Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease

Abstract

Importance: Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening.

Objective: To determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation.

Design, setting, and participants: A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations.

Exposures: Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study.

Main outcomes and measures: Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI).

Results: The study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, -0.001; 95% CI, -0.009 to 0.006; MESA, 0.021; 95% CI, -0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, -0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, -0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort.

Conclusions and relevance: In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.

Figure 1.. Overview of the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) Study Population Selection

^aFor the ARIC population, participants with a diagnosis of coronary heart disease (CHD) at the time of their visit 1 examination (prevalent cases) or with a diagnosis of CHD that occurred between their visit 1 and visit 4 (10 year) examinations (incident cases) were excluded from the primary analyses of incident CHD risk. The primary analyses used visit 4 as the starting point and examined incident events that occurred after that visit. SNP indicates single-nucleotide polymorphism.

Figure 2.. Reclassification of 10-Year Predicted Coronary Heart Disease Risk

Columns and rows refer to categories of 10-year predicted risk. The numbers represent the counts of individuals assigned to the indicated risk category. The number of events differs from those in the main analyses because the table is restricted to events occurring over the first 10 years of follow-up. The standard coronary heart disease (CHD) model includes sex, age, 5 principal components, and the binary classifier for low or high risk are based on the pooled risk equations. Thus, among the 496 individuals in the Atherosclerosis Risk in Communities (ARIC) cohort with events, 2 were correctly up classified and 8 individuals were incorrectly down classified. The net proportion of correct reclassifications for events is –6/496 = –0.012. Among ARIC nonevents, 146 were correctly down classified and 27 were incorrectly up classified. The net proportion of correct reclassifications for nonevents is 119/3672 = 0.032. The overall net reclassification improvement is defined as the sum of the net reclassifications for events and nonevents (eg, –0.012 + 0.032 = 0.02). MESA indicates Multi-Ethnic Study of Atherosclerosis.