{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:22:35Z","timestamp":1762100555329},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"19","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Several statistical methods that combine analysis of differential gene expression with biological knowledge databases have been proposed for a more rapid interpretation of expression data. However, most such methods are based on a series of univariate statistical tests and do not properly account for the complex structure of gene interactions.<\/jats:p>\n               <jats:p>Results: We present a simple yet effective multivariate statistical procedure for assessing the correlation between a subspace defined by a group of genes and a binary phenotype. A subspace is deemed significant if the samples corresponding to different phenotypes are well separated in that subspace. The separation is measured using Hotelling's T2 statistic, which captures the covariance structure of the subspace. When the dimension of the subspace is larger than that of the sample space, we project the original data to a smaller orthonormal subspace. We use this method to search through functional pathway subspaces defined by Reactome, KEGG, BioCarta and Gene Ontology. To demonstrate its performance, we apply this method to the data from two published studies, and visualize the results in the principal component space.<\/jats:p>\n               <jats:p>Contact: \u00a0peter_park@harvard.edu<\/jats:p>","DOI":"10.1093\/bioinformatics\/btl401","type":"journal-article","created":{"date-parts":[[2006,7,30]],"date-time":"2006-07-30T18:13:51Z","timestamp":1154283231000},"page":"2373-2380","source":"Crossref","is-referenced-by-count":99,"title":["A multivariate approach for integrating genome-wide expression data and biological knowledge"],"prefix":"10.1093","volume":"22","author":[{"given":"Sek Won","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Cardiology 1 \u00a0 1 \u00a0 \u00a0 300 Longwood Avenue, Boston, MA 02115, USA"},{"name":"Informatics Program, Children's Hospital Boston 2 \u00a0 2 \u00a0 \u00a0 300 Longwood Avenue, Boston, MA 02115, USA"}]},{"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cardiology 1 \u00a0 1 \u00a0 \u00a0 300 Longwood Avenue, Boston, MA 02115, USA"}]},{"given":"Peter J.","family":"Park","sequence":"additional","affiliation":[{"name":"Informatics Program, Children's Hospital Boston 2 \u00a0 2 \u00a0 \u00a0 300 Longwood Avenue, Boston, MA 02115, USA"},{"name":"Harvard-Partners Center for Genetics and Genomics, 77 Avenue Louis Pasteur 3 \u00a0 3 \u00a0 \u00a0 Boston, MA 02115, USA"}]}],"member":"286","published-online":{"date-parts":[[2006,7,28]]},"reference":[{"key":"2023012409234582400_b1","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1093\/bioinformatics\/btl140","article-title":"Improved scoring of functional groups from gene expression data by decorrelating GO graph structure","volume":"22","author":"Alexa","year":"2006","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nm0102-35","article-title":"Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy","volume":"8","author":"Asakura","year":"2002","journal-title":"Nat. Med."},{"key":"2023012409234582400_b3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrc1362","article-title":"The TOR pathway: a target for cancer therapy","volume":"4","author":"Bjornsti","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2023012409234582400_b4","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1093\/bioinformatics\/18.12.1600","article-title":"Between-group analysis of microarray data","volume":"18","author":"Culhane","year":"2002","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b5","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":"2023012409234582400_b6","doi-asserted-by":"crossref","first-page":"R7","DOI":"10.1186\/gb-2003-4-1-r7","article-title":"Mappfinder: using gene ontology and genmapp to create a global gene-expression profile from microarray data","volume":"4","author":"Doniger","year":"2003","journal-title":"Genome Biol."},{"key":"2023012409234582400_b7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1080\/01621459.1989.10478752","article-title":"Regularized discriminant analysis","volume":"84","author":"Friedman","year":"1989","journal-title":"J. Am. Stat. Asso."},{"key":"2023012409234582400_b8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/bioinformatics\/btg382","article-title":"A global test for groups of genes: testing association with a clinical outcome","volume":"20","author":"Goeman","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b9","first-page":"85","article-title":"An improved statistic for detecting over-representated gene ontology annotations in gene sets","author":"Grossmann","year":"2006"},{"key":"2023012409234582400_b10","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1152\/physiolgenomics.00004.2004","article-title":"Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks","volume":"17","author":"Hall","year":"2004","journal-title":"Physiol. Genomics"},{"key":"2023012409234582400_b11","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1161\/01.CIR.103.5.670","article-title":"Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure","volume":"103","author":"Haq","year":"2001","journal-title":"Circulation"},{"key":"2023012409234582400_b12","first-page":"73","article-title":"Penalized discriminant analysis","volume":"23","author":"Hastie","year":"1995","journal-title":"Annl. Stat."},{"key":"2023012409234582400_b13","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1056\/NEJMoa033513","article-title":"Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment","volume":"351","author":"Holleman","year":"2004","journal-title":"N Engl. J. Med."},{"key":"2023012409234582400_b14","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1073\/pnas.0537588100","article-title":"Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function","volume":"100","author":"Iwamoto","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409234582400_b15","doi-asserted-by":"crossref","first-page":"D428","DOI":"10.1093\/nar\/gki072","article-title":"Reactome: a knowledgebase of biological pathways","volume":"33","author":"Joshi-Tope","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2023012409234582400_b16","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/bioinformatics\/bti029","article-title":"Statistical methods of translating microarray data into clinically relevant diagnostic information in colorectal cancer","volume":"21","author":"Kim","year":"2005","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b17","doi-asserted-by":"crossref","first-page":"research0011.1","DOI":"10.1186\/gb-2002-3-3-research0011","article-title":"Vector algebra in the analysis of genome-wide expression data","volume":"3","author":"Kuruvilla","year":"2002","journal-title":"Genome Biol."