{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:39:01Z","timestamp":1776425941253,"version":"3.51.2"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,15]]},"abstract":"<jats:p>Motivation: Disease progression is driven by dynamic changes in both the activity and connectivity of molecular pathways. Understanding these dynamic events is critical for disease prognosis and effective treatment. Compared with activity dynamics, connectivity dynamics is poorly explored.<\/jats:p><jats:p>Results: We describe the M-module algorithm to identify gene modules with common members but varied connectivity across multiple gene co-expression networks (aka M-modules). We introduce a novel metric to capture the connectivity dynamics of an entire M-module. We find that M-modules with dynamic connectivity have distinct topological and biochemical properties compared with static M-modules and hub genes. We demonstrate that incorporation of module connectivity dynamics significantly improves disease stage prediction. We identify different sets of M-modules that are important for specific disease stage transitions and offer new insights into the molecular events underlying disease progression. Besides modeling disease progression, the algorithm and metric introduced here are broadly applicable to modeling dynamics of molecular pathways.<\/jats:p><jats:p>Availability and implementation: \u00a0M-module is implemented in R. The source code is freely available at http:\/\/www.healthcare.uiowa.edu\/labs\/tan\/M-module.zip.<\/jats:p><jats:p>Contact: \u00a0kai-tan@uiowa.edu<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary Data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btu298","type":"journal-article","created":{"date-parts":[[2014,4,26]],"date-time":"2014-04-26T04:03:50Z","timestamp":1398485030000},"page":"2343-2350","source":"Crossref","is-referenced-by-count":56,"title":["Modeling disease progression using dynamics of pathway connectivity"],"prefix":"10.1093","volume":"30","author":[{"given":"Xiaoke","family":"Ma","sequence":"first","affiliation":[{"name":"1 \u00a01Department of Internal Medicine and 2Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA"}]},{"given":"Long","family":"Gao","sequence":"additional","affiliation":[{"name":"1 \u00a01Department of Internal Medicine and 2Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA"}]},{"given":"Kai","family":"Tan","sequence":"additional","affiliation":[{"name":"1 \u00a01Department of Internal Medicine and 2Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA"}]}],"member":"286","published-online":{"date-parts":[[2014,4,25]]},"reference":[{"key":"2023012711523397600_btu298-B1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1158\/1078-0432.CCR-11-2701","article-title":"Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer","volume":"19","author":"Andre","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"2023012711523397600_btu298-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"2023012711523397600_btu298-B3","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1126\/science.1195618","article-title":"Rewiring of genetic networks in response to DNA damage","volume":"330","author":"Bandyopadhyay","year":"2010","journal-title":"Science"},{"key":"2023012711523397600_btu298-B4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate\u2013a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. B Methadol."},{"key":"2023012711523397600_btu298-B5","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/msb4100180","article-title":"Network-based classification of breast cancer metastasis","volume":"3","author":"Chuang","year":"2007","journal-title":"Mol. Syst. Biol."},{"key":"2023012711523397600_btu298-B6","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1126\/science.1105103","article-title":"Dynamic complex formation during the yeast cell cycle","volume":"307","author":"de Lichtenberg","year":"2005","journal-title":"Science"},{"key":"2023012711523397600_btu298-B7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ins.2010.08.041","article-title":"A history of graph entropy measures","volume":"181","author":"Dehmer","year":"2011","journal-title":"Inf. Sci."},{"key":"2023012711523397600_btu298-B8","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"2023012711523397600_btu298-B9","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.immuni.2012.08.021","article-title":"Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory","volume":"37","author":"Doering","year":"2012","journal-title":"Immunity"},{"key":"2023012711523397600_btu298-B10","volume-title":"AJCC Cancer Staging Manual","author":"Edge","year":"2010"},{"key":"2023012711523397600_btu298-B11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1073\/pnas.0605965104","article-title":"Resolution limit in community detection","volume":"104","author":"Fortunato","year":"2007","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012711523397600_btu298-B12","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1073\/pnas.0701361104","article-title":"The human disease network","volume":"104","author":"Goh","year":"2007","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012711523397600_btu298-B13","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature02555","article-title":"Evidence for dynamically organized modularity in the yeast protein-protein interaction network","volume":"430","author":"Han","year":"2004","journal-title":"Nature"},{"key":"2023012711523397600_btu298-B14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/jmcb\/mjs011","article-title":"Coexpression network analysis in chronic hepatitis B and C hepatic lesions reveals distinct patterns of disease progression to hepatocellular carcinoma","volume":"4","author":"He","year":"2012","journal-title":"J. Mol. Cell Biol."},{"key":"2023012711523397600_btu298-B15","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s000180050499","article-title":"The Ras family of GTPases in cancer cell invasion","volume":"57","author":"Hernandez-Alcoceba","year":"2000","journal-title":"Cell. Mol. Life Sci."