{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T16:51:48Z","timestamp":1715964708010},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Purely epistatic multi-locus interactions cannot generally be detected via single-locus analysis in case-control studies of complex diseases. Recently, many two-locus and multi-locus analysis techniques have been shown to be promising for the epistasis detection. However, exhaustive multi-locus analysis requires prohibitively large computational efforts when problems involve large-scale or genome-wide data. Furthermore, there is no explicit proof that a combination of multiple two-locus analyses can lead to the correct identification of multi-locus interactions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The proposed 2LOmb algorithm performs an omnibus permutation test on ensembles of two-locus analyses. The algorithm consists of four main steps: two-locus analysis, a permutation test, global <jats:italic>p<\/jats:italic>-value determination and a progressive search for the best ensemble. 2LOmb is benchmarked against an exhaustive two-locus analysis technique, a set association approach, a correlation-based feature selection (CFS) technique and a tuned ReliefF (TuRF) technique. The simulation results indicate that 2LOmb produces a low false-positive error. Moreover, 2LOmb has the best performance in terms of an ability to identify all causative single nucleotide polymorphisms (SNPs) and a low number of output SNPs in purely epistatic two-, three- and four-locus interaction problems. The interaction models constructed from the 2LOmb outputs via a multifactor dimensionality reduction (MDR) method are also included for the confirmation of epistasis detection. 2LOmb is subsequently applied to a type 2 diabetes mellitus (T2D) data set, which is obtained as a part of the UK genome-wide genetic epidemiology study by the Wellcome Trust Case Control Consortium (WTCCC). After primarily screening for SNPs that locate within or near 372 candidate genes and exhibit no marginal single-locus effects, the T2D data set is reduced to 7,065 SNPs from 370 genes. The 2LOmb search in the reduced T2D data reveals that four intronic SNPs in <jats:italic>PGM1<\/jats:italic> (phosphoglucomutase 1), two intronic SNPs in <jats:italic>LMX1A<\/jats:italic> (LIM homeobox transcription factor 1, alpha), two intronic SNPs in <jats:italic>PARK2<\/jats:italic> (Parkinson disease (autosomal recessive, juvenile) 2, parkin) and three intronic SNPs in <jats:italic>GYS2<\/jats:italic> (glycogen synthase 2 (liver)) are associated with the disease. The 2LOmb result suggests that there is no interaction between each pair of the identified genes that can be described by purely epistatic two-locus interaction models. Moreover, there are no interactions between these four genes that can be described by purely epistatic multi-locus interaction models with marginal two-locus effects. The findings provide an alternative explanation for the aetiology of T2D in a UK population.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>An omnibus permutation test on ensembles of two-locus analyses can detect purely epistatic multi-locus interactions with marginal two-locus effects. The study also reveals that SNPs from large-scale or genome-wide case-control data which are discarded after single-locus analysis detects no association can still be useful for genetic epidemiology studies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-10-294","type":"journal-article","created":{"date-parts":[[2009,9,24]],"date-time":"2009-09-24T09:49:29Z","timestamp":1253785769000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Detecting purely epistatic multi-locus interactions by an omnibus permutation test on ensembles of two-locus analyses"],"prefix":"10.1186","volume":"10","author":[{"given":"Waranyu","family":"Wongseree","sequence":"first","affiliation":[]},{"given":"Anunchai","family":"Assawamakin","sequence":"additional","affiliation":[]},{"given":"Theera","family":"Piroonratana","sequence":"additional","affiliation":[]},{"given":"Saravudh","family":"Sinsomros","sequence":"additional","affiliation":[]},{"given":"Chanin","family":"Limwongse","sequence":"additional","affiliation":[]},{"given":"Nachol","family":"Chaiyaratana","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,9,17]]},"reference":[{"key":"3024_CR1","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1126\/science.273.5281.1516","volume":"273","author":"N Risch","year":"1996","unstructured":"Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996, 273: 1516\u20131517. 