},{"key":"2023012409234582400_b18","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0092-8674(03)00570-1","article-title":"A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer","volume":"114","author":"Lamb","year":"2003","journal-title":"Cell"},{"key":"2023012409234582400_b19","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.yjmcc.2003.10.001","article-title":"Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models","volume":"35","author":"Liang","year":"2003","journal-title":"J. Mol. Cell Cardiol."},{"key":"2023012409234582400_b20","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1093\/bioinformatics\/bti496","article-title":"Hotelling's T2 multivariate profiling for detecting differential expression in microarrays","volume":"21","author":"Lu","year":"2005","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b21","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/nm1052","article-title":"mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways","volume":"10","author":"Majumder","year":"2004","journal-title":"Nat. Med."},{"key":"2023012409234582400_b22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev.physiol.65.092101.142249","article-title":"Stress-activated cytokines and the heart: from adaptation to maladaptation","volume":"65","author":"Mann","year":"2003","journal-title":"Annu. Rev. Physiol."},{"key":"2023012409234582400_b23","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1055\/s-0038-1633992","article-title":"Testing differential gene expression in functional groups. Goeman's global test versus an ANCOVA approach","volume":"44","author":"Mansmann","year":"2005","journal-title":"Methods Inf. Med."},{"key":"2023012409234582400_b24","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":"2023012409234582400_b25","doi-asserted-by":"crossref","first-page":"8961","DOI":"10.1073\/pnas.0502674102","article-title":"Effects of threshold choice on biological conclusions reached during analysis of gene expression by DNA microarrays","volume":"102","author":"Pan","year":"2005","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409234582400_b26","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1093\/bioinformatics\/18.suppl_1.S120","article-title":"Linking gene expression data with patient survival times using partial least squares","volume":"18","author":"Park","year":"2002","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b27","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1023\/B:NERE.0000023608.29741.45","article-title":"Using the gene ontology for microarray data mining: a comparison of methods and application to age effects in human prefrontal cortex","volume":"29","author":"Pavlidis","year":"2004","journal-title":"Neurochem. Res."},{"key":"2023012409234582400_b28","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/415436a","article-title":"Prediction of central nervous system embryonal tumour outcome based on gene expression","volume":"415","author":"Pomeroy","year":"2002","journal-title":"Nature"},{"key":"2023012409234582400_b29","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1161\/01.CIR.0000085362.40608.DD","article-title":"Is nuclear factor kappaB an attractive therapeutic target for treating cardiac hypertrophy?","volume":"108","author":"Purcell","year":"2003","journal-title":"Circulation"},{"key":"2023012409234582400_b30","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/ng1434","article-title":"A module map showing conditional activity of expression modules in cancer","volume":"36","author":"Segal","year":"2004","journal-title":"Nat. Genet."},{"key":"2023012409234582400_b31","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genome-wide studies","volume":"100","author":"Storey","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409234582400_b32","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":"2023012409234582400_b33","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1093\/biostatistics\/4.4.555","article-title":"Multivariate exploratory tools for microarray data analysis","volume":"4","author":"Szabo","year":"2003","journal-title":"Biostatistics"},{"key":"2023012409234582400_b34","doi-asserted-by":"crossref","first-page":"13544","DOI":"10.1073\/pnas.0506577102","article-title":"Discovering statistically significant pathways in expression profiling studies","volume":"102","author":"Tian","year":"2005","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409234582400_b35","doi-asserted-by":"crossref","first-page":"6567","DOI":"10.1073\/pnas.082099299","article-title":"Diagnosis of multiple cancer types by shrunken centroids of gene expression","volume":"99","author":"Tibshirani","year":"2002","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012409234582400_b36","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/bioinformatics\/17.suppl_1.S107","article-title":"Identifying splits with clear separation: a new class discovery method for gene expression data","volume":"17","author":"von Heydebreck","year":"2001","journal-title":"Bioinformatics"},{"key":"2023012409234582400_b37","first-page":"704","article-title":"Ambiguity of human gene symbols in LocusLink and MEDLINE: creating an inventory and a disambiguation test collection","author":"Weeber","year":"2003","journal-title":"AMIA Annu. Symp. Proc."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/19\/2373\/48841298\/bioinformatics_22_19_2373.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/22\/19\/2373\/48841298\/bioinformatics_22_19_2373.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T10:10:00Z","timestamp":1674555000000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/22\/19\/2373\/241211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,7,28]]},"references-count":37,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2006,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btl401","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2006,10,1]]},"published":{"date-parts":[[2006,7,28]]}}}