Use of correct and incorrect methods of accounting for age in studies of epigenetic accelerated aging: Implications and recommendations for best practices
Open accessAbstract
Motivated by our conduct of a literature review on social exposures and accelerated aging as measured by a growing number of epigenetic “clocks” (which estimate age via DNA methylation (DNAm) patterns), we report on 3 different approaches in the epidemiologic literature—1 incorrect and 2 correct—on the treatment of age in these and other studies using other common exposures (i.e., body mass index and alcohol consumption). Among the 50 empirical articles reviewed, the majority (n = 29; 58%) used the incorrect method of analyzing accelerated aging detrended for age as the outcome and did not control for age as a covariate. By contrast, only 42% used correct methods, which are either to analyze accelerated aging detrended for age as the outcome and control for age as a covariate (n = 16; 32%) or to analyze raw DNAm age as the outcome and control for age as a covariate (n = 5; 10%). In accord with prior demonstrations of bias introduced by use of the incorrect approach, we provide simulation analyses and additional empirical analyses to illustrate how the incorrect method can lead to bias towards the null, and we discuss implications for extant research and recommendations for best practices.
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Chronological age was utilized as a covariate to ensure comparability across clocks and avoid spurious associations from age confounding.
“Following Krieger et al. (2023)’s recommendations, chronological age was utilized as a covariate to ensure comparability across clocks and avoid spurious associations from age confounding.”
From Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States (2026) · cites this paper as Krieger et al. (2023)
The Discussion recommends controlling for chronological age as a covariate to address age confounding and produce more accurate association estimates. It says this enables more robust comparisons across studies, but does not establish comparability across different clocks, as the claim states. (LLM, conf=0.87)
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Cites
Zhao, W., Ammous, F., Ratliff, S., Liu, J., Yu, M., Mosley, T. H., Kardia, S. L. R., & Smith, J. A. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16173141 · Cited by 113 · see citing works
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Research works printed but not linked: 26
- Morris, 1957, Uses of Epidemiology
- Kuh, 2004, A Life Course Approach to Chronic Disease Epidemiology, 10.1093/acprof:oso/9780198578154.001.0001 · DOI
- Yashi, 2014, Aging and Health: A Systems Biology Perspective, 10.1159/isbn.978-3-318-02730-3 · DOI
- Estes, 2019, Aging A–Z: Concepts Toward Emancipatory Gerontology, 10.4324/9780429055188 · DOI
- Krieger, 2021, Ecosocial Theory, Embodied Truths, and the People’s Health, 10.1093/oso/9780197510728.001.0001 · DOI
- Maroni, 2019, Tracking the epigenetic clock across the human life course: a meta-analysis of longitudinal cohort data, J Gerontol A Biol Sci Med Sci., 74, 57, 10.1093/gerona/gly060 · DOI
- Ryan, 2021, “Epigenetic clocks”: theory and applications in human biology, Am J Hum Biol., 33, 10.1002/ajhb.23488 · DOI
- Noroozi, 2021, DNA methylation-based age clocks: from age prediction to age reversion, Ageing Res Rev., 68, 10.1016/j.arr.2021.101314 · DOI
- Frisch, 1933, Partial time regressions as compared with individual trends, Econometrica., 1, 387, 10.2307/1907330 · DOI · Paper page
- Lovell, 1963, Seasonal adjustment of economic time series and multiple regression analysis, J Am Stat Assoc., 58, 993, 10.1080/01621459.1963.10480682 · DOI
- Rosenbaum, 1984, Difficulties with regression analyses of age-adjusted rates, Biometrics., 40, 437, 10.2307/2531396 · DOI
- Wooldridge, 2016, Introductory Econometrics: A Modern Approach
- Angrist, 2008, Mostly Harmless Econometrics: An Empiricist’s Companion, 10.2307/j.ctvcm4j72 · DOI · Paper page
- Demissie, 2011, Bias due to two-stage residual-outcome regression analysis in genetic association studies, Genet Epidemiol., 35, 592, 10.1002/gepi.20607 · DOI
- Che, 2012, Loss of power in two-stage residual-outcome regression analysis in genetic association studies, Genet Epidemiol., 36, 890, 10.1002/gepi.21671 · DOI
