830 0.783 0.854 0.872 0.843 0.874 182 0.755 0.858 0.812 0.880 0.903 0.859 0.919 183 0.718 0.824 0.776 0.851 0.867 0.834 0.872 184 0.778 0.852 0.809 0.875 0.896 0.863 0.902 185 0.771 0.857 0.818 0.876 0.897 0.865 0.904 186 0.772 0.848 0.807 0.869 0.896 0.867 0.900 187 0.769 0.839 0.798 0.862 0.888 0.858 0.893 188 0.777 0.853 0.810 0.878 0.897 0.868 0.900 189 0.772 0.855 0.817 0.876 0.895 0.867 0.898 190 0.772 0.847 0.806 0.870 0.895 0.871 0.894 191 0.749 0.846 0.797 0.870 0.900 0.857 0.913 192 0.769 0.839 0.798 0.864 0.888 0.862 0.888 193 0.750 0.841 0.789 0.866 0.896 0.850 0.911 194 0.761 0.849 0.796 0.878 0.900 0.857 0.910 195 0.758 0.854 0.806 0.878 0.899 0.858 0.909 196 0.753 0.841 0.789 0.868 0.896 0.858 0.903 197 0.743 0.848 0.803 0.870 0.884 0.861 0.885 198 0.747 0.849 0.803 0.872 0.885 0.865 0.882 199 0.746 0.799 0.770 0.819 0.871 0.851 0.875

