{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:29:10Z","timestamp":1792650550835,"version":"4.5.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"20","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1K01HL124050-01A1"],"award-info":[{"award-number":["1K01HL124050-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Motivation: Pathway enrichment analysis has become a key tool for biomedical researchers to gain insight into the underlying biology of differentially expressed genes, proteins and metabolites. It reduces complexity and provides a system-level view of changes in cellular activity in response to treatments and\/or in disease states. Methods that use existing pathway network information have been shown to outperform simpler methods that only take into account pathway membership. However, despite significant progress in understanding the association amongst members of biological pathways, and expansion of data bases containing information about interactions of biomolecules, the existing network information may be incomplete or inaccurate and is not cell-type or disease condition-specific.<\/jats:p>\n                  <jats:p>Results: We propose a constrained network estimation framework that combines network estimation based on cell- and condition-specific high-dimensional Omics data with interaction information from existing data bases. The resulting pathway topology information is subsequently used to provide a framework for simultaneous testing of differences in expression levels of pathway members, as well as their interactions. We study the asymptotic properties of the proposed network estimator and the test for pathway enrichment, and investigate its small sample performance in simulated and real data settings.<\/jats:p>\n                  <jats:p>Availability and Implementation: The proposed method has been implemented in the R-package netgsa available on CRAN.<\/jats:p>\n                  <jats:p>Contact: \u00a0jinma@upenn.edu<\/jats:p>\n                  <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btw410","type":"journal-article","created":{"date-parts":[[2016,6,29]],"date-time":"2016-06-29T21:40:11Z","timestamp":1467236411000},"page":"3165-3174","source":"Crossref","is-referenced-by-count":55,"title":["Network-based pathway enrichment analysis with incomplete network information"],"prefix":"10.1093","volume":"32","author":[{"given":"Jing","family":"Ma","sequence":"first","affiliation":[{"name":"1 Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, PA 19104, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Shojaie","sequence":"additional","affiliation":[{"name":"2 Department of Biostatistics, University of Washington, Seattle, WA 98915, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Michailidis","sequence":"additional","affiliation":[{"name":"3 Department of Statistics, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,6,29]]},"reference":[{"key":"2023020113462544800_btw410-B1","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1093\/bioinformatics\/bti457","article-title":"Discovering molecular functions significantly related to phenotypes by combining gene expression data and biological information","volume":"21","author":"Al-Shahrour","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020113462544800_btw410-B2","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. R Stat. Soc. B"},{"key":"2023020113462544800_btw410-B3","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1214\/aos\/1013699998","article-title":"The control of the false discovery rate in multiple testing under dependency","volume":"29","author":"Benjamini","year":"2001","journal-title":"Ann. Stat"},{"key":"2023020113462544800_btw410-B4","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1214\/08-AOS620","article-title":"Simultaneous analysis of lasso and dantzig selector","volume":"37","author":"Bickel","year":"2009","journal-title":"Ann. Stat"},{"key":"2023020113462544800_btw410-B5","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511804441","volume-title":"Convex Optimization","author":"Boyd","year":"2004"},{"key":"2023020113462544800_btw410-B6","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s10208-009-9045-5","article-title":"Exact matrix completion via convex optimization","volume":"9","author":"Candes","year":"2009","journal-title":"Found. Comput. Math"},{"key":"2023020113462544800_btw410-B7","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1182\/blood-2012-03-416461","article-title":"Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression","volume":"120","author":"Chuang","year":"2012","journal-title":"Blood"},{"key":"2023020113462544800_btw410-B8","article-title":"The