10.1126\/science.273.5281.1516","journal-title":"Science"},{"key":"3024_CR2","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1159\/000099179","volume":"63","author":"SK Musani","year":"2007","unstructured":"Musani SK, Shriner D, Liu N, Feng R, Coffey CS, Yi N, Tiwari HK, Allison DB: Detection of gene \u00d7 gene interactions in genome-wide association studies of human population data. Hum Hered 2007, 63: 67\u201384. 10.1159\/000099179","journal-title":"Hum Hered"},{"key":"3024_CR3","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature05911","volume":"447","author":"The Wellcome Trust Case Control Consortium","year":"2007","unstructured":"The Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447: 661\u2013678. 10.1038\/nature05911","journal-title":"Nature"},{"key":"3024_CR4","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1038\/ng2127","volume":"39","author":"The GAIN Collaborative Research Group","year":"2007","unstructured":"The GAIN Collaborative Research Group: New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 2007, 39: 1045\u20131051. 10.1038\/ng2127","journal-title":"Nat Genet"},{"key":"3024_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1471-2156-7-23","volume":"7","author":"AG Heidema","year":"2006","unstructured":"Heidema AG, Boer JMA, Nagelkerke N, Mariman ECM, van der A DL, Feskens EJM: The challenge for genetic epidemiologists: how to analyze large numbers of SNPs in relation to complex diseases. BMC Genet 2006, 7: 23. 10.1186\/1471-2156-7-23","journal-title":"BMC Genet"},{"key":"3024_CR6","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.2217\/14622416.8.9.1229","volume":"8","author":"AA Motsinger","year":"2007","unstructured":"Motsinger AA, Ritchie MD, Reif DM: Novel methods for detecting epistasis in pharmacogenomics studies. Pharmacogenomics 2007, 8: 1229\u20131241. 10.2217\/14622416.8.9.1229","journal-title":"Pharmacogenomics"},{"key":"3024_CR7","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.jtbi.2005.11.036","volume":"241","author":"JH Moore","year":"2006","unstructured":"Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC: A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 2006, 241: 252\u2013261. 10.1016\/j.jtbi.2005.11.036","journal-title":"J Theor Biol"},{"key":"3024_CR8","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1093\/bioinformatics\/btm344","volume":"23","author":"Y Saeys","year":"2007","unstructured":"Saeys Y, Inza I, Larra\u00f1aga P: A review of feature selection techniques in bioinformatics. Bioinformatics 2007, 23: 2507\u20132517. 10.1093\/bioinformatics\/btm344","journal-title":"Bioinformatics"},{"key":"3024_CR9","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1093\/bib\/3.2.146","volume":"3","author":"CM Lewis","year":"2002","unstructured":"Lewis CM: Genetic association studies: design, analysis and interpretation. Brief Bioinform 2002, 3: 146\u2013153. 10.1093\/bib\/3.2.146","journal-title":"Brief Bioinform"},{"key":"3024_CR10","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1093\/bib\/bbl028","volume":"7","author":"G Montana","year":"2006","unstructured":"Montana G: Statistical methods in genetics. Brief Bioinform 2006, 7: 297\u2013308. 10.1093\/bib\/bbl028","journal-title":"Brief Bioinform"},{"key":"3024_CR11","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1101\/gr.204001","volume":"11","author":"J Hoh","year":"2001","unstructured":"Hoh J, Wille A, Ott J: Trimming, weighting, and grouping SNPs in human case-control association studies. Genome Res 2001, 11: 2115\u20132119. 