{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T07:09:27Z","timestamp":1771744167826,"version":"3.50.1"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T00:00:00Z","timestamp":1530057600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U24CA184427"],"award-info":[{"award-number":["U24CA184427"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U54CA209891"],"award-info":[{"award-number":["U54CA209891"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P50GM085764"],"award-info":[{"award-number":["P50GM085764"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P41GM103504"],"award-info":[{"award-number":["P41GM103504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01GM070743"],"award-info":[{"award-number":["R01GM070743"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Network propagation has been widely used to aggregate and amplify the effects of tumor mutations using knowledge of molecular interaction networks. However, propagating mutations through interactions irrelevant to cancer leads to erosion of pathway signals and complicates the identification of cancer subtypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>To address this problem we introduce a propagation algorithm, Network-Based Supervised Stratification (NBS2), which learns the mutated subnetworks underlying tumor subtypes using a supervised approach. Given an annotated molecular network and reference tumor mutation profiles for which subtypes have been predefined, NBS2 is trained by adjusting the weights on interaction features such that network propagation best recovers the provided subtypes. After training, weights are fixed such that mutation profiles of new tumors can be accurately classified. We evaluate NBS2 on breast and glioblastoma tumors, demonstrating that it outperforms the best network-based approaches in classifying tumors to known subtypes for these diseases. By interpreting the interaction weights, we highlight characteristic molecular pathways driving selected subtypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The NBS2 package is freely available at: https:\/\/github.com\/wzhang1984\/NBSS.<\/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\/bty247","type":"journal-article","created":{"date-parts":[[2018,4,12]],"date-time":"2018-04-12T19:32:51Z","timestamp":1523561571000},"page":"i484-i493","source":"Crossref","is-referenced-by-count":40,"title":["Classifying tumors by supervised network propagation"],"prefix":"10.1093","volume":"34","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA, USA"}]},{"given":"Jianzhu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA, USA"}]},{"given":"Trey","family":"Ideker","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, CA, USA"},{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA"}]}],"member":"286","published-online":{"date-parts":[[2018,6,27]]},"reference":[{"key":"2023051605123475900_bty247-B2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1103\/RevModPhys.74.47","article-title":"Statistical mechanics of complex networks","volume":"74","author":"Albert","year":"2002","journal-title":"Rev. Mod. Phys"},{"key":"2023051605123475900_bty247-B3","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/ng.3138","article-title":"A multiscale statistical mechanical framework integrates biophysical and genomic data to assemble cancer networks","volume":"46","author":"AlQuraishi","year":"2014","journal-title":"Nat. Genet"},{"key":"2023051605123475900_bty247-B4","author":"Backstrom","year":"2010"},{"key":"2023051605123475900_bty247-B5","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.1093\/nar\/gku1393","article-title":"Patient-specific driver gene prediction and risk assessment through integrated network analysis of cancer omics profiles","volume":"43","author":"Bertrand","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023051605123475900_bty247-B6","volume-title":"Pattern Recognition and Machine Learning (Information Science and Statistics)","author":"Bishop","year":"2007","edition":"1st edn"},{"key":"2023051605123475900_bty247-B7","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/sj.bjc.6605587","article-title":"Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide","volume":"102","author":"Bray","year":"2010","journal-title":"Br. J. Cancer"},{"key":"2023051605123475900_bty247-B8","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.cell.2013.09.034","article-title":"The somatic genomic landscape of glioblastoma","volume":"155","author":"Brennan","year":"2013","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","author":"Cancer Genome Atlas Network","year":"2012","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B10","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nature10166","article-title":"Integrated genomic analyses of ovarian carcinoma","volume":"474","author":"Cancer Genome Atlas Research Network","year":"2011","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B11","doi-asserted-by":"crossref","first-page":"D685","DOI":"10.1093\/nar\/gkq1039","article-title":"Pathway commons, a web resource for biological pathway data","volume":"39","author":"Cerami","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2023051605123475900_bty247-B12","doi-asserted-by":"crossref","first-page":"129.","DOI":"10.1186\/s13059-016-0989-x","article-title":"MUFFINN: cancer gene discovery via network analysis of somatic mutation data","volume":"17","author":"Cho","year":"2016","journal-title":"Genome Biol"},{"key":"2023051605123475900_bty247-B13","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.cell.2015.09.033","article-title":"Comprehensive molecular portraits of invasive lobular breast cancer","volume":"163","author":"Ciriello","year":"2015","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B14","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":"2023051605123475900_bty247-B15","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg.2017.38","article-title":"Network