Abstract
The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE. Most work to date, including the assessment of tools, has focused on performance in individuals of European ancestries. Here we present evidence for the clinical validation of a new integrated risk tool (IRT), ASCVD-IRT, which combines ASCVD-PCE with PRS to predict 10-year risk of ASCVD across diverse ethnicity and ancestry groups. We demonstrate improved predictive performance of ASCVD-IRT over ASCVD-PCE, not only in individuals of self-reported White ethnicities (net reclassification improvement [NRI]; with 95% confidence interval = 2.7% [1.1 to 4.2]) but also Black / African American / Black Caribbean / Black African (NRI = 2.5% [0.6-4.3]) and South Asian (Indian, Bangladeshi or Pakistani) ethnicities (NRI = 8.7% [3.1 to 14.4]). NRI confidence intervals were wider and included zero for ethnicities with smaller sample sizes, including Hispanic (NRI = 7.5% [-1.4 to 16.5]), but PRS effect sizes in these ethnicities were significant and of comparable size to those seen in individuals of White ethnicities. Comparable results were obtained when individuals were analyzed by genetically inferred ancestry. Together, these results validate the performance of ASCVD-IRT in multiple ethnicities and ancestries, and favor their generalization to all ethnicities and ancestries.
Highlights
Current US guidelines for the primary prevention of cardiovascular disease are based on the quantification of an individual’s predicted risk of atherosclerotic cardiovascular disease (ASCVD) over the following 10 years using the ASCVD pooled cohort equations tool (ASCVD-PCE).[1−3]aGenomics plc, Oxford, UK; and bDivision of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California
We find that ASCVD-integrated risk tool (IRT) has, across the same large ethnicity and ancestry groups, a larger NRI than that of a tool constructed in the same way as ours, but using an alternative Polygenic risk scores (PRSs) previously shown to have good cross-ancestry performance
Our results indicate that ASCVD-IRT, a new tool for estimating 10-year ASCVD risk that incorporates a PRS for ASCVD, outperforms the existing standard-of-care tool ASCVD-PCE, and that this improvement extends across ethnicities and genetic ancestries
Summary
Current US guidelines for the primary prevention of cardiovascular disease are based on the quantification of an individual’s predicted risk of atherosclerotic cardiovascular disease (ASCVD) over the following 10 years using the ASCVD pooled cohort equations tool (ASCVD-PCE).[1−3]. AGenomics plc, Oxford, UK; and bDivision of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California. Manuscript received December 28, 2020; revised manuscript received and accepted February 23, 2021
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