Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study

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 CpGs, respectively, were established to predict health outcomes and mortality...

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Autores principales:	Xiangwei Li, Yan Zhang, Xīn Gào, Bernd Holleczek, Ben Schöttker, Hermann Brenner
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	DNA methylation epigenetic clock age acceleration frailty mortality Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/7904ed83a0ae423b8f72ea9ab9e56186
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spelling	oai:doaj.org-article:7904ed83a0ae423b8f72ea9ab9e561862021-11-22T04:27:02ZComparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study2352-396410.1016/j.ebiom.2021.103686https://doaj.org/article/7904ed83a0ae423b8f72ea9ab9e561862021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421004801https://doaj.org/toc/2352-3964Background: 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 CpGs, respectively, were 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 from Germany. Methods: DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). AgeAccelPheno, AgeAccelGrim, and a revised MRscore to adapt EPIC, the MRscore with 8 CpGs (MRscore-8CpGs), were calculated. Frailty was assessed by a frailty index (FI). Findings: During 17 years of follow-up, 458 deaths were observed. All DNAm algorithms and FI were positively correlated with each other. AgeAccelPheno, AgeAccelGrim, MRscore, and FI showed independent associations with all-cause mortality [hazard ratio (95% CI) per SD increase = 1·32 (1·19-1·46), 1·47 (1·32-1·64), 1·73 (1·49-2·01), and 1·31 (1·20-1·43), respectively]. Harrell's C-statistic was 0·710 for a model predicting mortality by age, sex, and leukocyte composition and increased to 0·759 in a model including MRscore-8CpGs and FI. The predictive performance was further improved (Harrell's C-statistic = 0·766) when additionally including AgeAccelPheno and AgeAccelGrim into the model. Interpretation: The combination of a DNA methylation score based on 8 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex. Funding: The ESTHER study was funded by grants from the Baden-Württemberg 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 (Saarbrücken, Germany). The work of Xiangwei Li was supported by a grant from Fondazione Cariplo (Bando Ricerca Malattie invecchiamento, #2017-0653).Xiangwei LiYan ZhangXīn GàoBernd HolleczekBen SchöttkerHermann BrennerElsevierarticleDNA methylationepigenetic clockage accelerationfrailtymortalityMedicineRMedicine (General)R5-920ENEBioMedicine, Vol 74, Iss , Pp 103686- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA methylation epigenetic clock age acceleration frailty mortality Medicine R Medicine (General) R5-920
spellingShingle	DNA methylation epigenetic clock age acceleration frailty mortality Medicine R Medicine (General) R5-920 Xiangwei Li Yan Zhang Xīn Gào Bernd Holleczek Ben Schöttker Hermann Brenner Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
description	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 CpGs, respectively, were 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 from Germany. Methods: DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). AgeAccelPheno, AgeAccelGrim, and a revised MRscore to adapt EPIC, the MRscore with 8 CpGs (MRscore-8CpGs), were calculated. Frailty was assessed by a frailty index (FI). Findings: During 17 years of follow-up, 458 deaths were observed. All DNAm algorithms and FI were positively correlated with each other. AgeAccelPheno, AgeAccelGrim, MRscore, and FI showed independent associations with all-cause mortality [hazard ratio (95% CI) per SD increase = 1·32 (1·19-1·46), 1·47 (1·32-1·64), 1·73 (1·49-2·01), and 1·31 (1·20-1·43), respectively]. Harrell's C-statistic was 0·710 for a model predicting mortality by age, sex, and leukocyte composition and increased to 0·759 in a model including MRscore-8CpGs and FI. The predictive performance was further improved (Harrell's C-statistic = 0·766) when additionally including AgeAccelPheno and AgeAccelGrim into the model. Interpretation: The combination of a DNA methylation score based on 8 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex. Funding: The ESTHER study was funded by grants from the Baden-Württemberg 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 (Saarbrücken, Germany). The work of Xiangwei Li was supported by a grant from Fondazione Cariplo (Bando Ricerca Malattie invecchiamento, #2017-0653).
format	article
author	Xiangwei Li Yan Zhang Xīn Gào Bernd Holleczek Ben Schöttker Hermann Brenner
author_facet	Xiangwei Li Yan Zhang Xīn Gào Bernd Holleczek Ben Schöttker Hermann Brenner
author_sort	Xiangwei Li
title	Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
title_short	Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
title_full	Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
title_fullStr	Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
title_full_unstemmed	Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study
title_sort	comparative validation of three dna methylation algorithms of ageing and a frailty index in relation to mortality: results from the esther cohort study
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/7904ed83a0ae423b8f72ea9ab9e56186
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Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study

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