Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries

• Published in: The American journal of cardiology Vol. 148; pp. 157 - 164
• Main Authors: Weale, Michael E., Riveros-Mckay, Fernando, Selzam, Saskia, Seth, Priyanka, Moore, Rachel, Tarran, William A., Gradovich, Eva, Giner-Delgado, Carla, Palmer, Duncan, Wells, Daniel, Saffari, Ayden, Sivley, R. Michael, Lachapelle, Alexander S., Wand, Hannah, Clarke, Shoa L., Knowles, Joshua W., O'Sullivan, Jack W., Ashley, Euan A., McVean, Gil, Plagnol, Vincent, Donnelly, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2021; Elsevier Limited
• Subjects: Arteriosclerosis; Atherosclerosis; Biobanks; Cardiology; Cardiovascular disease; Cardiovascular diseases; Confidence intervals; Ethnicity; Genealogy; Health risks; Minority & ethnic groups; Performance prediction; Questionnaires; Race; Racial identity; Reclassification; Risk analysis; Risk factors; United Kingdom > UK; United States > US
• ISSN: 0002-9149; 1879-1913; 1879-1913
• DOI: 10.1016/j.amjcard.2021.02.032

•A new integrated risk tool combines clinical and polygenic risk scores.•Prediction is significantly enhanced in multiple ethnicities and ancestries.•Ethnicities include Black and White, ancestries include African and European.•This is the first positive cross-ethnicity cross-ancestry validation of such a tool. 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.