10.1101\/gr.204001","journal-title":"Genome Res"},{"key":"3024_CR12","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/gepi.20155","volume":"30","author":"DM Potter","year":"2006","unstructured":"Potter DM: Omnibus permutation tests of the association of an ensemble of genetic markers with disease in case-control studies. Genet Epidemiol 2006, 30: 438\u2013446. 10.1002\/gepi.20155","journal-title":"Genet Epidemiol"},{"key":"3024_CR13","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1002\/gepi.20250","volume":"31","author":"J Chapman","year":"2007","unstructured":"Chapman J, Clayton D: Detecting association using epistatic information. Genet Epidemiol 2007, 31: 894\u2013909. 10.1002\/gepi.20250","journal-title":"Genet Epidemiol"},{"key":"3024_CR14","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1109\/TKDE.2003.1245283","volume":"15","author":"MA Hall","year":"2003","unstructured":"Hall MA, Holmes G: Benchmarking attribute selection techniques for discrete class data mining. IEEE Trans Knowl Data Eng 2003, 15: 1437\u20131447. 10.1109\/TKDE.2003.1245283","journal-title":"IEEE Trans Knowl Data Eng"},{"key":"3024_CR15","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1023\/A:1025667309714","volume":"53","author":"M Robnik-\u0160ikonja","year":"2003","unstructured":"Robnik-\u0160ikonja M, Kononenko I: Theoretical and empirical analysis of ReliefF and RReliefF. Mach Learn 2003, 53: 23\u201369. 10.1023\/A:1025667309714","journal-title":"Mach Learn"},{"key":"3024_CR16","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1007\/978-3-540-71783-6_16","volume-title":"Evolutionary Computation, Machine Learning and Data Mining in Bioinformatics","author":"JH Moore","year":"2007","unstructured":"Moore JH, White BC: Tuning ReliefF for genome-wide genetic analysis. In Evolutionary Computation, Machine Learning and Data Mining in Bioinformatics. Edited by: Marchiori E, Moore JH, Rajapakse JC. Berlin, Heidelberg: Springer; 2007:166\u2013175. [Goos G, Hartmanis J, van Leeuwen J (Founding and Former Series Editors): Lecture Notes in Computer Science, vol 4447]. [Goos G, Hartmanis J, van Leeuwen J (Founding and Former Series Editors): Lecture Notes in Computer Science, vol 4447]."},{"key":"3024_CR17","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1101\/gr.172901","volume":"11","author":"MR Nelson","year":"2001","unstructured":"Nelson MR, Kardia SLR, Ferrell RE, Sing CF: A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation. Genome Res 2001, 11: 458\u2013470. 10.1101\/gr.172901","journal-title":"Genome Res"},{"key":"3024_CR18","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1002\/gepi.20006","volume":"27","author":"R Culverhouse","year":"2004","unstructured":"Culverhouse R, Klein T, Shannon W: Detecting epistatic interactions contributing to quantitative traits. Genet Epidemiol 2004, 27: 141\u2013152. 10.1002\/gepi.20006","journal-title":"Genet Epidemiol"},{"key":"3024_CR19","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1086\/321276","volume":"69","author":"MD Ritchie","year":"2001","unstructured":"Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001, 69: 138\u2013147. 10.1086\/321276","journal-title":"Am J Hum Genet"},{"key":"3024_CR20","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1093\/bioinformatics\/btf869","volume":"19","author":"LW Hahn","year":"2003","unstructured":"Hahn LW, Ritchie MD, Moore JH: Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 2003, 19: 376\u2013382. 10.1093\/bioinformatics\/btf869","journal-title":"Bioinformatics"},{"key":"3024_CR21","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1093\/bioinformatics\/btl347","volume":"22","author":"WS Bush","year":"2006","unstructured":"Bush WS, Dudek SM, Ritchie MD: Parallel multifactor dimensionality reduction: a tool for the large-scale analysis of gene-gene interactions. Bioinformatics 2006, 22: 2173\u20132174. 