TABLE-US-00011 TABLE 4D AUC values for Panel Number 104 to 199 with NT-proBNP and with ANOVA correction for age, BMI and gender in different CHF sub-groups Panel CHF CHF DCMP DCMP HFpEF Number CHF asymptomatic symptomatic DCMP asymptomatic symptomatic HFpEF asymptomatic 104 0.892 0.842 0.930 0.949 0.908 0.969 0.772 0.723 105 0.892 0.842 0.931 0.948 0.907 0.969 0.772 0.719 106 0.889 0.842 0.927 0.948 0.912 0.964 0.770 0.719 107 0.891 0.842 0.929 0.950 0.912 0.968 0.770 0.721 108 0.889 0.842 0.926 0.948 0.912 0.964 0.770 0.719 109 0.886 0.833 0.927 0.940 0.895 0.963 0.763 0.700 110 0.882 0.832 0.922 0.939 0.896 0.959 0.759 0.698 111 0.885 0.833 0.926 0.940 0.895 0.963 0.764 0.701 112 0.882 0.833 0.921 0.939 0.895 0.958 0.760 0.699 113 0.885 0.834 0.925 0.941 0.896 0.963 0.767 0.708 114 0.881 0.833 0.920 0.939 0.897 0.958 0.761 0.703 115 0.885 0.834 0.924 0.941 0.896 0.963 0.766 0.708 116 0.890 0.841 0.928 0.946 0.908 0.964 0.771 0.716 117 0.881 0.833 0.919 0.939 0.896 0.958 0.761 0.703 118 0.892 0.842 0.930 0.948 0.907 0.968 0.772 0.719 119 0.889 0.841 0.927 0.946 0.907 0.964 0.771 0.717 120 0.890 0.841 0.929 0.945 0.900 0.967 0.778 0.729 121 0.886 0.839 0.924 0.943 0.900 0.962 0.774 0.723 122 0.889 0.840 0.928 0.945 0.899 0.967 0.777 0.729 123 0.886 0.839 0.923 0.943 0.900 0.962 0.773 0.723 124 0.892 0.843 0.930 0.950 0.912 0.968 0.771 0.722 125 0.895 0.844 0.935 0.948 0.910 0.968 0.776 0.723 126 0.896 0.844 0.936 0.948 0.910 0.968 0.779 0.725 127 0.893 0.841 0.934 0.947 0.906 0.968 0.772 0.721 128 0.894 0.841 0.935 0.947 0.903 0.968 0.775 0.721 129 0.895 0.847 0.933 0.950 0.920 0.968 0.774 0.720 130 0.896 0.849 0.934 0.951 0.920 0.968 0.776 0.722 131 0.896 0.843 0.936 0.948 0.913 0.967 0.776 0.719 132 0.897 0.845 0.937 0.948 0.913 0.967 0.778 0.721 133 0.895 0.844 0.936 0.948 0.908 0.968 0.783 0.733 134 0.892 0.840 0.933 0.947 0.903 0.968 0.775 0.727 135 0.893 0.840 0.934 0.947 0.901 0.968 0.778 0.729 136 0.895 0.847 0.932 0.949 0.918 0.968 0.778 0.727 137 0.896 0.849 0.933 0.951 0.918 0.968 0.780 0.731 138 0.895 0.843 0.935 0.947 0.911 0.967 0.780 0.726 139 0.896 0.845 0.936 0.948 0.911 0.967 0.782 0.729 140 0.896 0.844 0.935 0.950 0.914 0.969 0.777 0.725 141 0.896 0.845 0.936 0.950 0.913 0.969 0.779 0.728 142 0.893 0.842 0.934 0.949 0.909 0.969 0.772 0.723 143 0.894 0.841 0.935 0.949 0.906 0.968 0.775 0.724 144 0.895 0.847 0.932 0.952 0.922 0.969 0.774 0.722 145 0.897 0.849 0.933 0.953 0.922 0.969 0.777 0.725 146 0.896 0.844 0.936 0.949 0.916 0.968 0.776 0.722 147 0.897 0.845 0.937 0.950 0.916 0.968 0.778 0.723 148 0.894 0.842 0.935 0.947 0.909 0.967 0.775 0.720 149 0.895 0.843 0.935 0.948 0.909 0.967 0.778 0.723 150 0.892 0.839 0.933 0.947 0.904 0.967 0.771 0.719 151 0.893 0.839 0.934 0.947 0.902 0.967 0.773 0.719 152 0.894 0.846 0.932 0.950 0.919 0.967 0.773 0.718 153 0.896 0.847 0.933 0.951 0.919 0.968 0.775 0.720 154 0.895 0.842 0.935 0.947 0.912 0.967 0.774 0.716 155 0.896 0.843 0.936 0.948 0.912 0.967 0.777 0.718 156 0.894 0.842 0.935 0.947 0.909 0.967 0.776 0.720 157 0.895 0.843 0.935 0.947 0.908 0.968 0.778 0.723 158 0.891 0.839 0.933 0.947 0.904 0.967 0.771 0.718 159 0.892 0.839 0.934 0.947 0.901 0.967 0.773 0.716 160 0.894 0.846 0.932 0.949 0.918 0.967 0.773 0.717 161 0.895 0.847 0.933 0.951 0.918 0.968 0.776 0.720 162 0.894 0.842 0.935 0.947 0.911 0.967 0.775 0.716 163 0.896 0.843 0.936 0.948 0.912 0.967 0.778 0.719 164 0.895 0.843 0.935 0.947 0.908 0.968 0.781 0.730 165 0.890 0.838 0.931 0.941 0.900 0.962 0.776 0.719 166 0.890 0.839 0.931 0.944 0.898 0.967 0.777 0.731 167 0.892 0.841 0.931 0.949 0.911 0.968 0.770 0.723 168 0.886 0.831 0.929 0.939 0.893 0.963 0.763 0.702 169 0.885 0.833 0.927 0.940 0.894 0.962 0.766 0.710 170 0.891 0.840 0.932 0.944 0.895 0.966 0.779 0.732 171 0.892 0.841 0.932 0.948 0.907 0.967 0.773 0.723 172 0.886 0.830 0.930 0.938 0.889 0.962 0.766 0.702 173 0.894 0.843 0.934 0.945 0.904 0.967 0.783 0.733 174 0.886 0.833 0.928 0.939 0.890 0.962 0.768 0.710 175 0.894 0.847 0.931 0.948 0.915 0.967 0.780 0.731 176 0.895 0.848 0.931 0.952 0.924 0.968 0.773 0.723 177 0.890 0.839 0.929 0.943 0.909 0.963 0.766 0.701 178 0.890 0.841 0.928 0.944 0.911 0.962 0.770 0.711 179 0.895 0.849 0.932 0.949 0.915 0.967 0.783 0.733 180 0.896 0.849 0.932 0.953 0.924 0.968 0.776 0.725 181 0.891 0.840 0.930 0.944 0.909 0.963 0.769 0.708 182 0.895 0.844 0.934 0.950 0.915 0.968 0.776 0.725 183 0.891 0.843 0.929 0.945 0.912 0.963 0.773 0.716 184 0.894 0.843 0.934 0.944 0.907 0.966 0.782 0.729 185 0.895 0.844 0.934 0.949 0.917 0.967 0.774 0.721 186 0.889 0.835 0.932 0.939 0.901 0.962 0.768 0.700 187 0.889 0.837 0.930 0.940 0.903 0.961 0.771 0.709 188 0.895 0.845 0.935 0.945 0.908 0.966 0.784 0.732 189 0.896 0.844 0.935 0.949 0.917 0.966 0.777 0.723 190 0.890 0.836 0.933 0.940 0.901 0.962 0.771 0.703 191 0.889 0.835 0.931 0.940 0.898 0.963 0.768 0.706 192 0.890 0.838 0.931 0.941 0.904 0.962 0.774 0.712 193 0.889 0.837 0.931 0.940 0.900 0.962 0.773 0.714 194 0.895 0.845 0.935 0.945 0.904 0.967 0.785 0.736 195 0.896 0.845 0.935 0.950 0.914 0.967 0.779 0.727 196 0.889 0.835 0.932 0.940 0.897 0.962 0.771 0.709 197 0.891 0.840 0.931 0.947 0.906 0.967 0.770 0.722 198 0.892 0.840 0.932 0.947 0.903 0.967 0.772 0.723 199 0.870 0.814 0.916 0.923 0.890 0.941 0.737 0.656 Panel HFpEF HFrEF HFrEF ICMP ICMP Number symptomatic HFrEF asymptomatic symptomatic ICMP asymptomatic symptomatic 104 0.808 0.954 0.933 0.967 0.960 0.951 0.961 105 0.810 0.954 0.932 0.967 0.962 0.951 0.962 106 0.803 0.953 0.931 0.965 0.961 0.948 0.961 107 0.798 0.954 0.931 0.967 0.959 0.947 0.959 108 0.797 0.953 0.931 0.965 0.958 0.948 0.959 109 0.806 0.950 0.926 0.963 0.960 0.949 0.960 110 0.800 0.949 0.926 0.962 0.959 0.949 0.960 111 0.800 0.949 0.927 0.963 0.958 0.949 0.957 112 0.795 0.948 0.927 0.961 0.957 0.949 0.957 113 0.804 0.948 0.925 0.962 0.958 0.947 0.958 114 0.797 0.947 0.925 0.960 0.958 0.947 0.958 115 0.797 0.948 0.925 0.962 0.956 0.947 0.955 116 0.809 0.953 0.932 0.965 0.962 0.951 0.962 117 0.791 0.947 0.925 0.960 0.955 0.947 0.955 118 0.804 0.954 0.932 0.967 0.960 0.950 0.960 119 0.805 0.953 0.932 0.965 0.960 0.951 0.960 120 0.809 0.951 0.927 0.965 0.959 0.947 0.960 121 0.806 0.950 0.927 0.963 0.959 0.947 0.959 122 0.802 0.950 0.927 0.965 0.957 0.947 0.957 123 0.799 0.949 0.927 0.963 0.957 0.947 0.957 124 0.804 0.954 0.931 0.967 0.961 0.948 0.961 125 0.818 0.956 0.934 0.969 0.969 0.952 0.974 126 0.820 0.956 0.934 0.969 0.969 0.959 0.973 127 0.817 0.955 0.932 0.968 0.966 0.957 0.965 128 0.816 0.955 0.933 0.968 0.966 0.962 0.965 129 0.804 0.958 0.941 0.969 0.968 0.957 0.968 130 0.805 0.959 0.941 0.970 0.968 0.961 0.968 131 0.823 0.957 0.938 0.968 0.970 0.958 0.970 132 0.823 0.957 0.938 0.969 0.970 0.963 0.970 133 0.820 0.956 0.933 0.969 0.968 0.958 0.973 134 0.816 0.954 0.931 0.967 0.965 0.955 0.965 135 0.816 0.955 0.932 0.968 0.966 0.961 0.965 136 0.804 0.958 0.940 0.969 0.968 0.956 0.968 137 0.805 0.958 0.940 0.969 0.967 0.960 0.967 138 0.823 0.956 0.937 0.968 0.970 0.957 0.970 139 0.823 0.957 0.937 0.969 0.969 0.961 0.970 140 0.818 0.957 0.934 0.969 0.969 0.951 0.974 141 0.819 0.957 0.933 0.970 0.968 0.959 0.973 142 0.816 0.955 0.932 0.968 0.965 0.956 0.965 143 0.815 0.955 0.932 0.968 0.966 0.961 0.965 144 0.803 0.958 0.940 0.969 0.968 0.957 0.968 145 0.805 0.959 0.940 0.970 0.967 0.961 0.968 146 0.822 0.957 0.937 0.969 0.970 0.957 0.970 147 0.822 0.957 0.937 0.969 0.969 0.962 0.970 148 0.817 0.956 0.933 0.969 0.968 0.950 0.974 149 0.819 0.956 0.933 0.969 0.968 0.958 0.973 150 0.816 0.954 0.931 0.967 0.965 0.955 0.965 151 0.815 0.955 0.932 0.968 0.965 0.960 0.965 152 0.803 0.958 0.940 0.969 0.967 0.956 0.968 153 0.805 0.958 0.940 0.969 0.967 0.960 0.967 154 0.822 0.957 0.937 0.968 0.969 0.957 0.970 155 0.822 0.957 0.937 0.969 0.969 0.961 0.970 156 0.817 0.956 0.933 0.969 0.969 0.950 0.974 157 0.819 0.956 0.933 0.969 0.968 0.958 0.973 158 0.815 0.954 0.931 0.967 0.965 0.955 0.965 159 0.815 0.955 0.932 0.968 0.966 0.960 0.965 160 0.803 0.958 0.940 0.969 0.968 0.956 0.968 161 0.804 0.958 0.940 0.970 0.967 0.960 0.968 162 0.821 0.957 0.937 0.968 0.970 0.957 0.970 163 0.822 0.957 0.937 0.969 0.969 0.961 0.970 164 0.818 0.956 0.933 0.969 0.969 0.950 0.974 165 0.816 0.950 0.925 0.965 0.964 0.950 0.970 166 0.814 0.951 0.927 0.965 0.962 0.952 0.961 167 0.809 0.954 0.931 0.967 0.963 0.953 0.963 168 0.812 0.950 0.926 0.964 0.963 0.954 0.962 169 0.808 0.948 0.924 0.962 0.960 0.952 0.959 170 0.814 0.951 0.926 0.965 0.961 0.955 0.961 171 0.810 0.954 0.930 0.966 0.963 0.955 0.962 172 0.813 0.949 0.924 0.963 0.962 0.958 0.961 173 0.819 0.954 0.929 0.967 0.967 0.948 0.972 174 0.809 0.947 0.922 0.962 0.959 0.954 0.958 175 0.803 0.956 0.937 0.967 0.966 0.954 0.966 176 0.798 0.958 0.940 0.969 0.967 0.954 0.967 177 0.800 0.954 0.936 0.966 0.966 0.956 0.966 178 0.799 0.954 0.935 0.965 0.965 0.954 0.965 179 0.805 0.956 0.937 0.968 0.965 0.956 0.966 180 0.800 0.958 0.939 0.969 0.966 0.954 0.966 181 0.802 0.954 0.935 0.966 0.965 0.958 0.965 182 0.814 0.957 0.933 0.969 0.968 0.948 0.973 183 0.801 0.954 0.934 0.966 0.964 0.954 0.964 184 0.822 0.954 0.933 0.966 0.967 0.955 0.967 185 0.816 0.956 0.936 0.968 0.968 0.954 0.969 186 0.820 0.952 0.932 0.965 0.968 0.957 0.968 187 0.818 0.951 0.931 0.963 0.966 0.955 0.966 188 0.823 0.954 0.933 0.967 0.967 0.957 0.967 189 0.817 0.956 0.935 0.968 0.967 0.955 0.968 190 0.820 0.952 0.931 0.965 0.967 0.960 0.967 191 0.814 0.952 0.928 0.965 0.967 0.950 0.972 192 0.818 0.951 0.931 0.964 0.965 0.956 0.965 193 0.815 0.951 0.927 0.965 0.966 0.948 0.971 194 0.820 0.953 0.928 0.968 0.966 0.952 0.971 195 0.816 0.956 0.931 0.969 0.966 0.951 0.972 196 0.816 0.951 0.926 0.966 0.965 0.955 0.970 197 0.808 0.954 0.932 0.967 0.963 0.955 0.962 198 0.810 0.954 0.933 0.967 0.964 0.962 0.962 199 0.796 0.941 0.918 0.955 0.963 0.948 0.968

