{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T20:01:04Z","timestamp":1776110464063,"version":"3.50.1"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T00:00:00Z","timestamp":1517875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["0603616831"],"award-info":[{"award-number":["0603616831"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The biological pathways linking exposures and disease risk are often poorly understood. To gain insight into these pathways, studies may try to identify biomarkers that mediate the exposure\/disease relationship. Such studies often simultaneously test hundreds or thousands of biomarkers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We consider a set of m biomarkers and a corresponding set of null hypotheses, where the jth null hypothesis states that biomarker j does not mediate the exposure\/disease relationship. We propose a Multiple Comparison Procedure (MCP) that rejects a set of null hypotheses or, equivalently, identifies a set of mediators, while asymptotically controlling the Family-Wise Error Rate (FWER) or False Discovery Rate (FDR). We use simulations to show that, compared to currently available methods, our proposed method has higher statistical power to detect true mediators. We then apply our method to a breast cancer study and identify nine metabolites that may mediate the known relationship between an increased BMI and an increased risk of breast cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>R package MultiMed on https:\/\/github.com\/SiminaB\/MultiMed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty064","type":"journal-article","created":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T04:12:44Z","timestamp":1517890364000},"page":"2418-2424","source":"Crossref","is-referenced-by-count":34,"title":["FWER and FDR control when testing multiple mediators"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2875-3365","authenticated-orcid":false,"given":"Joshua N","family":"Sampson","sequence":"first","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA"}]},{"given":"Simina M","family":"Boca","sequence":"additional","affiliation":[{"name":"Department of Oncology and Department of Biostatistics, Bioinformatics & Biomathematics, Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA"}]},{"given":"Steven C","family":"Moore","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA"}]},{"given":"Ruth","family":"Heller","sequence":"additional","affiliation":[{"name":"Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel"}]}],"member":"286","published-online":{"date-parts":[[2018,2,6]]},"reference":[{"key":"2023012713011825900_bty064-B1","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1037\/0022-3514.51.6.1173","article-title":"The moderator\u2013mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations","volume":"51","author":"Baron","year":"1986","journal-title":"Journal of Person. 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Psychol"},{"key":"2023012713011825900_bty064-B2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/bioinformatics\/btt633","article-title":"Testing multiple biological mediators simultaneously","volume":"30","author":"Boca","year":"2014","journal-title":"Bioinformatics"},{"key":"2023012713011825900_bty064-B3","doi-asserted-by":"crossref","DOI":"10.1093\/biomet\/asy029","article-title":"Assessing replicability of findings across two studies of multiple features","author":"Bogomolov","year":"2018","journal-title":"Biometrika"},{"key":"2023012713011825900_bty064-B4","article-title":"High-dimensional multivariate mediation: with application to neuroimaging data","author":"Chen","year":"2017","journal-title":"Biostatistics"},{"key":"2023012713011825900_bty064-B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/biom.12248","article-title":"Causal mediation analysis with multiple mediators","volume":"71","author":"Daniel","year":"2015","journal-title":"Biom"},{"key":"2023012713011825900_bty064-B6","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/biom.12421","article-title":"Hypothesis test of mediation effect in causal mediation model with high-dimensional continuous mediators","volume":"72","author":"Huang","year":"2016","journal-title":"Biom"},{"key":"2023012713011825900_bty064-B7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev.publhealth.23.100901.140546","article-title":"The importance of the normality assumption in large public health data sets","volume":"23","author":"Lumley","year":"2002","journal-title":"Annu. 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