{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T19:48:43Z","timestamp":1772135323588,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"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\/100000051","name":"NHGRI","doi-asserted-by":"publisher","award":["R01 HG010480"],"award-info":[{"award-number":["R01 HG010480"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>A major task in genetic studies is to identify genes related to human diseases and traits to understand functional characteristics of genetic mutations and enhance patient diagnosis. Compared with marginal analyses of individual genes, identification of gene pathways, i.e. a set of genes with known interactions that collectively contribute to specific biological functions, can provide more biologically meaningful results. Such gene pathway analysis can be formulated into a high-dimensional two-sample testing problem. Given the typically limited sample size of gene expression datasets, most existing two-sample tests tend to have compromised powers because they ignore or only inefficiently incorporate the auxiliary pathway information on gene interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We propose T2-DAG, a Hotelling\u2019s T2-type test for detecting differentially expressed gene pathways, which efficiently leverages the auxiliary pathway information on gene interactions from existing pathway databases through a linear structural equation model. We further establish its asymptotic distribution under pertinent assumptions. Simulation studies under various scenarios show that T2-DAG outperforms several representative existing methods with well-controlled type-I error rates and substantially improved powers, even with incomplete or inaccurate pathway information or unadjusted confounding effects. We also illustrate the performance of T2-DAG in an application to detect differentially expressed KEGG pathways between different stages of lung cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>The R (R Development Core Team, 2021) package T2DAG which implements the proposed T2-DAG test is available on Github at https:\/\/github.com\/Jin93\/T2DAG.<\/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\/btab770","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T12:23:59Z","timestamp":1636115039000},"page":"1005-1014","source":"Crossref","is-referenced-by-count":5,"title":["T2-DAG: a powerful test for differentially expressed gene pathways via graph-informed structural equation modeling"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8357-8585","authenticated-orcid":false,"given":"Jin","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University , Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University , Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"2023020108510410600_btab770-B1","author":"Am\u00e9ndola","year":"2020"},{"key":"2023020108510410600_btab770-B2","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"},{"key":"2023020108510410600_btab770-B3","first-page":"311","article-title":"Effect of high dimension: by an example of a two sample problem","volume":"6","author":"Bai","year":"1996","journal-title":"Statistica Sinica"},{"key":"2023020108510410600_btab770-B4","first-page":"3","article-title":"Teoria statistica delle classi e calcolo delle probabilita","volume":"8","author":"Bonferroni","year":"1936","journal-title":"Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commericiali di Firenze"},{"key":"2023020108510410600_btab770-B5","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1080\/03610920701271095","article-title":"High-dimensional discriminant analysis","volume":"36","author":"Bouveyron","year":"2007","journal-title":"Commun. Stat. Theory Methods"},{"key":"2023020108510410600_btab770-B6","doi-asserted-by":"crossref","first-page":"CIN.S13882","DOI":"10.4137\/CIN.S13882","article-title":"Revealing biological pathways implicated in lung cancer from TCGA gene expression data using gene set enrichment analysis","volume":"13s1","author":"Cai","year":"2014","journal-title":"Cancer Inf"},{"key":"2023020108510410600_btab770-B7","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1038\/s41388-018-0588-2","article-title":"Lce: an open web portal to explore gene expression and clinical associations in lung cancer","volume":"38","author":"Cai","year":"2019","journal-title":"Oncogene"},{"key":"2023020108510410600_btab770-B8","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/rssb.12034","article-title":"Two-sample test of high dimensional means under dependence","volume":"76","author":"Cai","year":"2014","journal-title":"J. R. Stat. Soc. Ser. B (Stat. Methodol.)"