propagation: a universal amplifier of genetic associations","volume":"18","author":"Cowen","year":"2017","journal-title":"Nat. Rev. Genet"},{"key":"2023051605123475900_bty247-B16","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cell.2015.08.057","article-title":"Unmasking determinants of specificity in the human kinome","volume":"163","author":"Creixell","year":"2015","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B17","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nmeth.3440","article-title":"Pathway and network analysis of cancer genomes","volume":"12","author":"Creixell","year":"2015","journal-title":"Nat. Methods"},{"key":"2023051605123475900_bty247-B18","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.cell.2015.08.056","article-title":"Kinome-wide decoding of network-attacking mutations rewiring cancer signaling","volume":"163","author":"Creixell","year":"2015","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B19","doi-asserted-by":"crossref","first-page":"290","DOI":"10.5486\/PMD.1959.6.3-4.12","article-title":"On random graphs I","volume":"6","author":"Erdos","year":"1959","journal-title":"Publ. Math. Debrecen"},{"key":"2023051605123475900_bty247-B20","doi-asserted-by":"crossref","first-page":"e1378.","DOI":"10.1038\/cddis.2014.339","article-title":"Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells","volume":"5","author":"Fujiki","year":"2014","journal-title":"Cell Death Dis"},{"key":"2023051605123475900_bty247-B21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nrc1299","article-title":"A census of human cancer genes","volume":"4","author":"Futreal","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2023051605123475900_bty247-B22","doi-asserted-by":"crossref","first-page":"16361.","DOI":"10.1038\/srep16361","article-title":"Identifying robust communities and multi-community nodes by combining top-down and bottom-up approaches to clustering","volume":"5","author":"Gaiteri","year":"2015","journal-title":"Sci. Rep"},{"key":"2023051605123475900_bty247-B23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nature11245","article-title":"Architecture of the human regulatory network derived from ENCODE data","volume":"489","author":"Gerstein","year":"2012","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B24","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/nmeth.2651","article-title":"Network-based stratification of tumor mutations","volume":"10","author":"Hofree","year":"2013","journal-title":"Nat. Methods"},{"key":"2023051605123475900_bty247-B25","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nmeth.4514","article-title":"NetSig: network-based discovery from cancer genomes","volume":"15","author":"Horn","year":"2018","journal-title":"Nat. Methods"},{"key":"2023051605123475900_bty247-B26","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nature08987","article-title":"International network of cancer genome projects","volume":"464","author":"International Cancer Genome Consortium","year":"2010","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B27","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cell.2016.06.017","article-title":"A landscape of pharmacogenomic interactions in cancer","volume":"166","author":"Iorio","year":"2016","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B28","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1128\/MCB.26.7.2501-2510.2006","article-title":"Primary and compensatory roles for RB family members at cell cycle gene promoters that are deacetylated and downregulated in doxorubicin-induced senescence of breast cancer cells","volume":"26","author":"Jackson","year":"2006","journal-title":"Mol. Cell. Biol"},{"key":"2023051605123475900_bty247-B29","doi-asserted-by":"crossref","first-page":"11566.","DOI":"10.1038\/srep11566","article-title":"Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer","volume":"5","author":"Jin","year":"2015","journal-title":"Sci. Rep"},{"key":"2023051605123475900_bty247-B30","doi-asserted-by":"crossref","first-page":"e1004747","DOI":"10.1371\/journal.pcbi.1004747","article-title":"Understanding genotype-phenotype effects in cancer via network approaches","volume":"12","author":"Kim","year":"2016","journal-title":"PLoS Comput. Biol"},{"key":"2023051605123475900_bty247-B31","author":"Kingma","year":"2014"},{"key":"2023051605123475900_bty247-B32","doi-asserted-by":"crossref","first-page":"a016725.","DOI":"10.1101\/cshperspect.a016725","article-title":"Molecular structure, function, and dynamics of clathrin-mediated membrane traffic","volume":"6","author":"Kirchhausen","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol"},{"key":"2023051605123475900_bty247-B33","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":"2023051605123475900_bty247-B34","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":"2023051605123475900_bty247-B35","doi-asserted-by":"crossref","first-page":"4486","DOI":"10.1182\/blood-2009-04-218123","article-title":"Gene expression-based classification and regulatory networks of pediatric acute lymphoblastic leukemia","volume":"114","author":"Li","year":"2009","journal-title":"Blood"},{"key":"2023051605123475900_bty247-B36","doi-asserted-by":"crossref","first-page":"14356.","DOI":"10.1038\/ncomms14356","article-title":"The OncoPPi network of cancer-focused protein\u2013protein interactions to inform biological insights and therapeutic strategies","volume":"8","author":"Li","year":"2017","journal-title":"Nat. Commun"},{"key":"2023051605123475900_bty247-B37","doi-asserted-by":"crossref","first-page":"6009","DOI":"10.1128\/MCB.16.11.6009","article-title":"Transcriptional activation of the human epidermal growth factor receptor promoter by human p53","volume":"16","author":"Ludes-Meyers","year":"1996","journal-title":"Mol. Cell. Biol"},{"key":"2023051605123475900_bty247-B38","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":"2023051605123475900_bty247-B39","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00401-005-0991-y","article-title":"Epidemiology