{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T04:37:33Z","timestamp":1769056653368,"version":"3.49.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2016,11,10]],"date-time":"2016-11-10T00:00:00Z","timestamp":1478736000000},"content-version":"vor","delay-in-days":73,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HG005690, R01HG007069"],"award-info":[{"award-number":["R01HG005690, R01HG007069"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01CA180776"],"award-info":[{"award-number":["R01CA180776"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["GRFP DGE 0228243"],"award-info":[{"award-number":["GRFP DGE 0228243"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and Implementation<\/jats:title><jats:p>See http:\/\/compbio.cs.brown.edu\/projects\/wext for software.<\/jats:p><\/jats:sec><jats:sec><jats:title>Contact<\/jats:title><jats:p>braphael@cs.brown.edu<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btw462","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T07:53:39Z","timestamp":1472716419000},"page":"i736-i745","source":"Crossref","is-referenced-by-count":48,"title":["A weighted exact test for mutually exclusive mutations in cancer"],"prefix":"10.1093","volume":"32","author":[{"given":"Mark DM","family":"Leiserson","sequence":"first","affiliation":[{"name":"Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA"}]},{"given":"Matthew A","family":"Reyna","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA"}]},{"given":"Benjamin J","family":"Raphael","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA"}]}],"member":"286","published-online":{"date-parts":[[2016,8,29]]},"reference":[{"key":"2023020113303516200_btw462-B1"},{"key":"2023020113303516200_btw462-B2"},{"key":"2023020113303516200_btw462-B3"},{"key":"2023020113303516200_btw462-B4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13059-015-0612-6","article-title":"Systematic identification of cancer driving signaling pathways based on mutual exclusivity of genomic alterations","volume":"16","author":"Babur","year":"2015","journal-title":"Genome Biol"},{"key":"2023020113303516200_btw462-B5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol"},{"key":"2023020113303516200_btw462-B6","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511619083","volume-title":"Saddlepoint Approximations with Applications","author":"Butler","year":"2007"},{"key":"2023020113303516200_btw462-B7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1101\/gr.125567.111","article-title":"Mutual exclusivity analysis identifies oncogenic network modules","volume":"22","author":"Ciriello","year":"2012","journal-title":"Genome Res"},{"key":"2023020113303516200_btw462-B8","first-page":"968","article-title":"TiMEx: a waiting time model for mutually exclusive cancer alterations","volume":"32","author":"Constantinescu","year":"2015","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2023020113303516200_btw462-B9","first-page":"i617","article-title":"Fast randomization of large genomic datasets while preserving alteration counts","volume":"30","author":"Gobbi","year":"2014","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2023020113303516200_btw462-B10","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"2023020113303516200_btw462-B11","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/mutage\/ger075","article-title":"The role of ABC transporters in progression and clinical outcome of colorectal cancer","volume":"27","author":"Hlavata","year":"2012","journal-title":"Mutagenesis"},{"key":"2023020113303516200_btw462-B12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.csda.2012.10.006","article-title":"On computing the distribution function for the Poisson binomial distribution","volume":"59","author":"Hong","year":"2013","journal-title":"Comput. Stat. Data Anal"},{"key":"2023020113303516200_btw462-B13","doi-asserted-by":"crossref","first-page":"i284","DOI":"10.1093\/bioinformatics\/btv247","article-title":"MEMCover: integrated analysis of mutual exclusivity and functional network reveals dysregulated pathways across multiple cancer types","volume":"31","author":"Kim","year":"2015","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2023020113303516200_btw462-B14","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btw242","article-title":"Wesme: Uncovering mutual exclusivity of cancer drivers and beyond","author":"Kim","year":"2016"},{"key":"2023020113303516200_btw462-B15","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer and the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"2023020113303516200_btw462-B16","doi-asserted-by":"crossref","first-page":"e1003054.","DOI":"10.1371\/journal.pcbi.1003054","article-title":"Simultaneous identification of multiple driver pathways in cancer","volume":"9","author":"Leiserson","year":"2013","journal-title":"PLoS Comput. Biol"},{"key":"2023020113303516200_btw462-B17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/ng.3168","article-title":"Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes","volume":"47","author":"Leiserson","year":"2015","journal-title":"Nat. Genet"},{"key":"2023020113303516200_btw462-B18","doi-asserted-by":"crossref","first-page":"160.","DOI":"10.1186\/s13059-015-0700-7","article-title":"CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer","volume":"16","author":"Leiserson","year":"2015","journal-title":"Genome Biol"},{"key":"2023020113303516200_btw462-B19","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N. Engl. J. Med"},{"key":"2023020113303516200_btw462-B20","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1089\/cmb.2016.0038","article-title":"A