},{"key":"2023020108510410600_btab770-B9","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.trsl.2015.08.001","article-title":"The impact of the cancer genome atlas on lung cancer","volume":"166","author":"Chang","year":"2015","journal-title":"Transl. Res"},{"key":"2023020108510410600_btab770-B10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1198\/jasa.2011.ap10599","article-title":"A regularized hotelling\u2019s t 2 test for pathway analysis in proteomic studies","volume":"106","author":"Chen","year":"2011","journal-title":"J. Am. Stat. Assoc"},{"key":"2023020108510410600_btab770-B11","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1214\/09-AOS716","article-title":"A two-sample test for high-dimensional data with applications to gene-set testing","volume":"38","author":"Chen","year":"2010","journal-title":"Ann. Stat"},{"key":"2023020108510410600_btab770-B12","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1080\/10618600.2014.956876","article-title":"Gene regulation network inference with joint sparse gaussian graphical models","volume":"24","author":"Chun","year":"2015","journal-title":"J. Comput. Graph. Stat"},{"key":"2023020108510410600_btab770-B13","doi-asserted-by":"crossref","first-page":"e85249","DOI":"10.1371\/journal.pone.0085249","article-title":"Robust prognostic gene expression signatures in bladder cancer and lung adenocarcinoma depend on cell cycle related genes","volume":"9","author":"Dancik","year":"2014","journal-title":"PLoS One"},{"key":"2023020108510410600_btab770-B14","first-page":"2810","author":"Fan","year":"2019"},{"key":"2023020108510410600_btab770-B15","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":"2023020108510410600_btab770-B16","doi-asserted-by":"crossref","first-page":"D330","DOI":"10.1093\/nar\/gky1055","article-title":"The gene ontology resource: 20 years and still going strong","volume":"47","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023020108510410600_btab770-B17","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1080\/01621459.2014.934826","article-title":"A two-sample test for equality of means in high dimension","volume":"110","author":"Gregory","year":"2015","journal-title":"J. Am. Stat. Assoc"},{"key":"2023020108510410600_btab770-B18","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1214\/aoms\/1177732979","article-title":"The generalization of student\u2019s ratio","volume":"2","author":"Hotelling","year":"1931","journal-title":"Ann. Math. Stat"},{"key":"2023020108510410600_btab770-B19","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1093\/biomet\/93.1.85","article-title":"Covariance matrix selection and estimation via penalised normal likelihood","volume":"93","author":"Huang","year":"2006","journal-title":"Biometrika"},{"key":"2023020108510410600_btab770-B20","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1214\/11-AOAS528","article-title":"More power via graph-structured tests for differential expression of gene networks","volume":"6","author":"Jacob","year":"2012","journal-title":"Ann. Appl. Stat"},{"key":"2023020108510410600_btab770-B21","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":"2023020108510410600_btab770-B22","doi-asserted-by":"crossref","first-page":"D590","DOI":"10.1093\/nar\/gky962","article-title":"New approach for understanding genome variations in kegg","volume":"47","author":"Kanehisa","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023020108510410600_btab770-B23","doi-asserted-by":"crossref","first-page":"e1007793","DOI":"10.1371\/journal.pcbi.1007793","article-title":"Dynamical network analysis reveals key micrornas in progressive stages of lung cancer","volume":"16","author":"Kong","year":"2020","journal-title":"PLOS Comput. Biol"},{"key":"2023020108510410600_btab770-B24","first-page":"70","author":"Krishnamoorthy","year":"2013"},{"key":"2023020108510410600_btab770-B25","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1080\/10618600.2016.1278002","article-title":"Precision matrix estimation with rope","volume":"26","author":"Kuismin","year":"2017","journal-title":"J. Comput. Graph. Stat"},{"key":"2023020108510410600_btab770-B26","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1080\/01621459.2011.644498","article-title":"Sparse estimation of conditional graphical models with application to gene networks","volume":"107","author":"Li","year":"2012","journal-title":"J. Am. Stat. Assoc"},{"key":"2023020108510410600_btab770-B27","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1214\/19-AOS1869","article-title":"An adaptable generalization of hotelling\u2019s t2 test in high dimension","volume":"48","author":"Li","year":"2020","journal-title":"Ann. Stat"},{"key":"2023020108510410600_btab770-B28","first-page":"3065","article-title":"High-dimensional learning of linear causal networks via inverse covariance estimation","volume":"15","author":"Loh","year":"2014","journal-title":"J. Mach. Learn. Res"},{"key":"2023020108510410600_btab770-B29","first-page":"2029","article-title":"Identification of differentially expressed genes and enriched pathways in lung cancer using bioinformatics