{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T14:26:16Z","timestamp":1776781576208,"version":"3.51.2"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01LM014142"],"award-info":[{"award-number":["R01LM014142"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01CA285337"],"award-info":[{"award-number":["R01CA285337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Commonwealth Universal Research Enhancement"},{"DOI":"10.13039\/100004897","name":"Pennsylvania Department of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>Causal mediation analysis investigates the role of mediators in the relationship between exposure and outcome. In the analysis of omics or imaging data, mediators are often high-dimensional, presenting challenges such as multicollinearity and interpretability. Existing methods either compromise interpretability or fail to effectively prioritize mediators. To address these challenges and advance causal mediation analysis in high-dimensional contexts, we propose the Partial Sum Statistic and Sample Splitting Strategy (PS5) framework. Through extensive simulations, we demonstrate that PS5 offers superior type I error control, higher statistical power, reduced bias in mediation effect estimation, and more accurate mediator selection. We apply PS5 to an imaging genetics dataset of chronic obstructive pulmonary disease (COPD) patients from the COPDGene study. The results show successful estimation of the global indirect effect and identification of mediating image regions. Notably, we identify a region in the lower lobe of the lung that exhibits a strong and concordant mediation effect for both genetic and environmental exposures, suggesting potential targets for treatment to mitigate COPD severity caused by genetic and smoking effects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>PS5 is publicly available at https:\/\/github.com\/hung-ching-chang\/PS5Med.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf493","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:22:50Z","timestamp":1757524970000},"source":"Crossref","is-referenced-by-count":1,"title":["High-dimensional causal mediation analysis by partial sum statistic and sample splitting strategy in imaging genetics application"],"prefix":"10.1093","volume":"41","author":[{"given":"Hung-Ching","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh , Pittsburgh, PA 15261,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusi","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh , Pittsburgh, PA 15261,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4790-4675","authenticated-orcid":false,"given":"Michael T","family":"Gorczyca","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh , Pittsburgh, PA 15261,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayhan","family":"Batmanghelich","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering, Boston University , Boston, MA 02215,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5447-1014","authenticated-orcid":false,"given":"George C","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh , Pittsburgh, PA 15261,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2025101607392548100_btaf493-B1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/EDE.0000000000001313","article-title":"Insights into the cross-world independence assumption of causal mediation analysis","volume":"32","author":"Andrews","year":"2021","journal-title":"Epidemiology"},{"key":"2025101607392548100_btaf493-B2","doi-asserted-by":"crossref","first-page":"824069","DOI":"10.3389\/fnins.2022.824069","article-title":"Imaging genetic based mediation analysis for human cognition","volume":"16","author":"Chen","year":"2022","journal-title":"Front Neurosci"},{"key":"2025101607392548100_btaf493-B3","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S2213-2600(14)70002-5","article-title":"Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis","volume":"2","author":"Cho","year":"2014","journal-title":"Lancet Respir Med"},{"key":"2025101607392548100_btaf493-B4","author":"Clark-Boucher","year":"2023"},{"key":"2025101607392548100_btaf493-B5","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":"2025101607392548100_btaf493-B6","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1214\/15-STS527","article-title":"High-dimensional inference: confidence intervals, p-values and R-software hdi","volume":"30","author":"Dezeure","year":"2015","journal-title":"Statist Sci"},{"key":"2025101607392548100_btaf493-B7","first-page":"1115","article-title":"Heavy-tailed distribution for combining dependent p-values with asymptotic robustness","volume":"33","author":"Fang","year":"2024","journal-title":"Stat Sin"},{"key":"2025101607392548100_btaf493-B8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jeconom.2022.03.001","article-title":"Statistical inference for linear mediation models with high-dimensional mediators and application to studying stock reaction to covid-19 pandemic","volume":"235","author":"Guo","year":"2023","journal-title":"J Econom"},{"key":"2025101607392548100_btaf493-B9","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/jrsssb\/qkad129","article-title":"Adaptive bootstrap tests for composite null hypotheses in the mediation pathway analysis","volume":"86","author":"He","year":"2024","journal-title":"J R Stat Soc Series B Stat Methodol"},{"key":"2025101607392548100_btaf493-B10","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":"Biometrics"},{"key":"2025101607392548100_btaf493-B11","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1214\/10-AOAS393","article-title":"An adaptively weighted statistic for detecting differential gene expression when combining multiple transcriptomic studies","volume":"5","author":"Li","year":"2011","journal-title":"Ann Appl