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Mediation analysis has emerged as a promising statistical tool to identify and quantify the intermediate mechanisms by which a gene affects an outcome. However, existing methods lack a unified approach to handle various types of outcome variables, making them unsuitable for high-throughput molecular profiling data with highly interconnected variables.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We develop a general mediation analysis framework for proteogenomic data that include multiple exposures, multivariate mediators on various scales of effects as appropriate for continuous, binary and survival outcomes. Our estimation method avoids imposing constraints on model parameters such as the rare disease assumption, while accommodating multiple exposures and high-dimensional mediators. We compare our approach to other methods in extensive simulation studies at a range of sample sizes, disease prevalence and number of false mediators. Using kidney renal clear cell carcinoma proteogenomic data, we identify genes that are mediated by proteins and the underlying mechanisms on various survival outcomes that capture short- and long-term disease-specific clinical characteristics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Software is made available in an R package (https:\/\/github.com\/longjp\/mediateR).<\/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\/btad023","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T12:11:39Z","timestamp":1673871099000},"source":"Crossref","is-referenced-by-count":4,"title":["A unified mediation analysis framework for integrative cancer proteogenomics with clinical outcomes"],"prefix":"10.1093","volume":"39","author":[{"given":"Licai","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehsan","family":"Irajizad","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D","family":"Doecke","sequence":"additional","affiliation":[{"name":"CSIRO, Royal Brisbane and Women\u2019s Hospital , Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim-Anh","family":"Do","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5165-1642","authenticated-orcid":false,"given":"Min Jin","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Health Informatics and Biostatistics, Graduate School of Public Health, Yonsei University , Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"2023012702144161000_btad023-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms4887","article-title":"A pan-cancer proteomic perspective on the cancer genome atlas","volume":"5","author":"Akbani","year":"2014","journal-title":"Nat. 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