analysis","volume":"19","author":"Long","year":"2019","journal-title":"Mol. Med. Rep"},{"key":"2023020108510410600_btab770-B30","first-page":"1206","article-title":"A more powerful two-sample test in high dimensions using random projection","author":"Lopes","year":"2011","journal-title":"Adv. Neural Inf. Process. Syst"},{"key":"2023020108510410600_btab770-B31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2023020108510410600_btab770-B32","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nature13385","article-title":"Comprehensive molecular profiling of lung adenocarcinoma","volume":"511","author":"Network","year":"2014","journal-title":"Nature"},{"key":"2023020108510410600_btab770-B33","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"Biocarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotechnol. Softw. Internet Rep"},{"key":"2023020108510410600_btab770-B34","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/biomet\/ast043","article-title":"Identifiability of gaussian structural equation models with equal error variances","volume":"101","author":"Peters","year":"2014","journal-title":"Biometrika"},{"key":"2023020108510410600_btab770-B35","year":"2019"},{"key":"2023020108510410600_btab770-B36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edger: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020108510410600_btab770-B37","first-page":"89","article-title":"The role of gene expression profiling in early-stage non-small cell lung cancer","volume":"2","author":"Shao","year":"2010","journal-title":"J. Thoracic Dis"},{"key":"2023020108510410600_btab770-B38","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":"2023020108510410600_btab770-B39","doi-asserted-by":"crossref","first-page":"Article22","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":"2023020108510410600_btab770-B40","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.jmva.2006.11.002","article-title":"A test for the mean vector with fewer observations than the dimension","volume":"99","author":"Srivastava","year":"2008","journal-title":"J. Multivar. Anal"},{"key":"2023020108510410600_btab770-B41","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jmva.2012.10.011","article-title":"Tests for multivariate analysis of variance in high dimension under non-normality","volume":"115","author":"Srivastava","year":"2013","journal-title":"J. Multivar. Anal"},{"key":"2023020108510410600_btab770-B42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc. Ser. B (Methodological)"},{"key":"2023020108510410600_btab770-B43","first-page":"6572","article-title":"Differences in the early stage gene expression profiles of lung adenocarcinoma and lung squamous cell carcinoma","volume":"18","author":"Venugopal","year":"2019","journal-title":"Oncol. Lett"},{"key":"2023020108510410600_btab770-B44","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1097\/JTO.0b013e3181898774","article-title":"Pathway targets to explore in the treatment of non-small cell lung cancer","volume":"3","author":"Weiss","year":"2008","journal-title":"J. Thoracic Oncol"},{"key":"2023020108510410600_btab770-B45","doi-asserted-by":"crossref","first-page":"R92","DOI":"10.1186\/gb-2004-5-11-r92","article-title":"Sparse graphical Gaussian modeling of the isoprenoid gene network in arabidopsis thaliana","volume":"5","author":"Wille","year":"2004","journal-title":"Genome Biol"},{"key":"2023020108510410600_btab770-B46","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1093\/biomet\/90.4.831","article-title":"Nonparametric estimation of large covariance matrices of longitudinal data","volume":"90","author":"Wu","year":"2003","journal-title":"Biometrika"},{"key":"2023020108510410600_btab770-B47","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1093\/biomet\/asw029","article-title":"An adaptive two-sample test for high-dimensional means","volume":"103","author":"Xu","year":"2016","journal-title":"Biometrika"},{"key":"2023020108510410600_btab770-B48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/biomet\/ast059","article-title":"Sparse precision matrix estimation via lasso penalized d-trace loss","volume":"101","author":"Zhang","year":"2014","journal-title":"Biometrika"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btab770\/41355388\/btab770.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/4\/1005\/49007546\/btab770.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/4\/1005\/49007546\/btab770.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T15:35:07Z","timestamp":1726068907000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/38\/4\/1005\/6424893"}},"subtitle":[],"editor":[{"given":"Olga","family":"Vitek","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,10]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,1,27]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btab770","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,2,15]]},"published":{"date-parts":[[2021,11,10]]}}}