@article {12601, title = {A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking}, journal = {Nature Aging}, volume = {2}, year = {2022}, pages = {644{\textendash}661}, abstract = {Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show that technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components (PCs) from CpG-level data as input for biological age prediction. Our retrained PC versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro. This method entails only one additional step compared to traditional clocks, requires no replicates or previous knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of PC-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies and clinical trials of aging interventions.}, keywords = {Aging, Bioinformatics, computational models, DNA Methylation, predictive markers}, doi = {10.1038/s43587-022-00248-2}, author = {Higgins-Chen, Albert T. and Thrush, Kyra L. and Wang, Yunzhang and Minteer, Christopher J. and Kuo, Pei-Lun and Wang, Meng and Niimi, Peter and Sturm, Gabriel and Lin, Jue and Ann Zenobia Moore and Bandinelli, Stefania and Vinkers, Christiaan H. and Vermetten, Eric and Rutten, Bart P. F. and Geuze, Elbert and Okhuijsen-Pfeifer, Cynthia and van der Horst, Marte and Schreiter, Stefanie and Gutwinski, Stefan and Luykx, Jurjen J. and Picard, Martin and Ferrucci, Luigi and Eileen M. Crimmins and Boks, Marco P. and H{\"a}gg, Sara and Hu-Seliger, Tina T. and Morgan E. Levine} }