Sex-Specific Survival Bias and Interaction Modeling in Coronary Artery Disease Risk Prediction

Abstract

Background: The 10-year Atherosclerotic Cardiovascular Disease risk score is the standard approach to predict risk of incident cardiovascular events, and recently, addition of coronary artery disease (CAD) polygenic scores has been evaluated. Although age and sex strongly predict the risk of CAD, their interaction with genetic risk prediction has not been systematically examined. This study performed an extensive evaluation of age and sex effects in genetic CAD risk prediction. Methods: The population-based Norwegian HUNT2 (Trøndelag Health Study 2) cohort of 51 036 individuals was used as the primary dataset. Findings were replicated in the UK Biobank (372 410 individuals). Models for 10-year CAD risk were fitted using Cox proportional hazards, and Harrell concordance index, sensitivity, and specificity were compared. Results: Inclusion of age and sex interactions of CAD polygenic score to the prediction models increased the C-index and sensitivity by accounting for nonadditive effects of CAD polygenic score and likely countering the observed survival bias in the baseline. The sensitivity for females was lower than males in all models including genetic information. We identified a total of 82.6% of incident CAD cases by using a 2-step approach: (1) Atherosclerotic Cardiovascular Disease risk score (74.1%) and (2) the CAD polygenic score interaction model for those in low clinical risk (additional 8.5%). Conclusions: These findings highlight the importance and complexity of genetic risk in predicting CAD. There is a need for modeling age- and sex-interaction terms with polygenic scores to optimize detection of individuals at high risk, those who warrant preventive interventions. Sex-specific studies are needed to understand and estimate CAD risk with genetic information.

Using Sex‐Specific Polygenic Risk to Prognosticate Coronary Artery Disease in Women

“…Our work builds on prior descriptions in the UK Biobank of differences in risk discrimination by sex and demonstrates that some of this difference is related to gene‐sex interactions. 1 , 4 CAD PRS distribution across sex was similar, making sex‐participation bias an unlikely driver. 5 Efforts to understand and address barriers toward improved and less biased representation of women in genomic studies are imperative to resolve PRS performance discrepancies.…”

“…Compared with men, the risk is underrecognized and diagnosis is delayed, contributing to overall worse coronary artery disease (CAD) outcomes. 1 The mechanisms for elevated risk in women remain incompletely explained by conventional risk factors. The role of varying genetic effects in this elevation remains uncertain.…”

“…Analyses in the UK Biobank indicate older CAD PRS performs worse in women relative to men. 1 Whether similar performance differences exist in modern US populations with novel CAD PRS is unknown, and strategies to mitigate this bias are unclear.…”

Polygenic Scores and Preclinical Cardiovascular Disease in Individuals With HIV: Insights From the REPRIEVE Trial

“… 14 , 16 While it is well appreciated that PRSs perform differentially by genetic ancestry, 17 recent analyses have shown that age and sex also influence CAD PRS performance. 18 , 19 Therefore, there is a need to assess generalizability of CAD PRS, and its role in stratifying HIV‐associated CAD is not well understood. Coronary computed tomography angiography (CCTA) has emerged as a powerful tool to extract surrogate indices for clinical CAD risk to assess such novel biomarkers.…”