{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T02:43:30Z","timestamp":1775011410970,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":1490,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Assessing functional associations between an experimentally derived gene or protein set of interest and a database of known gene\/protein sets is a common task in the analysis of large-scale functional genomics data. For this purpose, a frequently used approach is to apply an over-representation-based enrichment analysis. However, this approach has four drawbacks: (i) it can only score functional associations of overlapping gene\/proteins sets; (ii) it disregards genes with missing annotations; (iii) it does not take into account the network structure of physical interactions between the gene\/protein sets of interest and (iv) tissue-specific gene\/protein set associations cannot be recognized.<\/jats:p><jats:p>Results: To address these limitations, we introduce an integrative analysis approach and web-application called EnrichNet. It combines a novel graph-based statistic with an interactive sub-network visualization to accomplish two complementary goals: improving the prioritization of putative functional gene\/protein set associations by exploiting information from molecular interaction networks and tissue-specific gene expression data and enabling a direct biological interpretation of the results. By using the approach to analyse sets of genes with known involvement in human diseases, new pathway associations are identified, reflecting a dense sub-network of interactions between their corresponding proteins.<\/jats:p><jats:p>Availability: EnrichNet is freely available at http:\/\/www.enrichnet.org.<\/jats:p><jats:p>Contact: \u00a0Natalio.Krasnogor@nottingham.ac.uk, reinhard.schneider@uni.lu or avalencia@cnio.es<\/jats:p><jats:p>Supplementary Information: \u00a0Supplementary data are available at Bioinformatics Online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/bts389","type":"journal-article","created":{"date-parts":[[2012,9,7]],"date-time":"2012-09-07T20:35:22Z","timestamp":1347050122000},"page":"i451-i457","source":"Crossref","is-referenced-by-count":263,"title":["EnrichNet: network-based gene set enrichment analysis"],"prefix":"10.1093","volume":"28","author":[{"given":"Enrico","family":"Glaab","sequence":"first","affiliation":[{"name":"1 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg"}]},{"given":"Ana\u00efs","family":"Baudot","sequence":"additional","affiliation":[{"name":"2 Luminy Institute of Mathematics (IML), Universit\u00e9 d'Aix-Marseille, 13288 Marseilles, France"}]},{"given":"Natalio","family":"Krasnogor","sequence":"additional","affiliation":[{"name":"3 Interdisciplinary Computing and Complex Systems (ICOS) Research Group, University of Nottingham, Nottingham NG8 1BB, UK"}]},{"given":"Reinhard","family":"Schneider","sequence":"additional","affiliation":[{"name":"1 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg"}]},{"given":"Alfonso","family":"Valencia","sequence":"additional","affiliation":[{"name":"4 Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}]}],"member":"286","published-online":{"date-parts":[[2012,9,3]]},"reference":[{"key":"2023012513030355500_B1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/1471-2105-8-114","article-title":"From genes to functional classes in the study of biological systems","volume":"8","author":"Al-Shahrour","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B2","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.1073\/pnas.96.12.6745","article-title":"Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays","volume":"96","author":"Alon","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023012513030355500_B3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/nar\/29.1.37","article-title":"The InterPro database, an integrated documentation resource for protein families, domains and functional sites","volume":"29","author":"Apweiler","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"issue":"Suppl. 2","key":"2023012513030355500_B5","doi-asserted-by":"crossref","first-page":"W186","DOI":"10.1093\/nar\/gkm323","article-title":"GeneTrail\u2014advanced gene set enrichment analysis","volume":"35","author":"Backes","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B6","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/sj.bjc.6601894","article-title":"The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website","volume":"91","author":"Bamford","year":"2004","journal-title":"Br. J. Cancer"},{"key":"2023012513030355500_B7","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1093\/bioinformatics\/btn250","article-title":"Ontologizer 2.0\u2014a multifunctional tool for GO term enrichment analysis and data exploration","volume":"24","author":"Bauer","year":"2008","journal-title":"Bioinformatics"},{"key":"2023012513030355500_B8","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/nm733","article-title":"Gene-expression profiles predict survival of patients with lung adenocarcinoma","volume":"8","author":"Beer","year":"2002","journal-title":"Nat. Med."