TABLE-US-00012 TABLE 5 Performance of three selected panels (panels number 1, 3, and 4 in Table 2, respectively) with or without NT-proBNP and with or without ANOVA correction for age, BMI and gender in different CHF subgroups in the testing (“VD”) data set, as compared to the known marker NT-proBNP alone. NT- With Panel proBNP Panel NT- With AUC AUC Number proBNP ANOVA SUBGROUP estimate estimate 1 yes no DCMP asymptomatic 0.887 0.845 1 yes no DCMP symptomatic 0.965 0.944 1 yes no DCMP 0.937 0.905 1 yes no HFrEF asymptomatic 0.950 0.911 1 yes no HFrEF symptomatic 0.974 0.939 1 yes no HFrEF 0.966 0.926 1 yes no ICMP asymptomatic 0.995 0.970 1 yes no ICMP symptomatic 0.983 0.936 1 yes no ICMP 0.988 0.949 1 yes no HFrEF LVEF < 35% 0.995 0.987 1 yes no HFrEF LVEF 35% to 0.942 0.873 50% 1 yes no HFrEF MALE 0.971 0.939 1 yes no HFrEF FEMALE 0.935 0.928 3 no no DCMP asymptomatic 0.800 0.845 3 no no DCMP symptomatic 0.872 0.944 3 no no DCMP 0.845 0.905 3 no no HFrEF asymptomatic 0.854 0.911 3 no no HFrEF symptomatic 0.887 0.939 3 no no HFrEF 0.875 0.926 3 no no ICMP asymptomatic 0.908 0.970 3 no no ICMP symptomatic 0.900 0.936 3 no no ICMP 0.904 0.949 3 no no HFrEF LVEF < 35% 0.914 0.987 3 no no HFrEF LVEF 35% to 0.841 0.873 50% 3 no no HFrEF MALE 0.862 0.939 3 no no HFrEF FEMALE 0.845 0.928 4 no no DCMP asymptomatic 0.774 0.845 4 no no DCMP symptomatic 0.843 0.944 4 no no DCMP 0.816 0.905 4 no no HFrEF asymptomatic 0.833 0.911 4 no no HFrEF symptomatic 0.862 0.939 4 no no HFrEF 0.851 0.926 4 no no ICMP asymptomatic 0.895 0.970 4 no no ICMP symptomatic 0.880 0.936 4 no no ICMP 0.886 0.949 4 no no HFrEF LVEF < 35% 0.887 0.987 4 no no HFrEF LVEF 35% to 0.821 0.873 50% 4 no no HFrEF MALE 0.839 0.939 4 no no HFrEF FEMALE 0.822 0.928

