{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T21:21:45Z","timestamp":1778275305627,"version":"3.51.4"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":2778,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/2.0\/uk\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Identification of disease-related genes using high-throughput microarray data is more difficult for complex diseases as compared with monogenic ones. We hypothesized that an endophenotype derived from transcriptional data is associated with a set of genes corresponding to a pathway cluster. We assumed that a complex disease is associated with multiple endophenotypes and can be induced by their up\/downregulated gene expression patterns. Thus, a neural network model was adopted to simulate the gene\u2013endophenotype\u2013disease relationship in which endophenotypes were represented by hidden nodes.<\/jats:p>\n               <jats:p>Results: We successfully constructed a three-endophenotype model for Taiwanese hypertensive males with high identification accuracy. Of the three endophenotypes, one is strongly protective, another is weakly protective and the third is highly correlated with developing young-onset male hypertension. Sixteen of the involved 101 genes were highly and consistently influential to the endophenotypes. Identification of SLC4A5, SLC5A10 and LDOC1 indicated that sodium\/bicarbonate transport, sodium\/glucose transport and cell-proliferation regulation may play important upstream roles and identification of BNIP1, APOBEC3F and LDOC1 suggested that apoptosis, innate immune response and cell-proliferation regulation may play important downstream roles in hypertension. The involved genes not only provide insights into the mechanism of hypertension but should also be considered in future gene mapping endeavors.<\/jats:p>\n               <jats:p>Availability: Microarray data and test program are available at http:\/\/ms.iis.sinica.edu.tw\/microarray\/index.htm<\/jats:p>\n               <jats:p>Contact: \u00a0pan@ibms.sinica.edu.tw or hsu@iis.sinica.edu.tw<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp106","type":"journal-article","created":{"date-parts":[[2009,2,24]],"date-time":"2009-02-24T01:26:06Z","timestamp":1235438766000},"page":"981-988","source":"Crossref","is-referenced-by-count":22,"title":["A neural network model for constructing endophenotypes of common complex diseases: an application to male young-onset hypertension microarray data"],"prefix":"10.1093","volume":"25","author":[{"given":"Ke-Shiuan","family":"Lynn","sequence":"first","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Lan","family":"Li","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Ju","family":"Lin","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiuen-Huei","family":"Wang","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Hui","family":"Sheng","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Hwa","family":"Lin","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Liao","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Lian","family":"Hsu","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Harn","family":"Pan","sequence":"additional","affiliation":[{"name":"1 Institute of Information Sciences, Academia Sinica, Taipei, 2Industrial Technology Research Institute, Hsinchu, 3Department of Biological Science and Technology, Hsinchu, China Medical University, Taichung, 4Phalanx Biotech Group, Inc., Hsinchu and 5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,2,23]]},"reference":[{"key":"2023051607023984300_B1","first-page":"176","article-title":"Statistical theory of overtraining\u2014Is cross validation asymptotically effective?","volume":"8","author":"Amari","year":"1996","journal-title":"Adv. Neural Inf. Process. Syst."},{"key":"2023051607023984300_B2","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1164\/rccm.200312-1686OC","article-title":"Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension","volume":"170","author":"Bull","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2023051607023984300_B3","doi-asserted-by":"crossref","first-page":"D262","DOI":"10.1093\/nar\/gkh021","article-title":"The Gene Ontology Annotation (GOA) database: sharing knowledge in Uniprot with gene ontology","volume":"32","author":"Camon","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023051607023984300_B4","doi-asserted-by":"crossref","first-page":"11887","DOI":"10.1074\/jbc.273.19.11887","article-title":"Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex","volume":"273","author":"Chen","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2023051607023984300_B5","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1161\/01.HYP.0000123071.35142.72","article-title":"Broadly altered gene expression in blood leukocytes in essential hypertension is absent during treatment","volume":"43","author":"Chon","year":"2004","journal-title":"Hypertension"},{"key":"2023051607023984300_B6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/BF03325101","article-title":"A comprehensive survey of evolutionary-based multiobjective optimization techniques","volume":"1","author":"Coello","year":"1999","journal-title":"Knowl. Inf. Syst."},{"key":"2023051607023984300_B7","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1126\/science.278.5343.1580","article-title":"Variations on a theme: cataloging human DNA sequence variation","volume":"278","author":"Collins","year":"1997","journal-title":"Science"},{"key":"2023051607023984300_B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1162\/evco.1995.3.1.1","article-title":"An overview of evolutionary algorithm in multiobjective optimization","volume":"3","author":"Fonseca","year":"1995","journal-title":"Evol. Comput."},{"key":"2023051607023984300_B9","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1176\/appi.ajp.160.4.636","article-title":"The endophenotype concept in psychiatry: etymology and strategic intentions","volume":"160","author":"Gottesman","year":"2003","journal-title":"Am. J. Psychiatry"},{"key":"2023051607023984300_B10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/gepi.220","article-title":"Role of gene expression microarray analysis in finding complex disease genes","volume":"23","author":"Gu","year":"2002","journal-title":"Genet. Epidemiol."