igraph software package for complex network research","author":"Csardi","year":"2006","journal-title":"InterJournal. Compl. Syst"},{"key":"2023020113462544800_btw410-B9","volume-title":"Analysis of Microarray Data: A Network-Based Approach","author":"Dehmer","year":"2008"},{"key":"2023020113462544800_btw410-B10","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2307\/2528966","article-title":"Covariance selection","volume":"28","author":"Dempster","year":"1972","journal-title":"Biometrics"},{"key":"2023020113462544800_btw410-B11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1214\/07-AOAS101","article-title":"On testing the significance of sets of genes","volume":"1","author":"Efron","year":"2007","journal-title":"Ann. Appl. Stat"},{"key":"2023020113462544800_btw410-B12","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1093\/biostatistics\/kxm045","article-title":"Sparse inverse covariance estimation with the graphical lasso","volume":"9","author":"Friedman","year":"2008","journal-title":"Biostatistics"},{"key":"2023020113462544800_btw410-B13","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/nature05992","article-title":"A viral microrna functions as an orthologue of cellular mir-155","volume":"450","author":"Gottwein","year":"2007","journal-title":"Nature"},{"key":"2023020113462544800_btw410-B14","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1073\/pnas.1019537108","article-title":"Signatures of murine b-cell development implicate yy1 as a regulator of the germinal center-specific program","volume":"108","author":"Green","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020113462544800_btw410-B15","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1016\/j.cellsig.2006.05.015","article-title":"Surviving cell death through epidermal growth factor (egf) signal transduction pathways: implications for cancer therapy","volume":"18","author":"Henson","year":"2006","journal-title":"Cell. Signal"},{"key":"2023020113462544800_btw410-B16","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/nature04634","article-title":"Reactive oxygen species have a causal role in multiple forms of insulin resistance","volume":"440","author":"Houstis","year":"2006","journal-title":"Nature"},{"key":"2023020113462544800_btw410-B17","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1158\/1940-6207.CAPR-11-0334","article-title":"Targeting the her\/egfr\/erbb family to prevent breast cancer","volume":"4","author":"Howe","year":"2011","journal-title":"Cancer Prevent. Res"},{"key":"2023020113462544800_btw410-B18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using david bioinformatics resources","volume":"4","author":"Huang","year":"2008","journal-title":"Nat. Protoc"},{"key":"2023020113462544800_btw410-B19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/nar\/26.1.55","article-title":"Regulondb: a database on transcriptional regulation in escherichia coli","volume":"26","author":"Huerta","year":"1998","journal-title":"Nucleic Acids Res"},{"key":"2023020113462544800_btw410-B20","doi-asserted-by":"crossref","first-page":"565.","DOI":"10.1038\/msb.2011.99","article-title":"Differential network biology","volume":"8","author":"Ideker","year":"2012","journal-title":"Mol. Syst. Biol"},{"key":"2023020113462544800_btw410-B21","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.cell.2011.03.007","article-title":"Boosting signal-to-noise in complex biology: prior knowledge is power","volume":"144","author":"Ideker","year":"2011","journal-title":"Cell"},{"key":"2023020113462544800_btw410-B22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1101\/sqb.2003.68.237","article-title":"The genome knowledgebase: A resource for biologists and bioinformaticists","volume":"68","author":"Joshi-Tope","year":"2003","journal-title":"Cold Spring Harb. Symp. Quant. Biol"},{"key":"2023020113462544800_btw410-B23","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":"2023020113462544800_btw410-B24","doi-asserted-by":"crossref","first-page":"e1002375.","DOI":"10.1371\/journal.pcbi.1002375","article-title":"Ten years of pathway analysis: current approaches and outstanding challenges","volume":"8","author":"Khatri","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2023020113462544800_btw410-B25","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198522195.001.0001","volume-title":"Graphical Models","author":"Lauritzen","year":"1996"},{"key":"2023020113462544800_btw410-B26","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1214\/009053606000000281","article-title":"High dimensional graphs and variable selection with the