},{"key":"2023012711523397600_btu298-B16","doi-asserted-by":"crossref","first-page":"I213","DOI":"10.1093\/bioinformatics\/bti1049","article-title":"Mining coherent dense subgraphs across massive biological networks for functional discovery","volume":"21","author":"Hu","year":"2005","journal-title":"Bioinformatics"},{"key":"2023012711523397600_btu298-B17","doi-asserted-by":"crossref","first-page":"I222","DOI":"10.1093\/bioinformatics\/btm222","article-title":"Systematic discovery of functional modules and context-specific functional annotation of human genome","volume":"23","author":"Huang","year":"2007","journal-title":"Bioinformatics"},{"key":"2023012711523397600_btu298-B18","doi-asserted-by":"crossref","first-page":"D109","DOI":"10.1093\/nar\/gkr988","article-title":"KEGG for integration and interpretation of large-scale molecular data sets","volume":"40","author":"Kanehisa","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023012711523397600_btu298-B19","doi-asserted-by":"crossref","first-page":"11394","DOI":"10.1073\/pnas.1534710100","article-title":"Conserved pathways within bacteria and yeast as revealed by global protein network alignment","volume":"100","author":"Kelley","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012711523397600_btu298-B20","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/bioinformatics\/bth919","article-title":"An efficient algorithm for detecting frequent subgraphs in biological networks","volume":"20","author":"Koyuturk","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012711523397600_btu298-B21","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/srep00336","article-title":"Consensus clustering in complex networks","volume":"2","author":"Lancichinetti","year":"2012","journal-title":"Sci. Rep."},{"key":"2023012711523397600_btu298-B22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1752-0509-1-54","article-title":"Eigengene networks for studying the relationships between co-expression modules","volume":"1","author":"Langfelder","year":"2007","journal-title":"BMC Syst. Biol."},{"key":"2023012711523397600_btu298-B23","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1101\/gr.118992.110","article-title":"Prioritizing candidate disease genes by network-based boosting of genome-wide association data","volume":"21","author":"Lee","year":"2011","journal-title":"Genome Res."},{"key":"2023012711523397600_btu298-B24","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2012.03.031","article-title":"Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks","volume":"149","author":"Lee","year":"2012","journal-title":"Cell"},{"key":"2023012711523397600_btu298-B25","doi-asserted-by":"crossref","first-page":"D257","DOI":"10.1093\/nar\/gkj079","article-title":"SMART 5: domains in the context of genomes and networks","volume":"34","author":"Letunic","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2023012711523397600_btu298-B26","doi-asserted-by":"crossref","first-page":"e1001106","DOI":"10.1371\/journal.pcbi.1001106","article-title":"Integrative analysis of many weighted co-expression networks using tensor computation","volume":"7","author":"Li","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"2023012711523397600_btu298-B27","doi-asserted-by":"crossref","first-page":"4550","DOI":"10.1158\/0008-5472.CAN-11-0180","article-title":"Correlation of somatic mutation and expression identifies genes important in human glioblastoma progression and survival","volume":"71","author":"Masica","year":"2011","journal-title":"Cancer Res."},{"key":"2023012711523397600_btu298-B28","doi-asserted-by":"crossref","first-page":"e1000742","DOI":"10.1371\/journal.pcbi.1000742","article-title":"Simultaneous clustering of multiple gene expression and physical interaction datasets","volume":"6","author":"Narayanan","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2023012711523397600_btu298-B29","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1073\/pnas.0601602103","article-title":"Modularity and community structure in networks","volume":"103","author":"Newman","year":"2006","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012711523397600_btu298-B30","doi-asserted-by":"crossref","first-page":"036104","DOI":"10.1103\/PhysRevE.74.036104","article-title":"Finding community structure in networks using the eigenvectors of matrices","volume":"74","author":"Newman","year":"2006","journal-title":"Phys. Rev. E"},{"key":"2023012711523397600_btu298-B31","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nrc2622","article-title":"Metastasis: from dissemination to organ-specific colonization","volume":"9","author":"Nguyen","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"2023012711523397600_btu298-B32","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"BioCarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotech. Softw. Internet Rep."},{"key":"2023012711523397600_btu298-B33","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/nature05670","article-title":"Quantifying social group evolution","volume":"446","author":"Palla","year":"2007","journal-title":"Nature"},{"key":"2023012711523397600_btu298-B34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature08658","article-title":"A comprehensive catalogue of somatic mutations from a human cancer genome","volume":"463","author":"Pleasance","year":"2010","journal-title":"Nature"},{"key":"2023012711523397600_btu298-B35","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, Proc","volume":"102","author":"Subramanian","year":"2005","journal-title":"Natl Acad. Sci. USA"},{"key":"2023012711523397600_btu298-B36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nbt.1522","article-title":"Dynamic modularity in protein interaction networks predicts breast cancer outcome","volume":"27","author":"Taylor","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2023012711523397600_btu298-B37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/ng1935","article-title":"Integrative molecular concept modeling of prostate cancer progression","volume":"39","author":"Tomlins","year":"2007","journal-title":"Nat. Genet."},{"key":"2023012711523397600_btu298-B38","doi-asserted-by":"crossref","first-page":"e1000641","DOI":"10.1371\/journal.pcbi.1000641","article-title":"Associating genes and protein complexes with disease via network propagation","volume":"6","author":"Vanunu","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2023012711523397600_btu298-B39","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":"2023012711523397600_btu298-B40","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2013.03.030","article-title":"Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease","volume":"153","author":"Zhang","year":"2013","journal-title":"Cell"},{"key":"2023012711523397600_btu298-B41","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/msb.2009.80","article-title":"Edgetic perturbation models of human inherited disorders","volume":"5","author":"Zhong","year":"2009","journal-title":"Mol. Syst. Biol."},{"key":"2023012711523397600_btu298-B42","first-page":"321","article-title":"Learning with local and global consistency","volume":"16","author":"Zhou","year":"2004","journal-title":"Adv. Neural Inf. Proc. Syst."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/30\/16\/2343\/48926206\/bioinformatics_30_16_2343.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/30\/16\/2343\/48926206\/bioinformatics_30_16_2343.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T06:00:02Z","timestamp":1716703202000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/30\/16\/2343\/2748226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,25]]},"references-count":42,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2014,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btu298","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,25]]}}}