- VanderWeele, 2015, Explanation in Causal Inference: Methods for Mediation and Interaction
- VanderWeele, 2019, Principles of confounder selection, Eur J Epidemiol., 34, 211, 10.1007/s10654-019-00494-6 · DOI · Paper page
- Schmitz, 2022, The socioeconomic gradient in epigenetic ageing clocks: evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study, Epigenetics., 17, 589, 10.1080/15592294.2021.1939479 · DOI
- Boyd, 2013, Cohort profile: the ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children, Int J Epidemiol., 42, 111, 10.1093/ije/dys064 · DOI · Paper page
- Fraser, 2013, Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort, Int J Epidemiol., 42, 97, 10.1093/ije/dys066 · DOI · Paper page
- Bespalov, 2019, Be positive about negatives—recommendations for the publication of negative (or null) results, Eur Neuropsychopharmacol., 29, 1312, 10.1016/j.euroneuro.2019.10.007 · DOI · Paper page
- Wang, 2020, Associations of annual ambient PM2.5 components with DNAm PhenoAge acceleration in elderly men: the Normative Aging Study, Environ Pollut., 258, 10.1016/j.envpol.2019.113690 · DOI
- Zindler, 2020, Simulating ComBat: how batch correction can lead to the systematic introduction of false positive results in DNA methylation microarray studies, BMC Bioinformatics., 21, 271, 10.1186/s12859-020-03559-6 · DOI
- Sugden, 2020, Patterns of reliability: assessing the reproducibility and integrity of DNA methylation measurement, Patterns (N Y)., 1
- Simons, 2021, The effects of social adversity, discrimination, and health risk behaviors on the accelerated aging of African Americans: further support for the weathering hypothesis, Soc Sci Med., 282, 10.1016/j.socscimed.2020.113169 · DOI
- Quach, 2017, Epigenetic clock analysis of diet, exercise, education, and lifestyle factors, Aging (Albany NY)., 9, 419, 10.18632/aging.101168 · DOI · Paper page
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Grandparent Caregiving and Epigenetic Aging among Midlife and Older Adults in the United States
Bhat, A. C., Trexberg, K. M., Apsley, A. T., Almeida, D. M., & Shalev, I. (2026) · The journals of gerontology. Series B, Psychological sciences and social sciences · doi:10.1093/geronb/gbaf255 · Cited by 2 · see citing works
“Following Krieger et al. (2023)’s recommendations, chronological age was utilized as a covariate to ensure comparability across clocks and avoid spurious associations from age confounding.”
- Authors
- Krieger, N., Chen, J. T., Testa, C., Diez Roux, A., Tilling, K., Watkins, S., Simpkin, A. J., Suderman, M., Davey Smith, G., De Vivo, I., Waterman, P. D., & Relton, C.
- Affiliations
- Harvard University (US)
- University of Bristol (GB)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Corresponding author
- Krieger, Nancy
- ORCID
- Venue
- American Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-01-30
- Volume
- 192
- Issue
- 5
- Pages
- 800-811
- ISSN
- 0002-9262 (ISSN-L)
- 1476-6256
- PMC
- PMC10160768
- OpenAlex
- W4318754780
- Cited by
- 52
- References
- 1
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 16 · 2023: 5
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Epidemiology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc)
- Funders
- Harvard University
- Drexel University
- Harvard T.H. Chan School of Public Health
- National University of Ireland
- Wellcome Trust (217065/Z/19/Z, 217065)
- University of Bristol (217065/Z/19/Z, MC_UU_12013/8, BB/I025263/1, MC_UU_12013/2)
- University of Galway
- National Institutes of Health (217065/Z/19/Z)
- Directorate for Biological Sciences
- Medical Research Council (217065/Z/19/Z, MC_UU_12013_2, MC_UU_12013, MC UU 12013/8, 217065, MC_UU_00032/4, MC_UU_00032/1, MC_PC_15018, MC_UU_00011/1, MC_PC_19009)
- Biotechnology and Biological Sciences Research Council (BB/I025263/1, BB/I025751/1, BB/I025751/1 and BB/I025263/1)
- Economic and Social Research Council (ES/N000498/1)
- National Institute on Minority Health and Health Disparities (R01MD014304)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Keywords
- accelerated aging, epigenetic clocks, DNA methylation, age as covariate, body mass index, alcohol consumption, social exposure
- MeSH terms
- Aging, Humans, Body Mass Index, DNA Methylation, Epigenesis, Genetic, Epigenomics
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