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Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (<jats:italic>N<\/jats:italic>\u2009=\u20094677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>By employing data from six European cohorts (<jats:italic>N<\/jats:italic>\u2009=\u20092883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78\u2009\u00b1\u20090.06, while the 5 and 23 CpG models achieved 0.83\u2009\u00b1\u20090.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (<jats:italic>N<\/jats:italic>\u2009=\u20091794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67\u2009\u00b1\u20090.02 in the internal cross-validation and 0.61\u20130.66 in the external validation datasets.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13148-021-01186-3","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T17:02:52Z","timestamp":1635267772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Validating biomarkers and models for epigenetic inference of alcohol consumption from blood"],"prefix":"10.1186","volume":"13","author":[{"given":"Silvana C. 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The RS has been entered into the Netherlands National Trial Register (NTR; ) and into the WHO International Clinical Trials Registry Platform (ICTRP; ) under shared catalogue number NTR6831. CODAM by the Medical Ethical Committee of the Maastricht University; NTR by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre; LLS by the Ethical committee of the Leiden University Medical Center (registration number P01.113); PAN by the Institutional review board of the University Medical Centre Utrecht; KORA by the Ethics Committee of the Bavarian Medical Association (REC reference number: #06068); SHIP by the medical ethics committee of the University of Greifswald; and the TwinsUK study by the St Thomas\u2019 Hospital Local Ethics Committee. The experimental methods comply with the Helsinki Declaration. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"198"}}