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dc.contributor.authorZhang, Qian
dc.contributor.authorVallerga, Costanza L
dc.contributor.authorWalker, Rosie M
dc.contributor.authorLin, Tian
dc.contributor.authorHenders, Anjali K
dc.contributor.authorMontgomery, Grant W
dc.contributor.authorHe, Ji
dc.contributor.authorFan, Dongsheng
dc.contributor.authorFowdar, Javed
dc.contributor.authorKennedy, Martin
dc.contributor.authorPitcher, Toni
dc.contributor.authorPearson, John
dc.contributor.authorHalliday, Glenda
dc.contributor.authorKwok, John B
dc.contributor.authorHickie, Ian
dc.contributor.authorLewis, Simon
dc.contributor.authorAnderson, Tim
dc.contributor.authorSilburn, Peter A
dc.contributor.authorMellick, George D
dc.contributor.authorHarris, Sarah E
dc.contributor.authorRedmond, Paul
dc.contributor.authorMurray, Alison D
dc.contributor.authorPorteous, David J
dc.contributor.authorHaley, Christopher S
dc.contributor.authorEvans, Kathryn L
dc.contributor.authorMcIntosh, Andrew M
dc.contributor.authorYang, Jian
dc.contributor.authorGratten, Jacob
dc.contributor.authorMarioni, Riccardo E
dc.contributor.authorWray, Naomi R
dc.contributor.authorDeary, Ian J
dc.contributor.authorMcRae, Allan F
dc.contributor.authorVisscher, Peter M
dc.date.accessioned2020-01-14T02:48:03Z
dc.date.available2020-01-14T02:48:03Z
dc.date.issued2019
dc.identifier.issn1756-994X
dc.identifier.doi10.1186/s13073-019-0667-1
dc.identifier.urihttp://hdl.handle.net/10072/390216
dc.description.abstractBackground: DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks’. The deviation of predicted age from the actual age (‘age acceleration residual’, AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. Methods: In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. Results: We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91–1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79–1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. Conclusions: This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherBMC
dc.relation.ispartofissue1
dc.relation.ispartofjournalGenome Medicine
dc.relation.ispartofvolume11
dc.subject.fieldofresearchGenetics
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3105
dc.subject.fieldofresearchcode3202
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsGenetics & Heredity
dc.subject.keywordsDNA methylation
dc.subject.keywordsAge prediction
dc.titleImproved precision of epigenetic clock estimates across tissues and its implication for biological ageing
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationZhang, Q; Vallerga, CL; Walker, RM; Lin, T; Henders, AK; Montgomery, GW; He, J; Fan, D; Fowdar, J; Kennedy, M; Pitcher, T; Pearson, J; Halliday, G; Kwok, JB; Hickie, I; Lewis, S; Anderson, T; Silburn, PA; Mellick, GD; Harris, SE; Redmond, P; Murray, AD; Porteous, DJ; Haley, CS; Evans, KL; McIntosh, AM; Yang, J; Gratten, J; Marioni, RE; Wray, NR; Deary, IJ; McRae, AF; Visscher, PM, Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing, Genome Medicine, 2019, 11 (1)
dcterms.dateAccepted2019-08-16
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2020-01-14T02:45:10Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
gro.hasfulltextFull Text
gro.griffith.authorMellick, George


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