},{"key":"2023051607023984300_B11","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1161\/01.HYP.0000196949.26088.3c","article-title":"Sodium bicarbonate cotransporter polymorphisms are associated with baseline and 10-year follow-up blood pressures","volume":"47","author":"Hunt","year":"2006","journal-title":"Hypertension"},{"key":"2023051607023984300_B12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1586\/14737159.3.2.185","article-title":"Gene expression in cancer: the application of microarrays","volume":"3","author":"Macgregor","year":"2003","journal-title":"Expert Rev. Mol. Diagn."},{"key":"2023051607023984300_B13","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1159\/000053338","article-title":"The complexity of linkage analysis with neural networks","volume":"51","author":"Marinov","year":"2001","journal-title":"Hum. Hered."},{"key":"2023051607023984300_B14","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/ijc.10534","article-title":"Application of differential display to identify genes for lung cancer detection in peripheral blood","volume":"100","author":"Matsunaga","year":"2002","journal-title":"Int. J. Cancer"},{"key":"2023051607023984300_B15","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1161\/01.RES.81.4.611","article-title":"Role of angiotensin II in activation of the JAK\/STAT pathway induced by acute pressure overload in the rat heart","volume":"81","author":"Pan","year":"1997","journal-title":"Circ. Res."},{"key":"2023051607023984300_B16","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/sj.jhh.1001268","article-title":"Prevalence, awareness, treatment and control of hypertension in Taiwan: results of nutrition and health survey in Taiwan (NAHSIT) 1993-1996","volume":"15","author":"Pan","year":"2001","journal-title":"J. Hum. Hypertens."},{"key":"2023051607023984300_B17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/gepi.20136","article-title":"Using endophenotypes for pathway cluster to map complex disease genes","volume":"30","author":"Pan","year":"2006","journal-title":"Genet. Epidemiol."},{"key":"2023051607023984300_B18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/978-0-387-39978-2_8","article-title":"Microarrays for cancer diagnosis and classification","volume":"593","author":"Perez-Diez","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"key":"2023051607023984300_B19","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/ng1032","article-title":"Microarray data normalization and transformation","volume":"32","author":"Quackenbush","year":"2002","journal-title":"Nat. Genet."},{"key":"2023051607023984300_B20","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1056\/NEJMra042342","article-title":"Microarray analysis and tumor classification","volume":"354","author":"Quackenbush","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2023051607023984300_B21","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/oxfordjournals.aje.a112335","article-title":"Causes","volume":"104","author":"Rothman","year":"1976","journal-title":"Am. J. Epidemiol."},{"key":"2023051607023984300_B22","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1161\/01.ATV.0000075081.51227.86","article-title":"Genes, environment, and cardiovascular disease","volume":"23","author":"Sing","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2023051607023984300_B23","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1291\/hypres.24.729","article-title":"The change and significance of the Na+-K+-ATPase alpha-subunit in ouabain-hypertensive rats","volume":"24","author":"Tian","year":"2001","journal-title":"Hypertens. Res."},{"key":"2023051607023984300_B24","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1093\/bioinformatics\/bti162","article-title":"Sample size for gene expression microarray experiments","volume":"21","author":"Tsai","year":"2005","journal-title":"Bioinformatics"},{"key":"2023051607023984300_B25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1749-6632.2002.tb04888.x","article-title":"Pattern recognition techniques in microarray data analysis: a survey","volume":"980","author":"Valafar","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2023051607023984300_B26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1152\/physiolgenomics.00314.2004","article-title":"Microarray analysis of gene expression: considerations in data mining and statistical treatment","volume":"25","author":"Verducci","year":"2006","journal-title":"Physiol. Genomics"},{"key":"2023051607023984300_B27","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/genetics\/143.1.463","article-title":"Genotype-environment interaction: apolipoprotein E (Apo E) gene effects and age as an index of time and spatial context in the human","volume":"143","author":"Zerba","year":"1996","journal-title":"Genetics"},{"key":"2023051607023984300_B28","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1109\/4235.797969","article-title":"Multiobjective evolutionary algorithms: a comparative case study and the strength Pareto approach","volume":"3","author":"Zitzler","year":"1999","journal-title":"IEEE Trans. Evol. Comput."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/8\/981\/50287571\/bioinformatics_25_8_981.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/25\/8\/981\/50287571\/bioinformatics_25_8_981.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T07:07:56Z","timestamp":1684220876000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/25\/8\/981\/324586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,23]]},"references-count":28,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2009,4,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btp106","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,4,15]]},"published":{"date-parts":[[2009,2,23]]}}}