symmetric length-aware enrichment test","volume":"23","author":"Manescu","year":"2015","journal-title":"J. Comput. Biol"},{"key":"2023020113303516200_btw462-B21","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1890\/03-0101","article-title":"Randomization of presence-absence matrices: comments and new algorithms","volume":"85","author":"Mikl\u00f3s","year":"2004","journal-title":"Ecology"},{"key":"2023020113303516200_btw462-B22","doi-asserted-by":"crossref","first-page":"34.","DOI":"10.1186\/1755-8794-4-34","article-title":"Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors","volume":"4","author":"Miller","year":"2011","journal-title":"BMC Med. Genomics"},{"key":"2023020113303516200_btw462-B23","article-title":"On the uniform generation of random graphs with prescribed degree sequences","author":"Milo","year":"2003","journal-title":"arXiv Preprint cond-Mat\/0312028"},{"key":"2023020113303516200_btw462-B24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"Responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet"},{"key":"2023020113303516200_btw462-B25","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrc3816","article-title":"Hypermutation in human cancer genomes: footprints and mechanisms","volume":"14","author":"Roberts","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"2023020113303516200_btw462-B26","doi-asserted-by":"crossref","first-page":"e1004595.","DOI":"10.1371\/journal.pcbi.1004595","article-title":"Network-based integration of disparate omic data to identify \u201csilent players\u201d in cancer","volume":"11","author":"Ruffalo","year":"2015","journal-title":"PLoS Comput. Biol"},{"key":"2023020113303516200_btw462-B27","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020113303516200_btw462-B28","doi-asserted-by":"crossref","first-page":"e1003503.","DOI":"10.1371\/journal.pcbi.1003503","article-title":"Modeling mutual exclusivity of cancer mutations","volume":"10","author":"Szczurek","year":"2014","journal-title":"PLoS Comput. Biol"},{"key":"2023020113303516200_btw462-B29","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","author":"The Cancer Genome Atlas Research Network","year":"2012","journal-title":"Nature"},{"key":"2023020113303516200_btw462-B30","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.cell.2014.09.050","article-title":"Integrated genomic characterization of papillary thyroid carcinoma","volume":"159","author":"The Cancer Genome Atlas Research Network","year":"2014","journal-title":"Cell"},{"key":"2023020113303516200_btw462-B31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature12113","article-title":"Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"The Cancer Genome Atlas Research Network","year":"2013","journal-title":"Nature"},{"key":"2023020113303516200_btw462-B32","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/ng1975","article-title":"High-throughput oncogene mutation profiling in human cancer","volume":"39","author":"Thomas","year":"2007","journal-title":"Nat. Genet"},{"key":"2023020113303516200_btw462-B33","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1089\/cmb.2010.0265","article-title":"Algorithms for detecting significantly mutated pathways in cancer","volume":"18","author":"Vandin","year":"2011","journal-title":"J. Comput. Biol"},{"key":"2023020113303516200_btw462-B34","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1101\/gr.120477.111","article-title":"De novo discovery of mutated driver pathways in cancer","volume":"22","author":"Vandin","year":"2012","journal-title":"Genome Res"},{"key":"2023020113303516200_btw462-B35","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1126\/science.1235122","article-title":"Cancer genome landscapes","volume":"339","author":"Vogelstein","year":"2013","journal-title":"Science"},{"key":"2023020113303516200_btw462-B36","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet"},{"key":"2023020113303516200_btw462-B37","first-page":"1595","article-title":"PathScan: a tool for discerning mutational significance in groups of putative cancer genes","volume":"27","author":"Wendl","year":"2011","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2023020113303516200_btw462-B38","doi-asserted-by":"crossref","first-page":"4204","DOI":"10.1128\/MCB.01912-07","article-title":"PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex","volume":"28","author":"Woiwode","year":"2008","journal-title":"Mol. Cell. Biol"},{"key":"2023020113303516200_btw462-B39","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1096\/fj.08-108985","article-title":"Combinatorial patterns of somatic gene mutations in cancer","volume":"22","author":"Yeang","year":"2008","journal-title":"FASEB J"},{"key":"2023020113303516200_btw462-B40","doi-asserted-by":"crossref","first-page":"271.","DOI":"10.1186\/1471-2105-15-271","article-title":"Discovery of co-occurring driver pathways in cancer","volume":"15","author":"Zhang","year":"2014","journal-title":"BMC Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/17\/i736\/49023587\/bioinformatics_32_17_i736.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/17\/i736\/49023587\/bioinformatics_32_17_i736.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T15:55:49Z","timestamp":1749570949000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/17\/i736\/2450792"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,29]]},"references-count":40,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2016,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btw462","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,9,1]]},"published":{"date-parts":[[2016,8,29]]}}}