{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T13:42:05Z","timestamp":1768743725249,"version":"3.49.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2019,5,28]],"date-time":"2019-05-28T00:00:00Z","timestamp":1559001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01LM012806"],"award-info":[{"award-number":["R01LM012806"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"the Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["CPRIT RP180734"],"award-info":[{"award-number":["CPRIT RP180734"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"the Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP170668"],"award-info":[{"award-number":["RP170668"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Genome-wide multi-omics profiling of complex diseases provides valuable resources and opportunities to discover associations between various measures of genes and diseases. Currently, a pressing challenge is how to effectively detect functional genes associated with or causing phenotypic outcomes. We developed CNet to identify groups of genomic signatures whose combinatory effect is significantly associated with clinical and phenotypical outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CNet builds on a generalized sequential feedforward method, augmented by a down-sampling bootstrap strategy to reduce random hitchhiking signatures. It further applies a dynamic trimming procedure to remove relatively less informative signatures at every step. CNet can manage heterogeneous genomic signature profiles simultaneously and select the best signature to represent a specific gene. To deal with various forms of clinical and phenotypical measurements, we introduced four models to deal with continuous, categorical and censored data. We tested CNet using drug-response data, multidimensional cancer genomics data and genome-wide association study data for multiple traits. Our results demonstrated that in various scenarios, CNet could effectively identify signatures that are associated with the outcomes. In addition, we applied CNet to identify likely disease-causing chains involving somatic mutations, pathway activities and patient outcomes. With appropriate setting, CNet can be applied in many biological conditions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>CNet can be downloaded at https:\/\/github.com\/bsml320\/CNet.<\/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\/btz441","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T19:33:50Z","timestamp":1558640030000},"page":"5207-5215","source":"Crossref","is-referenced-by-count":8,"title":["CNet: a multi-omics approach to detecting clinically associated, combinatory genomic signatures"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4523-4153","authenticated-orcid":false,"given":"Peilin","family":"Jia","sequence":"first","affiliation":[{"name":"Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston , Houston, TX 77030, USA"}]},{"given":"Guangsheng","family":"Pei","sequence":"additional","affiliation":[{"name":"Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston , Houston, TX 77030, USA"}]},{"given":"Zhongming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston , Houston, TX 77030, USA"},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center , Nashville, TN 37203, USA"}]}],"member":"286","published-online":{"date-parts":[[2019,5,28]]},"reference":[{"key":"2023013108375921900_btz441-B1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: a network-based approach to human disease","volume":"12","author":"Barabasi","year":"2011","journal-title":"Nat. Rev. Genet"},{"key":"2023013108375921900_btz441-B2","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"},{"key":"2023013108375921900_btz441-B3","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1093\/bioinformatics\/btt660","article-title":"Pathway Commons at virtual cell: use of pathway data for mathematical modeling","volume":"30","author":"Blinov","year":"2014","journal-title":"Bioinformatics"},{"key":"2023013108375921900_btz441-B4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1136\/jmedgenet-2012-100918","article-title":"wANNOVAR: annotating genetic variants for personal genomes via the web","volume":"49","author":"Chang","year":"2012","journal-title":"J. Med. Genet"},{"key":"2023013108375921900_btz441-B5","doi-asserted-by":"crossref","first-page":"D369","DOI":"10.1093\/nar\/gkw1102","article-title":"The BioGRID interaction database: 2017 update","volume":"45","author":"Chatr-Aryamontri","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023013108375921900_btz441-B6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s10238-012-0224-3","article-title":"Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia areata","volume":"14","author":"Conteduca","year":"2014","journal-title":"Clin. Exp. Med"},{"key":"2023013108375921900_btz441-B7","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1093\/bioinformatics\/btu848","article-title":"PRSice: polygenic Risk Score software","volume":"31","author":"Euesden","year":"2015","journal-title":"Bioinformatics"},{"key":"2023013108375921900_btz441-B8","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/nm.4405","article-title":"Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence","volume":"23","author":"Goh","year":"2017","journal-title":"Nat. Med"},{"key":"2023013108375921900_btz441-B9","doi-asserted-by":"crossref","first-page":"7.","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"Hanzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2023013108375921900_btz441-B10","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s12020-010-9318-4","article-title":"A polymorphism near osteoprotegerin gene confer risk of obesity in Uyghurs","volume":"37","author":"Jiang","year":"2010","journal-title":"Endocrine"},{"key":"2023013108375921900_btz441-B11","doi-asserted-by":"crossref","first-page":"e1002549","DOI":"10.1371\/journal.pcbi.1002549","article-title":"Data