Development and validation of a risk prediction algorithm for high-risk populations combining genetic and...

To develop a model for cardiovascular disease (CVD) risk, combining polygenic risk score (PRS) with traditional risk factors while assessing the added value of PRS in two cohorts of biobank participants.

Data of 128 209 participants from the Estonian Biobank recruited between 2002-2017 and 2018-2022 without prevalent cardiovascular disease, was included. Hazard ratios (HR) for polygenic risk versus conventional risk factors were estimated with Cox proportional hazards models, cumulative incidence was assessed with Aalen-Johansen curves. Predictive performance was tested using a split-sample approach and competing risk modelling. Age at CVD event served as the outcome, and the impact of the PRS was evaluated by age group (25-59 vs. 60+), sex, and recruitment period, using HRs, Harrell's C-index, and net reclassification indices (NRI).

The estimated HR per one standard deviation (SD) of PRS ranged from 1.1, 95% CI 1.06-1.15 (age 60 + , earlier cohort) to 1.36, 95% CI 1.24-1.49 (men 25-59, later cohort). Adding PRS to the conventional risk factors in the age group 25-59 increased the C-statistic by 0.028 (p < 0.0001) for men. In the age group 60 + , the increase was 0.016 (p = 0.0002) across all. In the independent validation set, the continuous NRI was 19.1% (95% CI 13.3%-24.9%) in the 25-59 group and 13.9% (95% CI 8.1%-19.6%) in the 60 + group.

In a high-risk population, PRS is a strong independent risk factor for CVD and should be considered in routine risk assessment, starting at a relatively young age.