Comparative Validation of Three DNA Methylation Algorithms of Ageing and a Frailty Index in Relation to Mortality: Results From the ESTHER Cohort Study

Abstract

Background: Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030 and 10 CpG sites, respectively, were recently established to predict health outcomes and mortality. We aimed to compare and validate the predictive ability of these scores and frailty in relation to mortality in a population-based cohort of older adults (50-75 years at baseline) from Germany. Methods: DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) and used to calculate the three methylation algorithms in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). Frailty was assessed by a frailty index (FI) based on percentage of 34 selected deficits. Findings: During 14 years of follow-up, a total of 346 deaths were observed. AgeAccelPheno, AgeAccelGrim, MRscore and FI were positively correlated. Although each of them was strongly and independently associated with mortality, the association was strongest for MRscore [adjusted hazard ratio (95% CI) per SD increase = 1·73 (1·46-2·06]. Harrell’s C-statistic was 0·706 for a model predicting mortality by age and sex alone and increased to 0·752 in a model including MRscore and the FI. Interpretation: The combination of a DNA methylation score based on 10 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex. Funding Information: The ESTHER study was funded by grants from the Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland State Ministry of Health, Social Affairs, Women and the Family (Saarbrucken, Germany). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: The ESTHER study was approved by the ethics committees of the medical faculty of the University of Heidelberg and the medical board of the state of Saarland. Written informed consent was obtained from each participant.