TABLE-US-00013 TABLE 5a Performance of further selected panels (Table 2a) with or without NT-proBNP and without ANOVA correction for age, BMI and gender in different CHF subgroups in the testing (“VD”) data set, as compared to the known marker NT-proBNP alone NT- With Panel proBNP Panel NT- AUC AUC No. proBNP Subgroup estimate Estimate 200 yes CHF 0.908 0.848 200 yes ICM 0.987 0.949 200 yes DCM 0.936 0.905 200 yes HFrEF 0.964 0.926 200 yes HFpEF 0.820 0.706 200 yes CHF asymptomatic 0.875 0.801 200 yes ICMP asymptomatic 0.994 0.970 200 yes DCMP asymptomatic 0.884 0.845 200 yes HFrEF asymptomatic 0.948 0.911 200 yes HFpEF asymptomatic 0.801 0.670 200 yes CHF symptomatic 0.936 0.890 200 yes ICMP symptomatic 0.981 0.936 200 yes DCMP symptomatic 0.964 0.944 200 yes HFrEF symptomatic 0.973 0.939 200 yes HFpEF symptomatic 0.845 0.754 200 yes ICMP LVEF 35% to 0.978 0.925 50% 200 yes DCMP LVEF 35% to 0.874 0.792 50% 200 yes HFrEF LVEF 35% to 0.939 0.873 50% 200 yes ICMP LVEF < 35% 0.999 0.989 200 yes DCMP LVEF < 35% 0.989 0.986 200 yes HFrEF LVEF < 35% 0.995 0.987 200 no CHF 0.813 0.848 200 no ICM 0.902 0.949 200 no DCM 0.824 0.905 200 no HFrEF 0.863 0.926 200 no HFpEF 0.723 0.706 200 no CHF asymptomatic 0.792 0.801 200 no ICMP asymptomatic 0.905 0.970 200 no DCMP asymptomatic 0.784 0.845 200 no HFrEF asymptomatic 0.844 0.911 200 no HFpEF asymptomatic 0.732 0.670 200 no CHF symptomatic 0.830 0.890 200 no ICMP symptomatic 0.899 0.936 200 no DCMP symptomatic 0.849 0.944 200 no HFrEF symptomatic 0.874 0.939 200 no HFpEF symptomatic 0.707 0.754 200 no ICMP LVEF 35% to 0.889 0.925 50% 200 no DCMP LVEF 35% to 0.747 0.792 50% 200 no HFrEF LVEF 35% to 0.833 0.873 50% 200 no ICMP LVEF < 35% 0.930 0.989 200 no DCMP LVEF < 35% 0.880 0.986 200 no HFrEF LVEF < 35% 0.898 0.987 201 yes CHF 0.895 0.848 201 yes ICM 0.981 0.949 201 yes DCM 0.931 0.905 201 yes HFrEF 0.958 0.926 201 yes HFpEF 0.795 0.706 201 yes CHF asymptomatic 0.859 0.801 201 yes ICMP asymptomatic 0.991 0.970 201 yes DCMP asymptomatic 0.873 0.845 201 yes HFrEF asymptomatic 0.940 0.911 201 yes HFpEF asymptomatic 0.778 0.670 201 yes CHF symptomatic 0.927 0.890 201 yes ICMP symptomatic 0.973 0.936 201 yes DCMP symptomatic 0.964 0.944 201 yes HFrEF symptomatic 0.969 0.939 201 yes HFpEF symptomatic 0.819 0.754 201 yes ICMP LVEF 35% to 0.968 0.925 50% 201 yes DCMP LVEF 35% to 0.859 0.792 50% 201 yes HFrEF LVEF 35% to 0.926 0.873 50% 201 yes ICMP LVEF < 35% 0.999 0.989 201 yes DCMP LVEF < 35% 0.989 0.986 201 yes HFrEF LVEF < 35% 0.994 0.987 201 no CHF 0.794 0.848 201 no ICM 0.887 0.949 201 no DCM 0.814 0.905 201 no HFrEF 0.851 0.926 201 no HFpEF 0.690 0.706 201 no CHF asymptomatic 0.764 0.801 201 no ICMP asymptomatic 0.893 0.970 201 no DCMP asymptomatic 0.759 0.845 201 no HFrEF asymptomatic 0.825 0.911 201 no HFpEF asymptomatic 0.694 0.670 201 no CHF symptomatic 0.817 0.890 201 no ICMP symptomatic 0.883 0.936 201 no DCMP symptomatic 0.848 0.944 201 no HFrEF symptomatic 0.866 0.939 201 no HFpEF symptomatic 0.683 0.754 201 no ICMP LVEF 35% to 0.863 0.925 50% 201 no DCMP LVEF 35% to 0.738 0.792 50% 201 no HFrEF LVEF 35% to 0.814 0.873 50% 201 no ICMP LVEF < 35% 0.938 0.989 201 no DCMP LVEF < 35% 0.869 0.986 201 no HFrEF LVEF < 35% 0.895 0.987 202 yes CHF 0.893 0.848 202 yes ICM 0.981 0.949 202 yes DCM 0.929 0.905 202 yes HFrEF 0.957 0.926 202 yes HFpEF 0.790 0.706 202 yes CHF asymptomatic 0.857 0.801 202 yes ICMP asymptomatic 0.992 0.970 202 yes DCMP asymptomatic 0.869 0.845 202 yes HFrEF asymptomatic 0.938 0.911 202 yes HFpEF asymptomatic 0.775 0.670 202 yes CHF symptomatic 0.924 0.890 202 yes ICMP symptomatic 0.972 0.936 202 yes DCMP symptomatic 0.963 0.944 202 yes HFrEF symptomatic 0.968 0.939 202 yes HFpEF symptomatic 0.810 0.754 202 yes ICMP LVEF 35% to 0.969 0.925 50% 202 yes DCMP LVEF 35% to 0.855 0.792 50% 202 yes HFrEF LVEF 35% to 0.926 0.873 50% 202 yes ICMP LVEF < 35% 0.999 0.989 202 yes DCMP LVEF < 35% 0.988 0.986 202 yes HFrEF LVEF < 35% 0.994 0.987 203 no CHF 0.791 0.848 203 no ICM 0.883 0.949 203 no DCM 0.816 0.905 203 no HFrEF 0.850 0.926 203 no HFpEF 0.683 0.706 203 no CHF asymptomatic 0.761 0.801 203 no ICMP asymptomatic 0.887 0.970 203 no DCMP asymptomatic 0.754 0.845 203 no HFrEF asymptomatic 0.819 0.911 203 no HFpEF asymptomatic 0.692 0.670 203 no CHF symptomatic 0.815 0.890 203 no ICMP symptomatic 0.879 0.936 203 no DCMP symptomatic 0.854 0.944 203 no HFrEF symptomatic 0.867 0.939 203 no HFpEF symptomatic 0.669 0.754 203 no ICMP LVEF 35% to 0.855 0.925 50% 203 no DCMP LVEF 35% to 0.731 0.792 50% 203 no HFrEF LVEF 35% to 0.806 0.873 50% 203 no ICMP LVEF < 35% 0.943 0.989 203 no DCMP LVEF < 35% 0.877 0.986 203 no HFrEF LVEF < 35% 0.901 0.987 204 yes CHF 0.872 0.848 204 yes ICM 0.971 0.949 204 yes DCM 0.911 0.905 204 yes HFrEF 0.943 0.926 204 yes HFpEF 0.756 0.706 204 yes CHF asymptomatic 0.832 0.801 204 yes ICMP asymptomatic 0.986 0.970 204 yes DCMP asymptomatic 0.849 0.845 204 yes HFrEF asymptomatic 0.924 0.911 204 yes HFpEF asymptomatic 0.733 0.670 204 yes CHF symptomatic 0.908 0.890 204 yes ICMP symptomatic 0.962 0.936 204 yes DCMP symptomatic 0.949 0.944 204 yes HFrEF symptomatic 0.956 0.939 204 yes HFpEF symptomatic 0.788 0.754 204 yes ICMP LVEF 35% to 0.953 0.925 50% 204 yes DCMP LVEF 35% to 0.822 0.792 50% 204 yes HFrEF LVEF 35% to 0.902 0.873 50% 204 yes ICMP LVEF < 35% 0.999 0.989 204 yes DCMP LVEF < 35% 0.983 0.986 204 yes HFrEF LVEF < 35% 0.991 0.987 204 no CHF 0.749 0.848 204 no ICM 0.852 0.949 204 no DCM 0.779 0.905 204 no HFrEF 0.816 0.926 204 no HFpEF 0.627 0.706 204 no CHF asymptomatic 0.708 0.801 204 no ICMP asymptomatic 0.840 0.970 204 no DCMP asymptomatic 0.705 0.845 204 no HFrEF asymptomatic 0.772 0.911 204 no HFpEF asymptomatic 0.632 0.670 204 no CHF symptomatic 0.783 0.890 204 no ICMP symptomatic 0.858 0.936 204 no DCMP symptomatic 0.824 0.944 204 no HFrEF symptomatic 0.842 0.939 204 no HFpEF symptomatic 0.618 0.754 204 no ICMP LVEF 35% to 0.811 0.925 50% 204 no DCMP LVEF 35% to 0.681 0.792 50% 204 no HFrEF LVEF 35% to 0.760 0.873 50% 204 no ICMP LVEF < 35% 0.934 0.989 204 no DCMP LVEF < 35% 0.850 0.986 204 no HFrEF LVEF < 35% 0.881 0.987 205 yes CHF 0.897 0.848 205 yes ICM 0.983 0.949 205 yes DCM 0.935 0.905 205 yes HFrEF 0.961 0.926 205 yes HFpEF 0.789 0.706 205 yes CHF asymptomatic 0.863 0.801 205 yes ICMP asymptomatic 0.994 0.970 205 yes DCMP asymptomatic 0.883 0.845 205 yes HFrEF asymptomatic 0.947 0.911 205 yes HFpEF asymptomatic 0.776 0.670 205 yes CHF symptomatic 0.926 0.890 205 yes ICMP symptomatic 0.975 0.936 205 yes DCMP symptomatic 0.965 0.944 205 yes HFrEF symptomatic 0.971 0.939 205 yes HFpEF symptomatic 0.806 0.754 205 yes ICMP LVEF 35% to 0.972 0.925 50% 205 yes DCMP LVEF 35% to 0.870 0.792 50% 205 yes HFrEF LVEF 35% to 0.931 0.873 50% 205 yes ICMP LVEF < 35% 0.999 0.989 205 yes DCMP LVEF < 35% 0.990 0.986 205 yes HFrEF LVEF < 35% 0.995 0.987 205 no CHF 0.779 0.848 205 no ICM 0.879 0.949 205 no DCM 0.795 0.905 205 no HFrEF 0.837 0.926 205 no HFpEF 0.676 0.706 205 no CHF asymptomatic 0.756 0.801 205 no ICMP asymptomatic 0.882 0.970 205 no DCMP asymptomatic 0.753 0.845 205 no HFrEF asymptomatic 0.817 0.911 205 no HFpEF asymptomatic 0.687 0.670 205 no CHF symptomatic 0.797 0.890 205 no ICMP symptomatic 0.875 0.936 205 no DCMP symptomatic 0.821 0.944 205 no HFrEF symptomatic 0.848 0.939 205 no HFpEF symptomatic 0.659 0.754 205 no ICMP LVEF 35% to 0.857 0.925 50% 205 no DCMP LVEF 35% to 0.727 0.792 50% 205 no HFrEF LVEF 35% to 0.807 0.873 50% 205 no ICMP LVEF < 35% 0.920 0.989 205 no DCMP LVEF < 35% 0.846 0.986 205 no HFrEF LVEF < 35% 0.872 0.987 206 yes CHF 0.887 0.848 206 yes ICM 0.978 0.949 206 yes DCM 0.924 0.905 206 yes HFrEF 0.953 0.926 206 yes HFpEF 0.780 0.706 206 yes CHF asymptomatic 0.850 0.801 206 yes ICMP asymptomatic 0.992 0.970 206 yes DCMP asymptomatic 0.862 0.845 206 yes HFrEF asymptomatic 0.935 0.911 206 yes HFpEF asymptomatic 0.762 0.670 206 yes CHF symptomatic 0.919 0.890 206 yes ICMP symptomatic 0.968 0.936 206 yes DCMP symptomatic 0.960 0.944 206 yes HFrEF symptomatic 0.964 0.939 206 yes HFpEF symptomatic 0.804 0.754 206 yes ICMP LVEF 35% to 0.964 0.925 50% 206 yes DCMP LVEF 35% to 0.842 0.792 50% 206 yes HFrEF LVEF 35% to 0.918 0.873 50% 206 yes ICMP LVEF < 35% 0.999 0.989 206 yes DCMP LVEF < 35% 0.987 0.986 206 yes HFrEF LVEF < 35% 0.993 0.987 206 no CHF 0.779 0.848 206 no ICM 0.873 0.949 206 no DCM 0.808 0.905 206 no HFrEF 0.841 0.926 206 no HFpEF 0.668 0.706 206 no CHF asymptomatic 0.750 0.801 206 no ICMP asymptomatic 0.883 0.970 206 no DCMP asymptomatic 0.743 0.845 206 no HFrEF asymptomatic 0.811 0.911 206 no HFpEF asymptomatic 0.678 0.670 206 no CHF symptomatic 0.803 0.890 206 no ICMP symptomatic 0.867 0.936 206 no DCMP symptomatic 0.848 0.944 206 no HFrEF symptomatic 0.858 0.939 206 no HFpEF symptomatic 0.652 0.754 206 no ICMP LVEF 35% to 0.846 0.925 50% 206 no DCMP LVEF 35% to 0.720 0.792 50% 206 no HFrEF LVEF 35% to 0.795 0.873 50% 206 no ICMP LVEF < 35% 0.931 0.989 206 no DCMP LVEF < 35% 0.872 0.986 206 no HFrEF LVEF < 35% 0.894 0.987

