SPLENDID incorporates continuous genetic ancestry in biobank-scale data to improve polygenic risk prediction across diverse populations

Abstract

Polygenic risk scores are widely used in disease risk stratification, but their accuracy varies across diverse populations. Recent methods large-scale leverage multi-ancestry data to improve accuracy in under-represented populations but require labelling individuals by ancestry for prediction. This poses challenges for practical use, as clinical practices are typically not based on ancestry. We propose SPLENDID, a novel penalized regression framework for diverse biobank-scale data. Our method utilizes ancestry principal component interactions to model genetic ancestry as a continuum within a single prediction model for all ancestries, eliminating the need for discrete labels. In extensive simulations and analyses of 9 traits from the All of Us Research Program (N=224,364) and UK Biobank (N=340,140), SPLENDID significantly outperformed existing methods in prediction accuracy and model sparsity. By directly incorporating continuous genetic ancestry in model training, SPLENDID stands as a valuable tool for robust risk prediction across diverse populations and fairer clinical implementation.