},{"key":"2023012513030355500_B9","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. Roy. Statist. Soc. Ser. B"},{"key":"2023012513030355500_B10","doi-asserted-by":"crossref","first-page":"13790","DOI":"10.1073\/pnas.191502998","article-title":"Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses","volume":"98","author":"Bhattacharjee","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023012513030355500_B11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0304-3940(95)12192-7","article-title":"Interleukin-1 [beta] and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients","volume":"202","author":"Blum-Degena","year":"1995","journal-title":"Neurosci. Lett."},{"key":"2023012513030355500_B12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/1471-2105-5-193","article-title":"Comparing functional annotation analyses with Catmap","volume":"5","author":"Breslin","year":"2004","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B13","doi-asserted-by":"crossref","first-page":"R3","DOI":"10.1186\/gb-2007-8-1-r3","article-title":"GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists","volume":"8","author":"Carmona-Saez","year":"2007","journal-title":"Genome Biol."},{"key":"2023012513030355500_B14","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/bies.20238","article-title":"Rho GTPase expression in tumourigenesis: evidence for a significant link","volume":"27","author":"del Pulgar","year":"2005","journal-title":"Bioessays"},{"key":"2023012513030355500_B15","doi-asserted-by":"crossref","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: database for annotation, visualization, and integrated discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol."},{"key":"2023012513030355500_B16","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/1471-2105-8-242","article-title":"Improving gene set analysis of microarray data by SAM-GS","volume":"8","author":"Dinu","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B17","doi-asserted-by":"crossref","first-page":"442","DOI":"10.14778\/2140436.2140441","article-title":"Fast and exact top-k search for random walk with restart","volume":"5","author":"Fujiwara","year":"2012","journal-title":"Proc. VLDB Endowment"},{"key":"2023012513030355500_B18","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":"2023012513030355500_B19","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1186\/1471-2105-11-597","article-title":"Extending pathways and processes using molecular interaction networks to analyse cancer genome data","volume":"11","author":"Glaab","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B20","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1093\/bioinformatics\/btq131","article-title":"TopoGSA: network topological gene set analysis","volume":"26","author":"Glaab","year":"2010","journal-title":"Bioinformatics"},{"key":"2023012513030355500_B21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<57::AID-HUMU12>3.0.CO;2-G","article-title":"Online Mendelian inheritance in man (OMIM)","volume":"15","author":"Hamosh","year":"2000","journal-title":"Hum. Mutat."},{"key":"2023012513030355500_B22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucleic Acids Res."},{"issue":"Suppl. 1","key":"2023012513030355500_B23","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"2023012513030355500_B24","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/bib\/bbr049","article-title":"Gene set enrichment analysis: performance evaluation and usage guidelines","volume":"13","author":"Hung","year":"2012","journal-title":"Brief. Bioinform."},{"issue":"Suppl. 1","key":"2023012513030355500_B25","first-page":"D428","article-title":"Reactome: a knowledgebase of biological pathways","volume":"33","author":"Joshi-Tope","year":"2005","journal-title":"Nucleic Acids Res."},{"issue":"Database Issue","key":"2023012513030355500_B26","doi-asserted-by":"crossref","first-page":"D354","DOI":"10.1093\/nar\/gkj102","article-title":"From genomics to chemical genomics: new developments in KEGG","volume":"34","author":"Kanehisa","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B27","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1093\/carcin\/bgi045","article-title":"Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer","volume":"26","author":"Kang","year":"2005","journal-title":"Carcinogenesis"},{"key":"2023012513030355500_B28","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/1471-2105-6-144","article-title":"PAGE: parametric analysis of gene set enrichment","volume":"6","author":"Kim","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B29","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1006\/mcne.2000.0914","article-title":"Inflammatory regulators in Parkinson's disease: iNOS, lipocortin-1, and cyclooxygenases-1 and-2","volume":"16","author":"Knott","year":"2000","journal-title":"Mol. Cell. Neurosci."},{"key":"2023012513030355500_B30","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.ajhg.2008.02.013","article-title":"Walking the interactome for prioritization of candidate disease genes","volume":"82","author":"K\u00f6hler","year":"2008","journal-title":"Am. J. Human Genet."