{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:38:53Z","timestamp":1774312733509,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"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\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1DP1DA048968-01"],"award-info":[{"award-number":["1DP1DA048968-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>The analysis of gene co-expression network (GCN) is critical in examining the gene-gene interactions and learning the underlying complex yet highly organized gene regulatory mechanisms. Numerous clustering methods have been developed to detect communities of co-expressed genes in the large network. The assumed independent community structure, however, can be oversimplified and may not adequately characterize the complex biological processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We develop a new computational package to extract interconnected communities from gene co-expression network. We consider a pair of communities be interconnected if a subset of genes from one community is correlated with a subset of genes from another community. The interconnected community structure is more flexible and provides a better fit to the empirical co-expression matrix. To overcome the computational challenges, we develop efficient algorithms by leveraging advanced graph norm shrinkage approach. We validate and show the advantage of our method by extensive simulation studies. We then apply our interconnected community detection method to an RNA-seq data from The Cancer Genome Atlas (TCGA) Acute Myeloid Leukemia (AML) study and identify essential interacting biological pathways related to the immune evasion mechanism of tumor cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availabilityand implementation<\/jats:title><jats:p>The software is available at Github: https:\/\/github.com\/qwu1221\/ICN and Figshare: https:\/\/figshare.com\/articles\/software\/ICN-package\/13229093.<\/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\/btab047","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T20:21:16Z","timestamp":1611260476000},"page":"1997-2003","source":"Crossref","is-referenced-by-count":5,"title":["ICN: extracting interconnected communities in gene co-expression networks"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-1899","authenticated-orcid":false,"given":"Qiong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Mathematics, University of Maryland , College Park, MD 20740, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3605-0811","authenticated-orcid":false,"given":"Tianzhou","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, School of Public Health, University of Maryland , College Park, MD 20740, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingzhi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald K","family":"Milton","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, School of Public Health, University of Maryland , College Park, MD 20740, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Statistics, Ohio State University , Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, School of Medicine, University of Maryland , Baltimore, MD 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"2023061310304767700_btab047-B1","first-page":"1981","article-title":"Mixed membership stochastic blockmodels","volume":"9","author":"Airoldi","year":"2008","journal-title":"J. Machine Learn. Res"},{"key":"2023061310304767700_btab047-B2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cell\u2019s functional organization","volume":"5","author":"Barabasi","year":"2004","journal-title":"Nat. Rev. Genet"},{"key":"2023061310304767700_btab047-B3","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1042\/ETLS20170142","article-title":"The mapk hypothesis: immune-regulatory effects of mapk-pathway genetic dysregulations and implications for breast cancer immunotherapy","volume":"1","author":"Bedognetti","year":"2017","journal-title":"Emerg. Top. Life Sci"},{"key":"2023061310304767700_btab047-B4","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1471-2164-7-40","article-title":"Gene connectivity, function, and sequence conservation: predictions from modular yeast co-expression networks","volume":"7","author":"Carlson","year":"2006","journal-title":"BMC Genomics"},{"key":"2023061310304767700_btab047-B5","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.csda.2018.05.008","article-title":"Estimating large covariance matrix with network topology for high-dimensional biomedical data","volume":"127","author":"Chen","year":"2018","journal-title":"Comput. Stat. Data Anal"},{"key":"2023061310304767700_btab047-B6","doi-asserted-by":"crossref","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","article-title":"Cluster analysis and display of genome-wide expression patterns","volume":"95","author":"Eisen","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023061310304767700_btab047-B7","doi-asserted-by":"crossref","first-page":"D649","DOI":"10.1093\/nar\/gkx1132","article-title":"The