A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data. Unfortunately, measurements for individual CpGs can be surprisingly unreliable due to technical noise, and this may limit the utility of epigenetic clocks. We report that noise produces deviations up to 3 to 9 years between technical replicates for six major epigenetic clocks. The elimination of low-reliability CpGs does not ameliorate this issue. Here, we present a novel computational multi-step solution to address this noise, involving performing principal component analysis on the CpG-level data followed by biological age prediction using principal components as input. This method extracts shared systematic variation in DNAm while minimizing random noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 0 to 1.5 years, equivalent or improved prediction of outcomes, and more stable trajectories in longitudinal studies and cell culture. This method entails only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The high reliability of principal component-based epigenetic clocks will make them particularly useful for applications in personalized medicine and clinical trials evaluating novel aging interventions.
Authors 23
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Albert Higgins‐Chen corresponding
Affiliation as printed
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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Affiliation as printed
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
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Affiliation as printed
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
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Affiliation as printed
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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Affiliation as printed
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
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Affiliation as printed
Geriatric Unit, Azienda Sanitaria Toscana Centro, Florence, Italy
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers
Affiliation as printed
Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
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Maastricht University Medical Centre
Affiliation as printed
School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, The Netherlands
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Utrecht University · University Medical Center Utrecht · Ministry of Defence
Affiliation as printed
Brain Research & Innovation Centre, Ministry of Defence, Utrecht, the Netherlands
Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
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Affiliation as printed
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
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University of Southern California
Affiliation as printed
Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Elysium Health, Inc. (United States)
Affiliation as printed
Elysium Health, Inc, New York, NY, USA
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Morgan E. Levine corresponding
Affiliation as printed
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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