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Online Supplementary Material

Online supplementary Figure 1. Adjusted* relative risk (RR) of adverse outcomes in individuals with troponin levels > 99th percentile value for a healthy population versus individuals with undetectable levels, excluding participants with previous/current cardiovascular disease

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*Adjusted for age, gender and race, smoking status, BMI, presence of diabetes mellitus, total cholesterol, HDL cholesterol, systolic blood pressure, antihypertensive medication use. Additional adjustments include:

Saunders: hs-CRP, BNP and eGFR

deFilippi: CVD mortality model- coronary heart disease, CRP, NT-proBNP

HF model- albumin and creatinine concentration coronary heart disease, heart rate, and left ventricle hypertrophy on electrocardiogram.

de Lemos: hs-CRP , GFR, NT-proBNP

Leistner: hscRP, NT-proBNP,eGFR

Sundstrom: previous myocardial infarction (MI), MI during follow up, NT-proBNP

Zethelius: lipid lowering treatment

Online Supplementary Figure 2. Adjusted* relative risk (RR) of cardiovascular events and all-cause mortality for troponin detection > 99th percentile reference value vs undetected for studies using the Roche hs-CTnT assay

[pic]

*Adjusted for age, gender and race, smoking status, BMI, presence of diabetes mellitus, total cholesterol, HDL cholesterol, systolic blood pressure, antihypertensive medication use.

Online Supplementary Table 1. Adjusted relative risk (RR) of clinical outcomes when assessing cardiac troponin T or I as a continuous variable

|Author |Troponin Assay |Continuous |Adjusted for |Adjusted RR (95% Cl) |

| | |Definition | | |

| | | |All cause mortality |CVD mortality |Incident heart failure |Non-fatal CHD |All CVD events | |deFilippi, et al1 |hs-cTnT (Roche) |1-ln increment |CVRF* |- |1.54

(1.44,1.67) |1.44

(1.33,1.55) |- |- | |de Lemos, et al 2 |hs-cTnT (Roche) |1-ln increment |CVRF+ BNP |1.5

(1.1,1.9) |not provided |- |- |- | |Eggers et al9 |hs-CTnT (Roche) |1-In increment |CVRF +BNP |1.1

(1.0,1.3) |1.2

(1.0,1.5) |- |- |- | |McKie et al10 |Hs-cTnI (Singulex) |1-S.D increment |CVRF +BNP |1.15

(0.98-1.33) |- |1.42

(1.20-1.68) |- |- | |Zeller et al11 |hs-cTnI (Abbott) |Cubic root transform |CVRF |- |1.37

(1.24,1.50) |- |- |1.28

(1.18 ,1.38) | |Eggers et al12 |hs-cTnI (Abbott) |1-In increment |CVRF |- |1.66 |- |- |- | |Wang et al13 |hs-cTnI (Singulex) |1 S.D. increment |CVRF |1.16

(1.07,1.26) |- |1.28

(1.14-1.45) |- |1.18

(1.07,1.29) | |Sundstrom et al 3 |cTnI (Beckman) |per 10ng/L |CVRF + BNP |- |- |1.22

(1.11,1.34) |- |- | |  | |  |CVRF only |- |- |1.26

(1.15,1.38) |- |- | |Zethelius et al4 |cTnI (Beckman) |1 S.D. increment |CVRF |1.36

(1.24,1.50) |1.60

(1.41,1.82) |- |1.31

(1.11,1.54) † |- | |Blankenberg et al 5 |cTnI (Abbott) |1 S.D. increment |CVRF |- |- |- |- |FINRISK97 cohort:

Men 1.18

(1.09,1.28) | | | | | | | | | |FINRISK 97 cohort: Women 1.10

(0.99,1.22) | | | | | | | | | |PRIME cohort:

1.107 (1.01,1.21) | | ln= natural logarithm

S.D. = Standard Deviation

n.a. The outcome was not examined in the study

* CVRF= Cardiovascular risk factors including age, gender, race, BMI, smoking status, diabetes, hypertension, HDL and total cholesterol. Additional adjustments included:

deFilippi: CVD morality outcome- coronary heart disease

HF outcome- albumin and creatinine concentration, coronary heart disease, heart rate, and left ventricle hypertrophy on electrocardiogram.

de Lemos: hs-CRP , GFR

Sundstrom: antihypertensive treatment, previous myocardial infarction (MI) and MI during follow-up

Zethelius: antihypertensive and lipid lowering treatment

Blankenberg: antihypertensive and lipid lowering treatment

† This data comes from an earlier study by Zethelius6 on the USLAM cohort

References

1. deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010;304(22):2494-502.

2. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010;304(22):2503-12.

3. Sundström J IE, Berglund L, Zethelius B, Lind L, Venge P, Arnlöv J. Cardiac troponin-I and risk of heart failure: a community-based cohort study. Eur Heart J. 2009;30(7):773-81. .

4. Zethelius B, Berglund L, Sundstrom J, Ingelsson E, Basu S, Larsso A, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008;358(20):2107-16.

5. Blankenberg S, Zeller T, Saarela O, Havulinna AS, Kee F, Tunstall-Pedoe H, et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation 2010;121(22):2388-97.

6. Zethelius B, Johnston N, Venge P. Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study. Circulation 2006;113(8):1071-78.

7. Leistner DM, Klotsche J, Pieper L, Stalla GK, Lehnert H, Silber S, et al. Circulating troponin as measured by a sensitive assay for cardiovascular risk assessment in primary prevention. Clin Chem. 2012;58:200-208

8. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin t measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the atherosclerosis risk in communities study. Circulation. 2011;123:1367-1376

9. Eggers KM, Al-Shakarchi J, Berglund L, Lindahl B, Siegbahn A, Wallentin L, et al. High-sensitive cardiac troponin T and its relations to cardiovascular risk factors, morbidity, and mortality in elderly men. Am Heart J. 2013;166(3):541-8.

10. McKie PM, AbouEzzeddine O, Scott C, Mehta R, Rodeheffer R, Redfield MM, et al. High Sensitivity Troponin I and Amino-Terminal Pro- B-Type Natriuretic Peptide Predict Heart Failure and Mortality in the General Population. Clin Chem. 2014;60(9):1225-33.

11.Zeller T, Tunstall-Pedoe H, Saarela O, Ojeda FM, Schnabel PA, Tuovinen T, et al. High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort. Eur Heart J. 2014;35(5):271-81.

12. Eggers KM, Venge P, Lindahl B, Lind L. Cardiac troponin I levels measured with a high-sensitive assay increase over time and are strong predictors of mortality in an elderly population. J Am Coll Cardiol. 2013;61(18):1906-13.

13. Wang TJ, Wollert KC, Larson MG, Coglianese E, McCabe EL, Cheng S, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation. 2012;126(13):1596-604.

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