and etiology of gliomas","volume":"109","author":"Ohgaki","year":"2005","journal-title":"Acta Neuropathol"},{"key":"2023051605123475900_bty247-B40","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":"2023051605123475900_bty247-B41","doi-asserted-by":"crossref","first-page":"9210","DOI":"10.1073\/pnas.0913813107","article-title":"C\/EBP\u03b4 targets cyclin D1 for proteasome-mediated degradation via induction of CDC27\/APC3 expression","volume":"107","author":"Pawar","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023051605123475900_bty247-B42","doi-asserted-by":"crossref","first-page":"342.","DOI":"10.1038\/072342a0","article-title":"The problem of the random walk","volume":"72","author":"Pearson","year":"1905","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B43","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"2023051605123475900_bty247-B44","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/978-1-4939-6783-4_13","article-title":"NDEx: a community resource for sharing and publishing of biological networks","volume":"1558","author":"Pillich","year":"2017","journal-title":"Methods Mol. Biol"},{"key":"2023051605123475900_bty247-B45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.molonc.2010.11.003","article-title":"Deconstructing the molecular portraits of breast cancer","volume":"5","author":"Prat","year":"2011","journal-title":"Mol. Oncol"},{"key":"2023051605123475900_bty247-B46","doi-asserted-by":"crossref","first-page":"e58","DOI":"10.1158\/0008-5472.CAN-17-0606","article-title":"NDEx 2.0: a clearinghouse for research on cancer pathways","volume":"77","author":"Pratt","year":"2017","journal-title":"Cancer Res"},{"key":"2023051605123475900_bty247-B47","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.cels.2015.10.001","article-title":"NDEx, the network data exchange","volume":"1","author":"Pratt","year":"2015","journal-title":"Cell Syst"},{"key":"2023051605123475900_bty247-B48","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1083\/jcb.146.5.1147","article-title":"Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells","volume":"146","author":"Rabinovitz","year":"1999","journal-title":"J. Cell Biol"},{"key":"2023051605123475900_bty247-B49","doi-asserted-by":"crossref","first-page":"e1004595.","DOI":"10.1371\/journal.pcbi.1004595","article-title":"Network-based integration of disparate omic data to identify \u2018silent players\u2019 in cancer","volume":"11","author":"Ruffalo","year":"2015","journal-title":"PLoS Comput. Biol"},{"key":"2023051605123475900_bty247-B50","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1074\/jbc.M309924200","article-title":"The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt\/PKB-mediated signaling in T cells","volume":"279","author":"Sade","year":"2004","journal-title":"J. Biol. Chem"},{"key":"2023051605123475900_bty247-B51","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1074\/jbc.274.6.3565","article-title":"Regulation of the c-met proto-oncogene promoter by p53","volume":"274","author":"Seol","year":"1999","journal-title":"J. Biol. Chem"},{"key":"2023051605123475900_bty247-B52","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0092-8674(00)80486-9","article-title":"Activation of phosphoinositide 3-OH kinase by the \u03b16\u03b24 integrin promotes carcinoma invasion","volume":"91","author":"Shaw","year":"1997","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B53","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1242\/jcs.068965","article-title":"Trp53 regulates Notch 4 signaling through Mdm2","volume":"124","author":"Sun","year":"2011","journal-title":"J. Cell Sci"},{"key":"2023051605123475900_bty247-B54","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"2023051605123475900_bty247-B55","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":"2023051605123475900_bty247-B56","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":"2023051605123475900_bty247-B57","first-page":"1","article-title":"Pattern discovery in breast cancer specific protein interaction network","volume":"2009","author":"Wu","year":"2009","journal-title":"Summit. Transl. Bioinform"},{"key":"2023051605123475900_bty247-B58","doi-asserted-by":"crossref","first-page":"8695","DOI":"10.1074\/jbc.M609135200","article-title":"The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-\u03b31 activation and human keratinocyte differentiation","volume":"282","author":"Xie","year":"2007","journal-title":"J. Biol. Chem"},{"key":"2023051605123475900_bty247-B59","first-page":"848","author":"Yan","year":"2003"},{"key":"2023051605123475900_bty247-B60","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0092-8674(00)00195-1","article-title":"Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N","volume":"103","author":"Ye","year":"2000","journal-title":"Cell"},{"key":"2023051605123475900_bty247-B61","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.celrep.2013.07.010","article-title":"Integrating genomic, epigenomic, and transcriptomic features reveals modular signatures underlying poor prognosis in ovarian cancer","volume":"4","author":"Zhang","year":"2013","journal-title":"Cell Rep"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/13\/i484\/50316143\/bioinformatics_34_13_i484.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/13\/i484\/50316143\/bioinformatics_34_13_i484.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T05:13:51Z","timestamp":1684214031000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/34\/13\/i484\/5045745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,27]]},"references-count":60,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2018,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bty247","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,7,1]]},"published":{"date-parts":[[2018,6,27]]}}}