Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease.
OBJECTIVE
Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions.


OBJECTIVE
To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins.


METHODS
Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from 2000 through 2002 and followed up through November 2011 (≤11.1 years). For the validation cohort (HUNT3, a Norwegian population-based study), participants were enrolled from 2006 through 2008 and followed up through April 2012 (5.6 years).


METHODS
Using modified aptamers, 1130 proteins were measured in plasma samples.


METHODS
A 9-protein risk score was derived and validated for 4-year probability of myocardial infarction, stroke, heart failure, and all-cause death. Tests, including the C statistic, were used to assess performance of the 9-protein risk score, which was compared with the Framingham secondary event model, refit to the cohorts in this study. Within-person change in the 9-protein risk score was evaluated in the Heart and Soul study from paired samples collected 4.8 years apart.


RESULTS
From the derivation cohort, 938 samples were analyzed, participants' median age at enrollment was 67.0 years, and 82% were men. From the validation cohort, 971 samples were analyzed, participants' median age at enrollment was 70.2 years, and 72% were men. In the derivation cohort, C statistics were 0.66 for refit Framingham, 0.74 for 9-protein, and 0.75 for refit Framingham plus 9-protein models. In the validation cohort, C statistics were 0.64 for refit Framingham, 0.70 for 9-protein, and 0.71 for refit Framingham plus 9-protein models. Adding the 9-protein risk score to the refit Framingham model increased the C statistic by 0.09 (95% CI, 0.06-0.12) in the derivation cohort, and in the validation cohort, the C statistic was increased by 0.05 (95% CI, 0.02-0.09). Compared with the refit Framingham model, the integrated discrimination index for the 9-protein model was 0.12 (95% CI, 0.08-0.16) in the derivation cohort and 0.08 (95% CI, 0.05-0.10) in the validation cohort. In analysis of paired samples among 139 participants with cardiovascular events after the second sample, absolute within-person annualized risk increased more for the 9-protein model (median, 1.86% [95% CI, 1.15%-2.54%]) than for the refit Framingham model (median, 1.00% [95% CI, 0.87%-1.19%]) (P = .002), while among 375 participants without cardiovascular events, both scores changed less and similarly (P = .30).


CONCLUSIONS
Among patients with stable CHD, a risk score based on 9 proteins performed better than the refit Framingham secondary event risk score in predicting cardiovascular events, but still provided only modest discriminative accuracy. Further research is needed to assess whether the score is more accurate in a lower-risk population.
Department of Medicine, University of California-San Francisco2Division of Cardiology, San Francisco General Hospital.
Peter
P
Ganz
Department of Medicine, University of California-San Francisco3Division of Cardiology, University of Zurich, Zurich, Switzerland.
Bettina
B
Heidecker
HUNT Research Center, Department of Public Health, NTNU, Levanger, Norway.
Kristian
K
Hveem
HUNT Research Center, Department of Public Health, NTNU, Levanger, Norway.
Christian
C
Jonasson
NEC Corporation of America, Irving, Texas.
Shintaro
S
Kato
Department of Epidemiology and Biostatistics, University of California-San Francisco.
Mark R
MR
Segal
SomaLogic, Boulder, Colorado.
David G
DG
Sterling
SomaLogic, Boulder, Colorado.
Stephen A
SA
Williams
D000368:Aged; D001798:Blood Proteins / Q000032:analysis*; D002423:Cause of Death; D003324:Coronary Artery Disease / Q000097:blood*; D005260:Female; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology; D009664:Norway; D011446:Prospective Studies; D040901:Proteomics; D018570:Risk Assessment; D012495:San Francisco; D020521:Stroke / Q000209:etiology
D001798:Blood Proteins