TABLE-US-00014 TABLE 5b Performance of four selected panels (panels number 1, 2, 3, and 4 in Table 2, respectively) with and without NT-proBNP and with or with-out ANOVA correction for age, BMI and gender in different CHF subgroups in the testing (“VD”) data set, as compared to the known marker NT-proBNP alone. AUC: Panel AUC: Panel (no NT- AUC: Panel (with NT- AUC: Panel AUC: proBNP, (no NT- proBNP, (with NT- NT-proBNP Panel with ANOVA proBNP, no with ANOVA proBNP, no (no ANOVA No. Subgroup correction) ANOVA correction) correction) ANOVA correction) correction) 1 CHF 0.787 0.813 0.891 0.911 0.848 1 ICMP 0.876 0.899 0.984 0.988 0.949 1 DCMP 0.793 0.819 0.935 0.937 0.905 1 HFrEF 0.835 0.860 0.961 0.966 0.926 1 HFpEF 0.701 0.729 0.774 0.826 0.706 1 CHF asymptomatic 0.767 0.797 0.857 0.879 0.801 1 ICMP asymptomatic 0.878 0.906 0.994 0.995 0.970 1 DCMP asymptomatic 0.755 0.787 0.893 0.887 0.845 1 HFrEF asymptomatic 0.815 0.845 0.952 0.950 0.911 1 HFpEF asymptomatic 0.711 0.742 0.756 0.810 0.670 1 CHF symptomatic 0.804 0.825 0.920 0.938 0.890 1 ICMP symptomatic 0.874 0.894 0.976 0.983 0.936 1 DCMP symptomatic 0.818 0.840 0.959 0.965 0.944 1 HFrEF symptomatic 0.846 0.868 0.967 0.974 0.939 1 HFpEF symptomatic 0.685 0.708 0.796 0.846 0.754 1 ICMP LVEF 35% to 50% 0.861 0.888 0.973 0.980 0.925 1 DCMP LVEF 35% to 0.718 0.749 0.886 0.880 0.792 50% 1 HFrEF LVEF 35% to 50% 0.805 0.833 0.939 0.942 0.873 1 ICMP LVEF <35% 0.909 0.924 0.999 0.999 0.989 1 DCMP LVEF <35% 0.847 0.870 0.989 0.989 0.986 1 HFrEF LVEF <35% 0.870 0.890 0.995 0.995 0.987 2/4 CHF 0.772 0.798 0.885 0.903 0.848 2/4 ICMP 0.863 0.886 0.981 0.985 0.949 2/4 DCMP 0.788 0.816 0.932 0.934 0.905 2/4 HFrEF 0.826 0.851 0.957 0.962 0.926 2/4 HFpEF 0.676 0.703 0.761 0.810 0.706 2/4 CHF asymptomatic 0.744 0.777 0.847 0.867 0.801 2/4 ICMP asymptomatic 0.869 0.895 0.993 0.993 0.970 2/4 DCMP asymptomatic 0.736 0.774 0.884 0.878 0.845 2/4 HFrEF asymptomatic 0.800 0.833 0.946 0.944 0.911 2/4 HFpEF asymptomatic 0.680 0.712 0.736 0.788 0.670 2/4 CHF symptomatic 0.794 0.815 0.917 0.933 0.890 2/4 ICMP symptomatic 0.859 0.880 0.971 0.978 0.936 2/4 DCMP symptomatic 0.823 0.843 0.959 0.964 0.944 2/4 HFrEF symptomatic 0.840 0.862 0.965 0.972 0.939 2/4 HFpEF symptomatic 0.667 0.688 0.794 0.840 0.754 2/4 ICMP LVEF 35% to 50% 0.846 0.876 0.968 0.976 0.925 2/4 DCMP LVEF 35% to 0.701 0.738 0.873 0.866 0.792 50% 2/4 HFrEF LVEF 35% to 50% 0.788 0.821 0.931 0.935 0.873 2/4 ICMP LVEF <35% 0.902 0.915 0.999 0.999 0.989 2/4 DCMP LVEF <35% 0.853 0.874 0.989 0.989 0.986 2/4 HFrEF LVEF <35% 0.869 0.887 0.994 0.994 0.987 3 CHF 0.801 0.826 (nd) (nd) 0.848 3 ICMP 0.876 0.904 (nd) (nd) 0.949 3 DCMP 0.824 0.845 (nd) (nd) 0.905 3 HFrEF 0.850 0.875 (nd) (nd) 0.926 3 HFpEF 0.711 0.739 (nd) (nd) 0.706 3 CHF asymptomatic 0.775 0.805 (nd) (nd) 0.801 3 ICMP asymptomatic 0.881 0.908 (nd) (nd) 0.970 3 DCMP asymptomatic 0.771 0.800 (nd) (nd) 0.845 3 HFrEF asymptomatic 0.825 0.854 (nd) (nd) 0.911 3 HFpEF asymptomatic 0.717 0.748 (nd) (nd) 0.670 3 CHF symptomatic 0.822 0.844 (nd) (nd) 0.890 3 ICMP symptomatic 0.872 0.900 (nd) (nd) 0.936 3 DCMP symptomatic 0.857 0.872 (nd) (nd) 0.944 3 HFrEF symptomatic 0.865 0.887 (nd) (nd) 0.939 3 HFpEF symptomatic 0.701 0.724 (nd) (nd) 0.754 3 ICMP LVEF 35% to 50% 0.851 0.887 (nd) (nd) 0.925 3 DCMP LVEF 35% to 0.742 0.771 (nd) (nd) 0.792 50% 3 HFrEF LVEF 35% to 50% 0.808 0.841 (nd) (nd) 0.873 3 ICMP LVEF <35% 0.929 0.942 (nd) (nd) 0.989 3 DCMP LVEF <35% 0.883 0.897 (nd) (nd) 0.986 3 HFrEF LVEF <35% 0.900 0.914 (nd) (nd) 0.987

