{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:44:44Z","timestamp":1753875884797,"version":"3.41.2"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473724"],"award-info":[{"award-number":["82473724"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>In ultra-high dimensional mediation analysis, confounding variables can influence both mediators and outcomes through complex functional forms. While machine learning (ML) approaches are effective at modeling such complex relationships, they can introduce bias when estimating mediation effects. In this article, we propose a debiased ML framework that mitigates this bias, enabling accurate identification of key mediators and precise estimation and inference of their respective contributions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We construct an orthogonalized score function and use cross-fitting to reduce bias introduced by ML. To tackle ultra-high dimensional potential mediators, we implement screening and regularization techniques for variable selection and effect estimation. For statistical inference of the mediators\u2019 contributions, we use an adjusted Sobel-type test. Simulation results demonstrate the superior performance of the proposed method in handling complex confounding. Applying this method to Alzheimer\u2019s Disease Neuroimaging Initiative data, we identify several cytosine-phosphate-guanine sites where DNA methylation mediates the effect of body mass index on Alzheimer\u2019s Disease.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The R function DML_HDMA implementing the proposed methods is available online at https:\/\/github.com\/Wei-Kecheng\/DML_HDMA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf282","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T14:45:47Z","timestamp":1746456347000},"source":"Crossref","is-referenced-by-count":0,"title":["Debiased machine learning for ultra-high dimensional mediation analysis"],"prefix":"10.1093","volume":"41","author":[{"given":"Kecheng","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-8183","authenticated-orcid":false,"given":"Yahang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]},{"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]},{"given":"Ruilang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4208-9480","authenticated-orcid":false,"given":"Yongfu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-3117","authenticated-orcid":false,"given":"Guoyou","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Fudan University , Shanghai 200032,","place":["China"]}]}],"member":"286","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"2025070408271829600_btaf282-B1","doi-asserted-by":"crossref","first-page":"107501","DOI":"10.1016\/j.csda.2022.107501","article-title":"High-dimensional causal mediation analysis based on partial linear structural equation models","volume":"174","author":"Cai","year":"2022","journal-title":"Comput Stat Data Anal"},{"key":"2025070408271829600_btaf282-B2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s13148-021-01162-x","article-title":"Impact of BMI and waist circumference on epigenomewide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multiethnic Asian individuals","volume":"13","author":"Chen","year":"2021","journal-title":"Clin Epigenetics"},{"key":"2025070408271829600_btaf282-B3","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.3390\/ijms25042293","article-title":"CD163-mediated small-vessel injury in Alzheimer\u2019s Disease: an exploration from neuroimaging to transcriptomics","volume":"25","author":"Chen","year":"2024","journal-title":"Int J Mol Sci"},{"key":"2025070408271829600_btaf282-B4","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1111\/ectj.12097","article-title":"Double\/debiased machine learning for treatment and structural parameters","volume":"21","author":"Chernozhukov","year":"2018","journal-title":"Econom J"},{"key":"2025070408271829600_btaf282-B5","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1214\/22-AOS2234","article-title":"Asymptotic properties of high-dimensional random forests","volume":"50","author":"Chi","year":"2022","journal-title":"Ann Stat"},{"key":"2025070408271829600_btaf282-B6","doi-asserted-by":"crossref","first-page":"e1011022","DOI":"10.1371\/journal.pgen.1011022","article-title":"Methods for mediation analysis with high dimensional DNA methylation data: possible choices and comparisons","volume":"19","author":"Clark-Boucher","year":"2023","journal-title":"PLoS Genet"},{"key":"2025070408271829600_btaf282-B7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1080\/01621459.2020.1765785","article-title":"A multiple-testing procedure for high dimensional mediation hypotheses","volume":"117","author":"Dai","year":"2022","journal-title":"J Am Stat Assoc"},{"key":"2025070408271829600_btaf282-B8","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/gepi.22510","article-title":"Methods for large-scale single mediator hypothesis testing: possible choices and comparisons","volume":"47","author":"Du","year":"2023","journal-title":"Genet Epidemiol"},{"key":"2025070408271829600_btaf282-B9","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/j.1467-9868.2008.00674.x","article-title":"Sure