lasso","volume":"34","author":"Meinshausen","year":"2006","journal-title":"Ann. Stat"},{"key":"2023020113462544800_btw410-B27","doi-asserted-by":"crossref","first-page":"476.","DOI":"10.1186\/1471-2407-11-476","article-title":"Gnrh receptor activation competes at a low level with growth signaling in stably transfected human breast cell lines","volume":"11","author":"Morgan","year":"2011","journal-title":"BMC Cancer"},{"key":"2023020113462544800_btw410-B28","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2016.00108","article-title":"Mixed effects models to find differences in multi-subject functional connectivity","volume":"10","author":"Narayan","year":"2016","journal-title":"Front. Neurosci"},{"key":"2023020113462544800_btw410-B29","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":"2023020113462544800_btw410-B30","doi-asserted-by":"crossref","first-page":"e9202.","DOI":"10.1371\/journal.pone.0009202","article-title":"Towards a rigorous assessment of systems biology models: the dream3 challenges","volume":"5","author":"Prill","year":"2010","journal-title":"PloS One"},{"key":"2023020113462544800_btw410-B31","doi-asserted-by":"crossref","first-page":"7376","DOI":"10.1158\/0008-5472.CAN-11-1154","article-title":"Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression","volume":"71","author":"Putluri","year":"2011","journal-title":"Cancer Res"},{"key":"2023020113462544800_btw410-B32","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1214\/08-EJS176","article-title":"Sparse permutation invariant covariance estimation","volume":"2","author":"Rothman","year":"2008","journal-title":"Electron. J. Stat"},{"key":"2023020113462544800_btw410-B33","volume-title":"Linear Models","author":"Searle","year":"1971"},{"key":"2023020113462544800_btw410-B34","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1089\/cmb.2008.0081","article-title":"Analysis of gene sets based on the underlying regulatory network","volume":"16","author":"Shojaie","year":"2009","journal-title":"J. Comput. Biol"},{"key":"2023020113462544800_btw410-B35","doi-asserted-by":"crossref","first-page":"22.","DOI":"10.2202\/1544-6115.1483","article-title":"Network enrichment analysis in complex experiments","volume":"9","author":"Shojaie","year":"2010","journal-title":"Stat. Appl. Genet. Mol. Biol"},{"key":"2023020113462544800_btw410-B36","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1158\/1535-7163.MCT-10-0502","article-title":"Jak1 activates stat3 activity in non-small\u2013cell lung cancer cells and il-6 neutralizing antibodies can suppress jak1-stat3 signaling","volume":"10","author":"Song","year":"2011","journal-title":"Mol. Cancer Ther"},{"key":"2023020113462544800_btw410-B37","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":"2023020113462544800_btw410-B38","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","author":"TCGA","year":"2012","journal-title":"Nature"},{"key":"2023020113462544800_btw410-B39","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1080\/01621459.1980.10477580","article-title":"Linear recursive equations, covariance selection, and path analysis","volume":"75","author":"Wermuth","year":"1980","journal-title":"J. Am. Stat. Assoc"},{"key":"2023020113462544800_btw410-B40","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ccr.2010.09.006","article-title":"Epigenetic antagonism between polycomb and swi\/snf complexes during oncogenic transformation","volume":"18","author":"Wilson","year":"2010","journal-title":"Cancer Cell"},{"key":"2023020113462544800_btw410-B41","doi-asserted-by":"crossref","first-page":"163.","DOI":"10.1186\/1471-2105-14-163","article-title":"Protein complex detection using interaction reliability assessment and weighted clustering coefficient","volume":"14","author":"Zaki","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2023020113462544800_btw410-B42","first-page":"2975","article-title":"High-dimensional covariance estimation based on gaussian graphical models","volume":"12","author":"Zhou","year":"2011","journal-title":"J. Mach. Learn. Res"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/20\/3165\/49021319\/bioinformatics_32_20_3165.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/20\/3165\/49021319\/bioinformatics_32_20_3165.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T20:58:54Z","timestamp":1718657934000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/20\/3165\/2196636"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,29]]},"references-count":42,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2016,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btw410","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,10,15]]},"published":{"date-parts":[[2016,6,29]]}}}