TABLE-US-00015 TABLE 6 Clinical performance of three selected panels combined with NT- proBNP using a predefined cut off determined to maximize the Youden index based on the ID data set in selected subgroups. Control Control NT proBNP VD Dataset Negative Positive Specificity Panel Negative 57 11 87% number 3 Positive 19 0 Specificity 78% Control NT proBNP VD Dataset Negative Positive Specificity Panel Negative 63 11 87% number 4 Positive 13 0 Specificity 85% Control NT proBNP VD Dataset Negative Positive Specificity Panel Negative 73 10 87% number 1 Positive 3 1 Specificity 95% ALL_CHF ALL_CHF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 24 34 65% number 3 Positive 48 99 Sensitivity 72% ALL_CHF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 31 43 65% number 4 Positive 41 90 Sensitivity 64% ALL_CHF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 45 18 65% number 1 Positive 27 115 Sensitivity 69% ALL_CHF, ALL_CHF, NYHA I - I/II NT proBNP NYHA I - I/II VD Dataset Negative Positive Sensitivity Panel Negative 17 14 55% number 3 Positive 25 37 Sensitivity 67% ALL_CHF, NYHA I - I/II NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 21 16 55% number 4 Positive 21 35 Sensitivity 60% ALL_CHF, NYHA I - I/II NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 30 11 55% number 1 Positive 12 40 Sensitivity 56% ALL_CHF, ALL_CHF, LVEF > 35% NT proBNP LVEF > 35% VD Dataset Negative Positive Sensitivity Panel Negative 24 27 51% number 3 Positive 47 47 Sensitivity 65% ALL_CHF, LVEF > 35% NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 31 33 51% number 4 Positive 40 41 Sensitivity 56% ALL_CHF, LVEF > 35% NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 45 15 51% number 1 Positive 26 59 Sensitivity 59% HFpEF HFpEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 18 15 35% number 3 Positive 30 11 Sensitivity 55% HFpEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 23 17 35% number 4 Positive 25 9 Sensitivity 46% HFpEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 32 11 35% number 1 Positive 16 15 Sensitivity 42% HFrEF HFrEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 6 19 82% number 3 Positive 18 88 Sensitivity 81% HFrEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 8 26 82% number 4 Positive 16 81 Sensitivity 74% HFrEF NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 13 7 82% number 1 Positive 11 100 Sensitivity 85% HFrEF, 35% < HFrEF, 35% < LVEF < 50% NT proBNP LVEF < 50% VD Dataset Negative Positive Sensitivity Panel Negative 6 12 68% number 3 Positive 17 36 Sensitivity 75% HFrEF, 35% < LVEF < 50% NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 8 16 68% number 4 Positive 15 32 Sensitivity 66% HFrEF, 35% < LVEF < 50% NT proBNP VD Dataset Negative Positive Sensitivity Panel Negative 13 4 68% number 1 Positive 10 44 Sensitivity 76%