independence screening for ultrahigh dimensional feature space","volume":"70","author":"Fan","year":"2008","journal-title":"J R Statist Soc B"},{"key":"2025070408271829600_btaf282-B10","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/ectj\/utac003","article-title":"Causal mediation analysis with double machine learning","volume":"25","author":"Farbmacher","year":"2022","journal-title":"Econom J"},{"key":"2025070408271829600_btaf282-B11","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/07350015.2023.2174548","article-title":"Estimations and tests for generalized mediation models with high-dimensional potential mediators","volume":"42","author":"Guo","year":"2024","journal-title":"J Bus Econ Stat"},{"key":"2025070408271829600_btaf282-B12","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-84858-7","volume-title":"The Elements of Statistical Learning: Data Mining, Inference, and Prediction","author":"Hastie","year":"2009"},{"key":"2025070408271829600_btaf282-B13","doi-asserted-by":"crossref","first-page":"102156","DOI":"10.1016\/j.nicl.2019.102156","article-title":"Body mass index is associated with smaller medial temporal lobe volume in those at risk for Alzheimer\u2019s disease","volume":"25","author":"Hayes","year":"2020","journal-title":"NeuroImage Clin"},{"key":"2025070408271829600_btaf282-B14","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1080\/15592294.2018.1543503","article-title":"DNA methylation in blood as a mediator of the association of mid-childhood body mass index with cardio-metabolic risk score in early adolescence","volume":"13","author":"Huang","year":"2018","journal-title":"Epigenetics"},{"key":"2025070408271829600_btaf282-B15","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1214\/18-AOAS1181","article-title":"Genome-wide analyses of sparse mediation effects under composite null hypotheses","volume":"13","author":"Huang","year":"2019","journal-title":"Ann Appl Stat"},{"key":"2025070408271829600_btaf282-B16","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1214\/10-STS321","article-title":"Identification, inference and sensitivity analysis for causal mediation effects","volume":"25","author":"Imai","year":"2010","journal-title":"Stat Sci"},{"key":"2025070408271829600_btaf282-B17","doi-asserted-by":"crossref","first-page":"qkae109","DOI":"10.1093\/jrsssb\/qkae109","article-title":"Causal mediation analysis: selection with asymptotically valid inference","author":"Jones","year":"2024","journal-title":"J R Statist Soc B"},{"journal-title":"Handbook of Statistical Methods for Precision Medicine","article-title":"Semiparametric doubly robust targeted double machine learning: a review","author":"Kennedy","key":"2025070408271829600_btaf282-B18"},{"key":"2025070408271829600_btaf282-B19","doi-asserted-by":"crossref","first-page":"bbae059","DOI":"10.1093\/bib\/bbae059","article-title":"High-dimensional generalized median adaptive lasso with application to omics data","volume":"25","author":"Liu","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025070408271829600_btaf282-B20","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/01621459.2021.1914634","article-title":"Large-scale hypothesis testing for causal mediation effects with applications in genome-wide epigenetic studies","volume":"117","author":"Liu","year":"2022","journal-title":"J Am Stat Assoc"},{"key":"2025070408271829600_btaf282-B21","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1093\/gerona\/glab117","article-title":"Body mass index and polygenic risk for Alzheimer\u2019s disease predict conversion to Alzheimer\u2019s disease","volume":"76","author":"Moody","year":"2021","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2025070408271829600_btaf282-B22","doi-asserted-by":"crossref","first-page":"e256","DOI":"10.1038\/tp.2013.13","article-title":"Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)","volume":"3","author":"Reitz","year":"2013","journal-title":"Transl Psychiatry"},{"key":"2025070408271829600_btaf282-B23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s12874-021-01426-3","article-title":"Mediation analysis methods used in observational research: a scoping review and recommendations","volume":"21","author":"Rijnhart","year":"2021","journal-title":"BMC Med Res Methodol"},{"key":"2025070408271829600_btaf282-B24","doi-asserted-by":"crossref","first-page":"ujad037","DOI":"10.1093\/biomtc\/ujad037","article-title":"Using instrumental variables to address unmeasured confounding in causal mediation analysis","volume":"80","author":"Rudolph","year":"2024","journal-title":"Biometrics"},{"key":"2025070408271829600_btaf282-B25","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jalz.2010.03.013","article-title":"Alzheimer\u2019s disease neuroimaging initiative biomarkers as quantitative phenotypes: genetics core aims, progress, and plans","volume":"6","author":"Saykin","year":"2010","journal-title":"Alzheimer's