Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
EBioMedicine. 2021 Dec;74:103686. doi: 10.1016/j.ebiom.2021.103686. Epub 2021 Nov 19.
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.
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).
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.
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.
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).
三种基于 DNA 甲基化（DNAm）的算法，即基于 513、1030 和 10 个 CpG 位点的 DNAm 表型年龄加速（AgeAccelPheno）、DNAm GrimAge 加速（AgeAccelGrim）和死亡率风险评分（MRscore），分别用于预测健康结果和死亡率。我们旨在比较和验证这些评分以及在德国基于人群的队列中与死亡率相关的脆弱性的预测能力。
在 ESTHER 队列研究的两个随机子集中（n=741 和 n=1030），通过 Infinium Methylation EPIC BeadChip 试剂盒（EPIC，Illumina，圣地亚哥，CA，美国）测量全血中的 DNA 甲基化。计算了 AgeAccelPheno、AgeAccelGrim 和为适应 EPIC 而修订的 MRscore，即具有 8 个 CpG 的 MRscore（MRscore-8CpGs）。通过脆弱性指数（FI）评估脆弱性。
在 17 年的随访期间，观察到 458 例死亡。所有 DNAm 算法和 FI 彼此之间呈正相关。AgeAccelPheno、AgeAccelGrim、MRscore 和 FI 与全因死亡率均呈独立相关[每增加一个标准差的风险比（95%可信区间）分别为 1.32（1.19-1.46）、1.47（1.32-1.64）、1.73（1.49-2.01）和 1.31（1.20-1.43）]。预测死亡率的模型中，年龄、性别和白细胞组成的 Harrell's C 统计量为 0.710，当模型中包含 MRscore-8CpGs 和 FI 时，增加到 0.759。当将 AgeAccelPheno 和 AgeAccelGrim 进一步纳入模型时，预测性能进一步提高（Harrell's C 统计量为 0.766）。
仅基于 8 个 CpG 的 DNA 甲基化评分和易于确定的脆弱性指数的组合可能会大大增强对死亡率的预测，超出年龄和性别因素。
ESTHER 研究由巴登-符腾堡州科学、研究和艺术部（德国斯图加特）、联邦教育和研究部（德国柏林）、联邦家庭事务、老年人、妇女和青年部（德国柏林）以及萨尔州卫生部、社会事务、妇女和家庭（萨尔布吕肯，德国）资助。李湘伟的工作得到了 Fondazione Cariplo（Bando Ricerca Malattie invecchiamento，#2017-0653）的资助。
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