TABLE-US-00016 TABLE 6A Clinical performance of Panel 1 combined with NT-proBNP compared to NT-proBNP alone Panel 1 combined with NT-proBNP Subgroup Cases Controls AUC Sens. Spec. LR+ LR− PPV NPV CHF 205 87 0.911 61.0% 97.7% 26.5 0.399 74.7% 95.8% ICMP 65 87 0.988 89.2% 97.7% 38.8 0.110 DCMP 66 87 0.937 71.2% 97.7% 31.0 0.295 HFrEF 131 87 0.966 80.2% 97.7% 34.9 0.203 64.7% 98.9% HFpEF 74 87 0.826 27.0% 97.7% 11.8 0.747 CHF asymptomatic 93 87 0.879 51.6% 97.7% 22.5 0.495 ICMP asymptomatic 24 87 0.995 95.8% 97.7% 41.7 0.043 DCMP asymptomatic 25 87 0.887 52.0% 97.7% 22.6 0.491 HFrEF asymptomatic 49 87 0.950 73.5% 97.7% 32.0 0.272 HFpEF asymptomatic 44 87 0.810 27.3% 97.7% 11.9 0.744 CHF symptomatic 112 87 0.938 68.8% 97.7% 29.9 0.320 ICMP symptomatic 41 87 0.983 85.4% 97.7% 37.1 0.150 DCMP symptomatic 41 87 0.965 82.9% 97.7% 36.1 0.175 HFrEF symptomatic 82 87 0.974 84.1% 97.7% 36.6 0.162 HFpEF symptomatic 30 87 0.846 26.7% 97.7% 11.6 0.751 ICMP LVEF 35% 43 87 0.980 83.7% 97.7% 36.4 0.167 to 50% DCMP LVEF 35% 28 87 0.880 42.9% 97.7% 18.6 0.585 to 50% HFrEF LVEF 35% 71 87 0.942 67.6% 97.7% 29.4 0.332 to 50% ICMP LVEF <35% 22 87 0.999 100.0% 97.7% 43.5 0.000 DCMP LVEF <35% 38 87 0.989 92.1% 97.7% 40.1 0.081 HFrEF LVEF <35% 60 87 0.995 95.0% 97.7% 41.3 0.051 NT-proBNP alone Assumed Subgroup AUC Sens Spec. LR+ LR− PPV NPV Prevalence CHF 0.848 64.9% 87.4% 5.13 0.402 36.3% 95.7% 10% ICMP 0.949 87.7% 87.4% 6.94 0.141 DCMP 0.905 75.8% 87.4% 5.99 0.278 HFrEF 0.926 81.7% 87.4% 6.46 0.210 25.4% 98.9% 5% HFpEF 0.706 35.1% 87.4% 2.78 0.743 CHF asymptomatic 0.801 54.8% 87.4% 4.34 0.517 ICMP asymptomatic 0.970 95.8% 87.4% 7.58 0.048 DCMP asymptomatic 0.845 64.0% 87.4% 5.06 0.412 HFrEF asymptomatic 0.911 79.6% 87.4% 6.29 0.234 HFpEF asymptomatic 0.670 27.3% 87.4% 2.16 0.833 CHF symptomatic 0.890 73.2% 87.4% 5.79 0.307 ICMP symptomatic 0.936 82.9% 87.4% 6.56 0.195 DCMP symptomatic 0.944 82.9% 87.4% 6.56 0.195 HFrEF symptomatic 0.939 82.9% 87.4% 6.56 0.195 HFpEF symptomatic 0.754 46.7% 87.4% 3.69 0.611 ICMP LVEF 35% 0.925 81.4% 87.4% 6.44 0.213 to 50% DCMP LVEF 35% 0.792 46.4% 87.4% 3.67 0.613 to 50% HFrEF LVEF 35% 0.873 67.6% 87.4% 5.35 0.371 to 50% ICMP LVEF <35% 0.989 100.0% 87.4% 7.91 0.000 DCMP LVEF <35% 0.986 97.4% 87.4% 7.70 0.030 HFrEF LVEF <35% 0.987 98.3% 87.4% 7.78 0.019

TABLE-US-00017 TABLE 7 Elution gradient and post-column addition for LC-MS/MS Elution Gradient Post-Column Addition Time Flow Rate Solvent Solvent Time Flow Solvent [min] [μl/min] A [%] B [%] [min] [μl/min] C [%] 0.00 400 100 0 0.00 0 100 0.10 400 100 0 0.20 400 100 0 gradient continued 0.40 500 58 42 gradient continued 3.20 0 100 3.30 500 32 68 3.30 200 100 5.00 600 15 85 gradient continued gradient continued 5.30 200 100 5.50 600 15 85 5.40 0 100 5.70 400 100 0 gradient continued 7.50 400 100 0 7.50 0 100

TABLE-US-00018 TABLE 8 MRM settings (Q1, first mass transition; Q3, second mass transition; DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential) and retention time (RT) for each metabolite biomarker. PC5 was scanned three times with different collision energies, as indicated by the names PC5-40, PC5-60, and PC5-70. Internal Standard For Calculation of Dwell Time Metabolite Biomarker Peak Area Ratios [msec] Q1 [Da] Q3 [Da] DP [V] EP [V] CE [V] CXP [V] RT [min] Glutamic acid 1 LPC C17:0 10 148.0 84.1 36 10 21 6 0.23 Glutamic acid 2 LPC C17:0 10 148.0 102.1 36 10 15 8 0.23 LPC C17:0* n/a 10 510.3 184.1 85 10 40 15 1.22 Cer(d18:1/17:0)* n/a 15 552.4 264.2 65 10 31 10 2.16 Cer(d18:1/23:0) Cer(d18:1/17:0) 15 636.5 264.2 65 10 31 10 2.95 Cer(d18:1/24:1) Cer(d18:1/17:0) 15 648.6 264.2 65 10 31 10 2.83 Cer(d18:2/24:0) Cer(d18:1/17:0) 15 648.6 262.2 65 10 31 10 2.9 Cer(d16:1/24:0) Cer(d18:1/17:0) 15 622.6 236.2 65 10 31 10 2.83 Cer(d17:1/24:0) Cer(d18:1/17:0) 15 636.6 250.2 65 10 31 10 2.95 SM2 PC 5-40 10 675.5 184.1 85 10 40 15 1.47 SM3 PC 5-40 10 689.5 184.1 85 10 40 15 1.52 SM29 PC 5-40 10 715.5 184.1 85 10 40 15 1.57 SM8 PC 5-40 10 727.5 184.1 85 10 40 15 1.55 SM9 PC 5-40 10 729.5 184.1 85 10 40 15 1.62 SM10 PC 5-40 10 731.5 184.1 85 10 40 15 1.7 SM18 PC 5-40 10 773.5 184.1 85 10 40 15 1.97 SM21 PC 5-40 10 787.5 184.1 85 10 40 15 2.05 SM23 PC 5-40 10 799.5 184.1 85 10 40 15 2.02 SM24 PC 5-40 10 801.5 184.1 85 10 40 15 2.16 SM5 PC 5-60 10 703.5 184.1 85 10 60 15 1.57 SM28 PC 5-40 10 815.5 184.1 85 10 40 15 2.27 PC 4 PC 5-70 10 758.6 184.1 85 10 70 15 1.72 PC 8 PC 5-60 10 786.6 184.1 85 10 60 15 1.88 PC 5-40* n/a 10 818.60 184.1 85 10 40 15 2.38 PC 5-60* n/a 10 818.60 184.1 85 10 60 15 2.38 PC 5-70* n/a 10 818.60 184.1 85 10 70 15 2.38 CE C17:0* n/a 10 656.7 369.3 56 10 22 20 4.65 CE C18:0 PC 5-40 10 670.7 369.3 56 10 22 20 4.72 CE C18:2 PC 5-40 10 666.7 369.3 56 10 40 20 4.47 PPP PC 5-40 10 824.8 551.5 75 10 35 10 4.61 PPO1 PC 5-40 10 850.8 577.5 75 10 35 10 4.64 SPP1 PC 5-40 10 852.9 579.6 75 10 35 10 4.74 MMM* n/a 10 866.8 579.6 75 10 35 10 4.8 SOP2 PC 5-40 10 878.9 577.6 75 10 35 10 4.76 SSP2 PC 5-40 10 880.9 579.6 75 10 35 10 4.85 OSS2 PC 5-40 10 906.9 605.4 75 10 35 10 4.87 SSS PC 5-40 10 908.9 607.6 75 10 35 10 4.96 *internal standard