sharing in the post-genomic world: the experience of the International Cancer Genome Consortium (ICGC) Data Access Compliance Office (DACO)","volume":"8","author":"Joly","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2023013108375921900_btz441-B12","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/nbt.3527","article-title":"Characterizing genomic alterations in cancer by complementary functional associations","volume":"34","author":"Kim","year":"2016","journal-title":"Nat. Biotechnol"},{"key":"2023013108375921900_btz441-B13","doi-asserted-by":"crossref","first-page":"e1004714","DOI":"10.1371\/journal.pcbi.1004714","article-title":"Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics","volume":"12","author":"Lamparter","year":"2016","journal-title":"PLoS Comput. Biol"},{"key":"2023013108375921900_btz441-B14","doi-asserted-by":"crossref","first-page":"96.","DOI":"10.1186\/s13073-017-0489-y","article-title":"Prospects for using risk scores in polygenic medicine","volume":"9","author":"Lewis","year":"2017","journal-title":"Genome Med"},{"key":"2023013108375921900_btz441-B15","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/mp.2015.40","article-title":"Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database","volume":"21","author":"Li","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"2023013108375921900_btz441-B16","doi-asserted-by":"crossref","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","article-title":"The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog)","volume":"45","author":"MacArthur","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023013108375921900_btz441-B17","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/ng.3936","article-title":"Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease","volume":"49","author":"Marigorta","year":"2017","journal-title":"Nat. Genet"},{"key":"2023013108375921900_btz441-B18","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1186\/gb-2011-12-4-r41","article-title":"GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers","volume":"12","author":"Mermel","year":"2011","journal-title":"Genome Biol"},{"key":"2023013108375921900_btz441-B19","doi-asserted-by":"crossref","first-page":"i640","DOI":"10.1093\/bioinformatics\/bts402","article-title":"PARADIGM-SHIFT predicts the function of mutations in multiple cancers using pathway impact analysis","volume":"28","author":"Ng","year":"2012","journal-title":"Bioinformatics"},{"key":"2023013108375921900_btz441-B20","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1200\/JCO.2008.18.1370","article-title":"Supervised risk predictor of breast cancer based on intrinsic subtypes","volume":"27","author":"Parker","year":"2009","journal-title":"J. Clin. Oncol"},{"key":"2023013108375921900_btz441-B21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12864-018-5373-7","article-title":"Investigation of multi-trait associations using pathway-based analysis of GWAS summary statistics","volume":"20","author":"Pei","year":"2019","journal-title":"BMC Genomics"},{"key":"2023013108375921900_btz441-B22","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/ng.3570","article-title":"Detection and interpretation of shared genetic influences on 42 human traits","volume":"48","author":"Pickrell","year":"2016","journal-title":"Nat. Genet"},{"key":"2023013108375921900_btz441-B23","doi-asserted-by":"crossref","first-page":"R986","DOI":"10.1016\/j.cub.2017.07.043","article-title":"Fanconi anemia pathway","volume":"27","author":"Rodriguez","year":"2017","journal-title":"Curr. Biol"},{"key":"2023013108375921900_btz441-B24","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":"2023013108375921900_btz441-B25","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1158\/1078-0432.CCR-12-2321","article-title":"A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients","volume":"19","author":"Tang","year":"2013","journal-title":"Clin Cancer Res"},{"key":"2023013108375921900_btz441-B26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","year":"2012","journal-title":"Nature"},{"key":"2023013108375921900_btz441-B27","doi-asserted-by":"crossref","DOI":"10.3390\/cancers10050135","article-title":"The guardian of the genome revisited: p53 downregulates genes required for telomere maintenance, DNA repair, and centromere structure","volume":"10","author":"Toufektchan","year":"2018","journal-title":"Cancers (Basel)"},{"key":"2023013108375921900_btz441-B28","doi-asserted-by":"crossref","first-page":"412","DOI":"10.5306\/wjco.v5.i3.412","article-title":"Biological subtypes of breast cancer: prognostic and therapeutic implications","volume":"5","author":"Yersal","year":"2014","journal-title":"World J. Clin. Oncol"},{"key":"2023013108375921900_btz441-B29","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1093\/hmg\/ddt575","article-title":"Multistage genome-wide association meta-analyses identified two new loci for bone mineral density","volume":"23","author":"Zhang","year":"2014","journal-title":"Hum. Mol. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz441\/28928393\/btz441.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5207\/48977882\/bioinformatics_35_24_5207.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5207\/48977882\/bioinformatics_35_24_5207.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T17:55:43Z","timestamp":1675187743000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/24\/5207\/5505417"}},"subtitle":[],"editor":[{"given":"Jonathan","family":"Wren","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2019,5,28]]},"references-count":29,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2019,12,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz441","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12,15]]},"published":{"date-parts":[[2019,5,28]]}}}