Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in...

Area of Science:

• Cardiovascular Medicine
• Genetics
• Preventive Cardiology

Background:

• The American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort equations (ASCVD-PCE) tool is standard for 10-year atherosclerotic cardiovascular disease (ASCVD) risk assessment.
• ASCVD-PCE currently excludes genetic risk factors, limiting its comprehensive predictive capability.
• Polygenic risk scores (PRS) show promise in quantifying genetic predisposition to ASCVD and enhancing risk prediction models.

Purpose of the Study:

• To clinically validate a novel integrated risk tool (ASCVD-IRT) that combines ASCVD-PCE with PRS.
• To assess the performance of ASCVD-IRT in predicting 10-year ASCVD risk across diverse ethnic and ancestry groups.
• To demonstrate the improved predictive accuracy of ASCVD-IRT compared to ASCVD-PCE in multi-ethnic populations.

Main Methods:

• Development of the ASCVD-IRT by integrating ASCVD-PCE with PRS.
• Clinical validation of ASCVD-IRT across self-reported White, Black/African American, South Asian, and Hispanic ethnicities.
• Analysis of performance using net reclassification improvement (NRI) and assessment by genetically inferred ancestry.

Main Results:

• ASCVD-IRT demonstrated improved predictive performance over ASCVD-PCE in White (NRI: 2.7%), Black/African American (NRI: 2.5%), and South Asian (NRI: 8.7%) ethnicities.
• While confidence intervals for Hispanic ethnicity (NRI: 7.5%) included zero, PRS effect sizes were significant and comparable to White ethnicities.
• Comparable performance improvements were observed when analyzing individuals by genetically inferred ancestry, supporting broad applicability.

Conclusions:

• The ASCVD-IRT is clinically validated and shows improved 10-year ASCVD risk prediction across multiple ethnicities and ancestries.
• The integration of PRS significantly enhances risk prediction beyond traditional factors in diverse populations.
• These findings support the generalization and clinical adoption of ASCVD-IRT for comprehensive cardiovascular risk assessment in all ethnicities.