Epistatic Features and Machine Learning Improve Alzheimer’s Risk Prediction Over Polygenic Risk Scores

BACKGROUND. Polygenic risk scores (PRS) are linear combinations of genetic markers weighted by effect size that are commonly used to predict disease risk. For complex heritable diseases such as late onset Alzheimer’s disease (LOAD), PRS models fail to capture much of the heritability. Additionally, PRS models are highly dependent on the population structure of data on which effect sizes are assessed, and have poor generalizability to new data. OBJECTIVE. The goal of this study is to construct a paragenic risk score that, in addition to single genetic marker data used in PRS, incorporates epistatic interaction features and machine learning methods to predict lifetime risk for LOAD. METHODS. We construct a new state-of-the-art genetic model for lifetime risk of Alzheimer’s disease. Our approach innovates over PRS models in two ways: First, by directly incorporating epistatic interactions between SNP loci using an evolutionary algorithm guided by shared pathway information; and second, by estimating risk via an ensemble of machine learning models (gradient boosting machines and deep learning) instead of simple logistic regression. We compare the paragenic model to a PRS model from the literature trained on the same dataset. RESULTS. The paragenic model is significantly more accurate than the PRS model under 10-fold cross-validation, obtaining an AUC of 83% and near-clinically significant matched sensitivity/specificity of 75%, and remains significantly more accurate when evaluated on an independent holdout dataset. Additionally, the paragenic model maintains accuracy within APOE genotypes. CONCLUSION. Paragenic models show potential for improving lifetime disease risk prediction for complex heritable diseases such as LOAD over PRS models.