Dementia"},{"key":"2025070408271829600_btaf282-B26","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.1093\/brain\/awaa334","article-title":"Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex","volume":"143","author":"Shireby","year":"2020","journal-title":"Brain"},{"key":"2025070408271829600_btaf282-B27","doi-asserted-by":"crossref","first-page":"290","DOI":"10.2307\/270723","article-title":"Asymptotic confidence intervals for indirect effects in structural equation models","volume":"13","author":"Sobel","year":"1982","journal-title":"Sociol Methodol"},{"key":"2025070408271829600_btaf282-B28","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1111\/biom.13189","article-title":"Bayesian shrinkage estimation of high dimensional causal mediation effects in omics studies","volume":"76","author":"Song","year":"2020","journal-title":"Biometrics"},{"key":"2025070408271829600_btaf282-B29","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1080\/01621459.2017.1319839","article-title":"Estimation and inference of heterogeneous treatment effects using random forests","volume":"113","author":"Wager","year":"2018","journal-title":"J Am Stat Assoc"},{"key":"2025070408271829600_btaf282-B30","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1093\/biostatistics\/kxad037","article-title":"DP2LM: leveraging deep learning approach for estimation and hypothesis testing on mediation effects with high dimensional mediators and complex confounders","volume":"25","author":"Wang","year":"2024","journal-title":"Biostatistics"},{"key":"2025070408271829600_btaf282-B31","doi-asserted-by":"crossref","first-page":"146957","DOI":"10.1016\/j.gene.2022.146957","article-title":"Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins","volume":"850","author":"Wang","year":"2023","journal-title":"Gene"},{"year":"2024","author":"Wei","key":"2025070408271829600_btaf282-B32","doi-asserted-by":"publisher","DOI":"10.1101\/2024.02.06.579228"},{"key":"2025070408271829600_btaf282-B33","first-page":"277","article-title":"DeepMed: semiparametric causal mediation analysis with debiased deep learning","volume":"25","author":"Xu","year":"2022","journal-title":"Adv Neural Inf Process Syst"},{"key":"2025070408271829600_btaf282-B34","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1080\/01621459.2023.2240461","article-title":"De-confounding causal inference using latent multiple-mediator pathways","volume":"119","author":"Yuan","year":"2024","journal-title":"J Am Stat Assoc"},{"key":"2025070408271829600_btaf282-B35","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1016\/j.csbj.2021.05.042","article-title":"Statistical methods for mediation analysis in the era of high-throughput genomics: current successes and future challenges","volume":"19","author":"Zeng","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"2025070408271829600_btaf282-B36","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/10705511.2024.2392139","article-title":"Efficient adjusted joint significance test and sobel-type confidence interval for mediation effect","volume":"32","author":"Zhang","year":"2025","journal-title":"Struct Equ Model"},{"key":"2025070408271829600_btaf282-B37","doi-asserted-by":"crossref","first-page":"btae055","DOI":"10.1093\/bioinformatics\/btae055","article-title":"High-dimensional quantile mediation analysis with application to a birth cohort study of mother\u2013newborn pairs","volume":"40","author":"Zhang","year":"2024","journal-title":"Bioinformatics"},{"key":"2025070408271829600_btaf282-B38","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1093\/bioinformatics\/btab564","article-title":"Mediation analysis for survival data with high dimensional mediators","volume":"37","author":"Zhang","year":"2021","journal-title":"Bioinformatics"},{"key":"2025070408271829600_btaf282-B39","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1093\/bioinformatics\/btw351","article-title":"Estimating and testing high dimensional mediation effects in epigenetic studies","volume":"32","author":"Zhang","year":"2016","journal-title":"Bioinformatics"},{"key":"2025070408271829600_btaf282-B40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4310\/21-SII673","article-title":"Pathway lasso: pathway estimation and selection with high dimensional mediators","volume":"15","author":"Zhao","year":"2022","journal-title":"Stat Its Interface"},{"key":"2025070408271829600_btaf282-B41","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1198\/016214506000000735","article-title":"The adaptive lasso and its oracle properties","volume":"101","author":"Zou","year":"2006","journal-title":"J Am Stat Assoc"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaf282\/63054852\/btaf282.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/6\/btaf282\/63054852\/btaf282.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/6\/btaf282\/63054852\/btaf282.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T12:27:31Z","timestamp":1751632051000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btaf282\/8125019"}},"subtitle":[],"editor":[{"given":"Christina","family":"Kendziorski","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,5,5]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaf282","relation":{},"ISSN":["1367-4811"],"issn-type":[{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,5,5]]},"article-number":"btaf282"}}