TABLE-US-00019 TABLE 9 Effects of medication on the sensitivity of Panel 1 and NT-proBNP alone in HFrEF patients. HFrEF HFrEF (35% ≦ EF ≦ 50%) HFrEF (EF <35%) NT- NT- NT- proBNP Lipid Panel proBNP Lipid Panel proBNP Lipid Panel Medication # Subjects Sens. [%] Sens. [%] # Subjects Sens. [%] Sens. [%] # Subjects Sens. [%] Sens. [%] HFrEF* 371 80.3 79.5 213 70.9 71.4 158 93.0 90.5 HFrEF receiving 248 80.2 81.9 152 71.1 75.0 96 94.8 92.7 statins** HFrEF receiving 230 88.3 86.1 94 80.9 78.7 136 93.4 91.2 diuretics** Neither*** 27 59.3 55.6 23 56.5 52.2 not shown; number of subjects <10 Statins*** 74 71.6 75.7 66 68.2 72.7 not shown; number of subjects <10 Diuretics*** 55 92.7 81.8 17 88.2 70.6 38 94.7 86.8 Diuretics and 97 90.7 87.6 39 82.1 79.5 58 96.6 93.1 statins*** *All HFrEF patients **HFrEF patients receiving the indicated medication regardless of any additional medication ***HFrEF patients receiving exactly the indicated medication plus beta-blockers and medication affecting the renin-angiotensin-system, but no antidiabetic treatment (untreated diabetic patients not excluded)

TABLE-US-00020 TABLE 10 Metabolites constituting a further lipid panel (Panel No. 300) and their changes in patients with systolic HF compared to healthy controls (ID cohort). Metabolite Lipid Class Direction Cer d17:1/24:0 Ceramides down CE 18:2 Cholesterylesters down Linoleic acid (18:2.sup.Δ9cis, Δ12cis) Phosphatidyl- down from PC cholines SM d17:1/24:1 Sphingomyelins down Stearic acid (18:0) from TAG Triglycerides up Oleic acid (18:1.sup.Δ9cis) from Triglycerides up TAG

TABLE-US-00021 TABLE 12 Mass-spectrometer settings optimized for the absolute quantification of SM23, PC 4, CE C18:2, and OSS2 (Q1, first mass transition; Q3, second mass transition; DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential) for each metabolite biomarker or standard. PC5 as internal standard was scanned two times with different collision energies. Biomarker or Dwell Standard for Time Q1 Q3 DP EP CE CXP Quantification [msec] [Da] [Da] [V] [V] [V] [V] SM23 10 799.5 184.1 60 10 40 15 SM27** 10 813.5 184.1 60 10 40 15 PC 4 10 758.6 184.1 60 10 85 15 PC 5-40* 10 818.60 184.1 60 10 40 15 PC 5-70* 10 818.62 184.1 60 10 85 15 CE C18:2 10 666.7 369.3 30 10 45 20 OSS2 10 906.9 605.4 30 10 35 10 *internal standard, **external standard for the calibration of SM23

TABLE-US-00022 TABLE 12a Biomarkers and Standards with respective retention times used for quantification Biomarker or Internal Standard Calibration Standard for RT For Calculation of Curve Used for Quantification [min] Peak Area Ratios Quantification SM23 2.02 PC 5-40 SM27 PC 4 1.72 PC 5-70 PC4 CE C18:2 4.47 PC 5-40 CE 18:2 OSS2 4.87 PC 5-40 OSS2 SM27 2.06 PC5-40 SM27

TABLE-US-00023 TABLE 13 Calibration solutions in MeOH/CH2Cl2 (2/1) for calibration samples preparation Concentration STD1 STD2 STD3 STD4 STD5 STD6 STD7 μg/ml PC4 146.423 117.138 87.854 58.569 29.285 14.642 4.881 CE 18:2 365.760 292.608 219.456 146.304 73.152 36.576 12.192 SM27 12.358 9.886 7.415 4.943 2.472 1.236 0.4119 OSS2 1.974 1.5792 1.1844 0.7896 0.3948 0.1974 0.0658 nmol/ml PC4 193.1542 154.5234 115.8925 77.26169 38.63085 19.31542 6.438475 CE 18:2 563.5053 450.8042 338.1032 225.4021 112.7011 56.35053 18.78351 SM27 15.18735 12.14988 9.112412 6.074941 3.037471 1.518735 0.506245 OSS2 2.219314 1.775451 1.331588 0.887726 0.443863 0.221931 0.073977

TABLE-US-00024 TABLE 13a Concentration ratios of the compounds within the calibration samples/calibration solutions for calibration sample preparation, e.g. for the determination of PC4, CE18:2, SM23, and OSS2 (Panel 200) Ratio (from molar concentrations; CE C18:2 set to “1”) STD1 STD2 STD3 STD4 STD5 STD6 STD7 PC 4 0.342773 0.274218 0.205664 0.137109 0.068555 0.034277 0.011426 CE 18:2 1 0.8 0.6 0.4 0.2 0.1 0.033333 SM27 0.026952 0.021561 0.016171 0.010781 0.00539 0.002695 0.000898 OSS2 0.003938 0.003151 0.002363 0.001575 0.000788 0.000394 0.000131

TABLE-US-00025 TABLE 13b Concentration ratios of the compounds within the calibration samples/calibration solutions for calibration sample preparation, e.g. for the determination of CE18:2, SM23, and OSS2 (Panel 2) Ratio (from molar concentrations; CE C18:2 set to “1”) STD1 STD2 STD3 STD4 STD5 STD6 STD7 CE 18:2 1 0.8 0.6 0.4 0.2 0.1 0.033333 SM27 0.026952 0.021561 0.016171 0.010781 0.00539 0.002695 0.000898 OSS2 0.003938 0.003151 0.002363 0.001575 0.000788 0.000394 0.000131

TABLE-US-00026 TABLE 13C Concentration ratios of the compounds within the calibration samples/calibration solutions for calibration sample preparation, e.g. for the determination of PC4, SM23, and OSS2 (Panel 1) Ratio (from molar concentrations; PC4 set to “1”) STD1 STD2 STD3 STD4 STD5 STD6 STD7 PC 4 1 0.8 0.6 0.4 0.2 0.1 0.033333 SM27 0.078628 0.062902 0.047177 0.031451 0.015726 0.007863 0.002621 OSS2 0.01149 0.009192 0.006894 0.004596 0.002298 0.001149 0.000383

TABLE-US-00027 TABLE 14 Absolute concentrations of the metabolite biomarkers SM 23, PC4, CE C18:2, and OSS2 in the CHF subgroups HFrEF and HFpEF as well as in the control subjects Mean* RSD** Control HFrEF HFpEF Control HFrEF HFpEF SM 23 1493 μg/dl 1138 μg/dl 1320 μg/dl 19% 22% 24% PC4 41996 μg/dl 35854 μg/dl 38006 μg/dl 13% 18% 18% CE C18:2 124300 μg/dl 105799 μg/dl 115489 μg/dl 10% 16% 15% OSS2 83 μg/dl 190 μg/dl 154 μg/dl 53% 57% 60% *The arithmetic mean was calculated on log.sub.10-transformed data and then back-transformed to the original scale **The relative standard deviation (RSD) was calculated from the standard deviation (SD) of the log.sub.10-transformed data as RSD = 1-10.sup.−SD

Means and Methods for Diagnosing Heart Failure in a Subject

Inventors

Cpc classification

Classification Explorer

G01N33/6893

PHYSICS

Classification Explorer

G01N2405/08

PHYSICS

Classification Explorer

G01N2405/02

PHYSICS

Classification Explorer

G16H10/40

PHYSICS

Classification Explorer

G01N2800/325

PHYSICS

Classification Explorer

G16H50/20

PHYSICS

Classification Explorer

G01N2405/04

PHYSICS

Classification Explorer

G01N33/92

PHYSICS

Classification Explorer

G01N2405/00

PHYSICS

International classification

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G01N33/92

PHYSICS

Abstract

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Description