Stat"},{"key":"2025101607392548100_btaf493-B12","first-page":"4874","article-title":"Context matters: graph-based self-supervised representation learning for medical images","volume":"35","author":"Li","year":"2021","journal-title":"Proc AAAI Conf Artif Intell"},{"key":"2025101607392548100_btaf493-B13","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":"2025101607392548100_btaf493-B14","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1111\/resp.14328","article-title":"Chronic obstructive pulmonary disease (COPD) mortality trends worldwide: an update to 2019","volume":"27","author":"Mei","year":"2022","journal-title":"Respirology"},{"key":"2025101607392548100_btaf493-B15","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1198\/jasa.2009.tm08647","article-title":"p-Values for high-dimensional regression","volume":"104","author":"Meinshausen","year":"2009","journal-title":"J Am Stat Assoc"},{"key":"2025101607392548100_btaf493-B16","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/S2213-2600(20)30101-6","article-title":"Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts","volume":"8","author":"Moll","year":"2020","journal-title":"Lancet Respir Med"},{"key":"2025101607392548100_btaf493-B17","first-page":"411","author":"Pearl","year":"2001"},{"key":"2025101607392548100_btaf493-B18","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s12859-022-04748-1","article-title":"HIMA2: high-dimensional mediation analysis and its application in epigenome-wide DNA methylation data","volume":"23","author":"Perera","year":"2022","journal-title":"BMC Bioinformatics"},{"key":"2025101607392548100_btaf493-B19","doi-asserted-by":"crossref","first-page":"e1000421","DOI":"10.1371\/journal.pgen.1000421","article-title":"A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci","volume":"5","author":"Pillai","year":"2009","journal-title":"PLoS Genet"},{"key":"2025101607392548100_btaf493-B20","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3109\/15412550903499522","article-title":"Genetic epidemiology of COPD (COPDGene) study design","volume":"7","author":"Regan","year":"2010","journal-title":"COPD: J Chron Obstruct Pulmon Dis"},{"key":"2025101607392548100_btaf493-B21","author":"Roy","year":"2024"},{"key":"2025101607392548100_btaf493-B22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ccm.2013.09.011","article-title":"Tobacco smoking and environmental risk factors for chronic obstructive pulmonary disease","volume":"35","author":"Salvi","year":"2014","journal-title":"Clin Chest Med"},{"key":"2025101607392548100_btaf493-B23","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1111\/rssc.12518","article-title":"Bayesian sparse mediation analysis with targeted penalization of natural indirect effects","volume":"70","author":"Song","year":"2021","journal-title":"J Roy Stat Soc Ser C"},{"key":"2025101607392548100_btaf493-B24","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":"2025101607392548100_btaf493-B25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2147\/COPD.S2639","article-title":"Imaging of pulmonary emphysema: a pictorial review","volume":"3","author":"Takahashi","year":"2008","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2025101607392548100_btaf493-B26","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1093\/bioinformatics\/btac687","article-title":"CoxMKF: a knockoff filter for high-dimensional mediation analysis with a survival outcome in epigenetic studies","volume":"38","author":"Tian","year":"2022","journal-title":"Bioinformatics"},{"key":"2025101607392548100_btaf493-B27","first-page":"95","article-title":"Mediation analysis with multiple mediators","volume":"2","author":"VanderWeele","year":"2014","journal-title":"Epidemiol Methods"},{"key":"2025101607392548100_btaf493-B28","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1146\/annurev-statistics-040622-031653","article-title":"Causal mediation analysis for integrating exposure, genomic, and phenotype data","volume":"12","author":"Yang","year":"2025","journal-title":"Annu Rev Stat Appl"},{"key":"2025101607392548100_btaf493-B29","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":"2025101607392548100_btaf493-B30","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1214\/09-AOS729","article-title":"Nearly unbiased variable selection under minimax concave penalty","volume":"38","author":"Zhang","year":"2010","journal-title":"Ann Statist"},{"key":"2025101607392548100_btaf493-B31","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":"2025101607392548100_btaf493-B32","doi-asserted-by":"crossref","first-page":"106835","DOI":"10.1016\/j.csda.2019.106835","article-title":"Sparse principal component based high-dimensional mediation analysis","volume":"142","author":"Zhao","year":"2020","journal-title":"Comput Stat Data Anal"},{"key":"2025101607392548100_btaf493-B33","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 Interface"},{"key":"2025101607392548100_btaf493-B34","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/biomet\/asaa016","article-title":"Estimation and inference for the indirect effect in high-dimensional linear mediation models","volume":"107","author":"Zhou","year":"2020","journal-title":"Biometrika"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaf493\/64237125\/btaf493.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/10\/btaf493\/64237125\/btaf493.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/10\/btaf493\/64237125\/btaf493.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T11:39:35Z","timestamp":1760614775000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btaf493\/8250682"}},"subtitle":[],"editor":[{"given":"Lenore","family":"Cowen","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":34,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaf493","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,10]]},"article-number":"btaf493"}}