reactome pathway knowledgebase","volume":"46","author":"Fabregat","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2023061310304767700_btab047-B8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.physrep.2009.11.002","article-title":"Community detection in graphs","volume":"486","author":"Fortunato","year":"2010","journal-title":"Phys. Rep"},{"key":"2023061310304767700_btab047-B10","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/3-540-48224-5_19","volume-title":"International Colloquium on Automata, Languages, and Programming","author":"Gandhi","year":"2001"},{"key":"2023061310304767700_btab047-B11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1137\/S0097539704444750","article-title":"A better-than-greedy approximation algorithm for the minimum set cover problem","volume":"35","author":"Hassin","year":"2005","journal-title":"SIAM J. Comput"},{"key":"2023061310304767700_btab047-B12","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-84858-7","volume-title":"The Elements of Statistical Learning: Data Mining, Inference, and Prediction","author":"Hastie","year":"2009"},{"key":"2023061310304767700_btab047-B13","doi-asserted-by":"crossref","first-page":"e1000117","DOI":"10.1371\/journal.pcbi.1000117","article-title":"Geometric interpretation of gene coexpression network analysis","volume":"4","author":"Horvath","year":"2008","journal-title":"PLoS Comput. Biol"},{"key":"2023061310304767700_btab047-B14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jnca.2018.02.011","article-title":"Community detection in networks: a multidisciplinary review","volume":"108","author":"Javed","year":"2018","journal-title":"J. Netw. Comput. Appl"},{"key":"2023061310304767700_btab047-B15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2023061310304767700_btab047-B16","first-page":"1386","author":"Kloster","year":"2014"},{"key":"2023061310304767700_btab047-B17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00453-009-9317-0","article-title":"A unified approach to approximating partial covering problems","volume":"59","author":"K\u00f6nemann","year":"2011","journal-title":"Algorithmica"},{"key":"2023061310304767700_btab047-B18","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an r package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2023061310304767700_btab047-B19","doi-asserted-by":"crossref","first-page":"18718","DOI":"10.1073\/pnas.0808709105","article-title":"A general framework for multiple testing dependence","volume":"105","author":"Leek","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023061310304767700_btab047-B20","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: an r\/bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"2023061310304767700_btab047-B21","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1172\/JCI12807","article-title":"Therapeutic targeting of the mek\/mapk signal transduction module in acute myeloid leukemia","volume":"108","author":"Milella","year":"2001","journal-title":"J. Clin. Investig"},{"key":"2023061310304767700_btab047-B22","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":"Network","year":"2013","journal-title":"N. Engl. J. Med"},{"key":"2023061310304767700_btab047-B23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1137\/S003614450342480","article-title":"The structure and function of complex networks","volume":"45","author":"Newman","year":"2003","journal-title":"SIAM Rev"},{"key":"2023061310304767700_btab047-B24","doi-asserted-by":"crossref","first-page":"026113","DOI":"10.1103\/PhysRevE.69.026113","article-title":"Finding and evaluating community structure in networks","volume":"69","author":"Newman","year":"2004","journal-title":"Phys. Rev. E"},{"key":"2023061310304767700_btab047-B25","doi-asserted-by":"crossref","first-page":"research0009.1","DOI":"10.1186\/gb-2002-3-2-research0009","article-title":"Model-based cluster analysis of microarray gene-expression data","volume":"3","author":"Pan","year":"2002","journal-title":"Genome Biol"},{"key":"2023061310304767700_btab047-B26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10142-003-0085-7","article-title":"A mixture model approach to detecting differentially expressed genes with microarray data","volume":"3","author":"Pan","year":"2003","journal-title":"Funct. Integrat. Genomics"},{"key":"2023061310304767700_btab047-B27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1140\/epjst\/e2010-01179-1","article-title":"The map equation","volume":"178","author":"Rosvall","year":"2009","journal-title":"Eur. Phys. J. Special Top"},{"key":"2023061310304767700_btab047-B28","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1752-0509-4-8","article-title":"A general co-expression network-based approach to gene expression analysis: comparison and applications","volume":"4","author":"Ruan","year":"2010","journal-title":"BMC