Comparison of genetic risk prediction models to improve prediction of coronary heart disease in two large cohorts of the MONICA/KORA study.

Overview

abstract

It is still unclear how genetic information, provided as single-nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population-based case-cohort was used as a trainingset (451 incident cases, 1488 noncases) and an independent cohort as testset (160 incident cases, 2749 noncases). The following strategies to quantify genetic information were compared: A weighted genetic risk score including Metabochip SNPs associated with CHD in the literature (GRS_Metabo ); selection of the most predictive SNPs among these literature-confirmed variants using priority-Lasso (PL_Metabo ); validation of two comprehensive polygenic risk scores: GRS_Gola based on Metabochip data, and GRS_Khera (available in the testset only) based on cross-validated genome-wide genotyping data. We used Cox regression to assess associations with incident CHD. C-index, category-free net reclassification index (cfNRI) and relative integrated discrimination improvement (IDI_rel ) were used to quantify the predictive performance of genetic information beyond Framingham risk score variables. In contrast to GRS_Metabo and PL_Metabo , GRS_Gola significantly improved the prediction (delta C-index [95% confidence interval]: 0.0087 [0.0044, 0.0130]; IDI_rel : 0.0509 [0.0131, 0.0894]; cfNRI improved only in cases: 0.1761 [0.0253, 0.3219]). GRS_Khera yielded slightly worse prediction results than GRS_Gola .