},{"key":"2023012513030355500_B31","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/1471-2105-6-269","article-title":"ErmineJ: tool for functional analysis of gene expression data sets","volume":"6","author":"Lee","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/1471-2105-10-161","article-title":"GAGE: generally applicable gene set enrichment for pathway analysis","volume":"10","author":"Luo","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2023012513030355500_B33","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"2023012513030355500_B34","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"BioCarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotech Software & Internet Report"},{"key":"2023012513030355500_B35","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1006\/jmbi.1999.3208","article-title":"Effective use of sequence correlation and conservation in fold recognition","volume":"293","author":"Olmea","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2023012513030355500_B36","doi-asserted-by":"crossref","first-page":"e184","DOI":"10.1371\/journal.pbio.0060184","article-title":"WikiPathways: pathway editing for the people","volume":"6","author":"Pico","year":"2008","journal-title":"PLoS Biol."},{"issue":"Suppl. 1","key":"2023012513030355500_B37","doi-asserted-by":"crossref","first-page":"D674","DOI":"10.1093\/nar\/gkn653","article-title":"PID: the pathway interaction database","volume":"37","author":"Schaefer","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B38","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1182\/blood-2006-12-061507","article-title":"Lesional gene expression profiling in cutaneous t-cell lymphoma reveals natural clusters associated with disease outcome","volume":"110","author":"Shin","year":"2007","journal-title":"Blood"},{"key":"2023012513030355500_B39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2202\/1544-6115.1027","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"Smyth","year":"2004","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2023012513030355500_B40","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1093\/nar\/28.18.3442","article-title":"STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene","volume":"28","author":"Snel","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B41","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":"2023012513030355500_B42","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s10115-007-0094-2","article-title":"Random walk, with restart: fast solutions and applications","volume":"14","author":"Tong","year":"2008","journal-title":"Knowledge Information Syst."},{"key":"2023012513030355500_B43","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2144\/05382RR04","article-title":"MEGO: gene functional module expression based on gene ontology","volume":"38","author":"Tu","year":"2005","journal-title":"Biotechniques"},{"key":"2023012513030355500_B44","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/nar\/gkg034","article-title":"STRING: a database of predicted functional associations between proteins","volume":"31","author":"Von Mering","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2023012513030355500_B45","article-title":"No free lunch theorems for search","volume-title":"Technical report SFI-TR-95-02-010","author":"Wolpert","year":"1995"},{"key":"2023012513030355500_B46","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1042\/BA20070107","article-title":"RNA-interference-mediated Cdc42 silencing down-regulates phosphorylation of STAT3 and suppresses growth in human bladder-cancer cells","volume":"49","author":"Wu","year":"2008","journal-title":"Biotechnol. Appl. Biochem."},{"key":"2023012513030355500_B47","first-page":"152","article-title":"A unified framework for link recommendation using random walks","volume-title":"Proceedings of the 2010 International Conference on Advances in Social Networks Analysis and Mining","author":"Yin","year":"2010"},{"key":"2023012513030355500_B48","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/bioinformatics\/btp618","article-title":"Phenopedia and genopedia: disease-centered and gene-centered views of the evolving knowledge of human genetic associations","volume":"26","author":"Yu","year":"2010","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/28\/18\/i451\/48883943\/bioinformatics_28_18_i451.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/28\/18\/i451\/48883943\/bioinformatics_28_18_i451.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T01:08:47Z","timestamp":1714352927000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/28\/18\/i451\/247049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,3]]},"references-count":48,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2012,9,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bts389","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2012,9,15]]},"published":{"date-parts":[[2012,9,3]]}}}