Methylomic survival predictors, frailty, and mortality.

Survival predictors are of potential use for informing on biological age and targeting prevention of aging-related morbidity. We assessed associations of 2 novel methylomic survival indicators, a methylation-based mortality risk score (MRscore) and the epigenetic clock-derived age acceleration (AA), with a well-known survival predictor, frailty index (FI), and compared the 3 indicators in mortality prediction. In a large population-based cohort with 14-year follow-up, we found both MRscore and AA to be independently associated with FI, but the association was much stronger for MRscore than for AA. Although all 3 indicators were individually associated with all-cause mortality, robust associations only persisted for MRscore and FI when simultaneously including the 3 indicators in regression models, with hazard ratios (95% CI) of 1.91 (1.63-2.22), 1.37 (1.25-1.51), and 1.05 (0.90-1.22), respectively, per standard deviation increase of MRscore, FI, and AA. Prediction error curves, Harrell's C-statistics, and time-dependent AUCs all showed higher predictive accuracy for MRscore than for FI and AA. These findings were validated in independent samples. Our study demonstrates the ability of the MRscore to strongly enhance survival prediction beyond established markers of biological age, such as FI and AA, and it thus bears potential of a surrogate endpoint for clinical research and intervention.