Syst. Biol"},{"key":"2023061310304767700_btab047-B29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/13024","article-title":"Crosstalk between camp-dependent kinase and map kinase through a protein tyrosine phosphatase","volume":"1","author":"Saxena","year":"1999","journal-title":"Nat. Cell Biol"},{"key":"2023061310304767700_btab047-B30","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1093\/bioinformatics\/bti062","article-title":"An empirical Bayes approach to inferring large-scale gene association networks","volume":"21","author":"Sch\u00e4fer","year":"2005","journal-title":"Bioinformatics"},{"key":"2023061310304767700_btab047-B31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2202\/1544-6115.1175","article-title":"A shrinkage approach to large-scale covariance matrix estimation and implications for functional genomics","volume":"4","author":"Sch\u00e4fer","year":"2005","journal-title":"Stat. Appl. Genet. Mol. Biol"},{"key":"2023061310304767700_btab047-B32","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1186\/1471-2105-13-328","article-title":"Comparison of co-expression measures: mutual information, correlation, and model based indices","volume":"13","author":"Song","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"2023061310304767700_btab047-B33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S0962-8924(02)02294-8","article-title":"Crosstalk between camp and map kinase signaling in the regulation of cell proliferation","volume":"12","author":"Stork","year":"2002","journal-title":"Trends Cell Biol"},{"key":"2023061310304767700_btab047-B34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1126\/science.1087447","article-title":"A gene-coexpression network for global discovery of conserved genetic modules","volume":"302","author":"Stuart","year":"2003","journal-title":"Science"},{"key":"2023061310304767700_btab047-B35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2051-1426-1-13","article-title":"Immune evasion in acute myeloid leukemia: current concepts and future directions","volume":"1","author":"Teague","year":"2013","journal-title":"J. Immunother. Cancer"},{"key":"2023061310304767700_btab047-B36","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1109\/TKDE.2016.2518687","article-title":"Overlapping community detection using neighborhood-inflated seed expansion","volume":"28","author":"Whang","year":"2016","journal-title":"IEEE Trans. Knowl. Data Eng"},{"key":"2023061310304767700_btab047-B9","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1214\/18-AOS1797","article-title":"Optimal rates for community estimation in the weighted stochastic block model","volume":"48","author":"Xu","year":"2020","journal-title":"Ann. Stat"},{"key":"2023061310304767700_btab047-B37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1137\/19M1272238","article-title":"Detecting overlapping communities in networks using spectral methods","volume":"2","author":"Zhang","year":"2020","journal-title":"SIAM J. Math. Data Sci"},{"key":"2023061310304767700_btab047-B38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.2202\/1544-6115.1128","article-title":"A general framework for weighted gene co-expression network analysis","volume":"4","author":"Zhang","year":"2005","journal-title":"Stat. Appl. Genet. Mol. Biol"},{"key":"2023061310304767700_btab047-B39","first-page":"606","author":"Zhang","year":"2012"},{"key":"2023061310304767700_btab047-B40","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/10543400903572753","article-title":"Weighted gene coexpression network analysis: state of the art","volume":"20","author":"Zhao","year":"2010","journal-title":"J. Biopharm. Stat"},{"key":"2023061310304767700_btab047-B41","doi-asserted-by":"crossref","first-page":"e1403","DOI":"10.1002\/wics.1403","article-title":"A survey on theoretical advances of community detection in networks","volume":"9","author":"Zhao","year":"2017","journal-title":"Wiley Interdisciplinary Rev. Comput. Stat"},{"key":"2023061310304767700_btab047-B42","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1186\/1471-2105-10-S1-S21","article-title":"Network-based support vector machine for classification of microarray samples","volume":"10","author":"Zhu","year":"2009","journal-title":"BMC Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btab047\/37466684\/btab047.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/14\/1997\/50578901\/btab047.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/14\/1997\/50578901\/btab047.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T20:27:18Z","timestamp":1724358438000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/37\/14\/1997\/6122693"}},"subtitle":[],"editor":[{"given":"Anthony","family":"Mathelier","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,28]]},"references-count":42,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2021,8,4]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btab047","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,7,15]]},"published":{"date-parts":[[2021,1,28]]}}}