10.1093\/bioinformatics\/btl347","journal-title":"Bioinformatics"},{"key":"3024_CR22","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/bioinformatics\/btl557","volume":"23","author":"Y Chung","year":"2007","unstructured":"Chung Y, Lee SY, Elston RC, Park T: Odds ratio based multifactor-dimensionality reduction method for detecting gene-gene interactions. Bioinformatics 2007, 23: 71\u201376. 10.1093\/bioinformatics\/btl557","journal-title":"Bioinformatics"},{"key":"3024_CR23","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1186\/1471-2105-9-238","volume":"9","author":"WS Bush","year":"2008","unstructured":"Bush WS, Edwards TL, Dudek SM, McKinney BA, Ritchie MD: Alternative contingency table measures improve the power and detection of multifactor dimensionality reduction. BMC Bioinformatics 2008, 9: 238. 10.1186\/1471-2105-9-238","journal-title":"BMC Bioinformatics"},{"key":"3024_CR24","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.ajhg.2008.09.001","volume":"83","author":"XY Lou","year":"2008","unstructured":"Lou XY, Chen GB, Yan L, Ma JZ, Mangold JE, Zhu J, Elston RC, Li MD: A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies. Am J Hum Genet 2008, 83: 457\u2013467. 10.1016\/j.ajhg.2008.09.001","journal-title":"Am J Hum Genet"},{"key":"3024_CR25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1159\/000181157","volume":"67","author":"TL Edwards","year":"2009","unstructured":"Edwards TL, Lewis K, Velez DR, Dudek SM, Ritchie MD: Exploring the performance of multifactor dimensionality reduction in large scale SNP studies and in the presence of genetic heterogeneity among epistatic disease models. Hum Hered 2009, 67: 183\u2013192. 10.1159\/000181157","journal-title":"Hum Hered"},{"key":"3024_CR26","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/1471-2105-9-146","volume":"9","author":"LE Mechanic","year":"2008","unstructured":"Mechanic LE, Luke BT, Goodman JE, Chanock SJ, Harris CC: Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions. BMC Bioinformatics 2008, 9: 146. 10.1186\/1471-2105-9-146","journal-title":"BMC Bioinformatics"},{"key":"3024_CR27","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1007\/s10038-006-0016-2","volume":"51","author":"KH Liang","year":"2006","unstructured":"Liang KH, Hwang Y, Shao WC, Chen EY: An algorithm for model construction and its applications to pharmacogenomic studies. J Hum Genet 2006, 51: 751\u2013759. 10.1007\/s10038-006-0016-2","journal-title":"J Hum Genet"},{"key":"3024_CR28","doi-asserted-by":"publisher","first-page":"i167","DOI":"10.1093\/bioinformatics\/btm205","volume":"23","author":"JK Estrada-Gil","year":"2007","unstructured":"Estrada-Gil JK, Fern\u00e1ndez-L\u00f3pez JC, Hern\u00e1ndez-Lemus E, Silva-Zolezzi I, Hidalgo-Miranda A, Jim\u00e9nez-S\u00e1nchez G, Vallejo-Clemente EE: GPDTI: a Genetic Programming Decision Tree Induction method to find epistatic effects in common complex diseases. Bioinformatics 2007, 23: i167-i174. 10.1093\/bioinformatics\/btm205","journal-title":"Bioinformatics"},{"key":"3024_CR29","doi-asserted-by":"publisher","first-page":"3280","DOI":"10.1093\/bioinformatics\/btm522","volume":"23","author":"R Nunkesser","year":"2007","unstructured":"Nunkesser R, Bernholt T, Schwender H, Ickstadt K, Wegener I: Detecting high-order interactions of single nucleotide polymorphisms using genetic programming. Bioinformatics 2007, 23: 3280\u20133288. 10.1093\/bioinformatics\/btm522","journal-title":"Bioinformatics"},{"key":"3024_CR30","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/1471-2156-5-32","volume":"5","author":"KL Lunetta","year":"2004","unstructured":"Lunetta KL, Hayward LB, Segal J, van Eerdewegh P: Screening large-scale association study data: exploiting interactions using random forests. BMC Genet 2004, 5: 32. 10.1186\/1471-2156-5-32","journal-title":"BMC Genet"},{"key":"3024_CR31","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1002\/gepi.20041","volume":"28","author":"A Bureau","year":"2005","unstructured":"Bureau A, Dupuis J, Falls K, Lunetta KL, Hayward B, Keith TP, van Eerdewegh P: Identifying SNPs predictive of phenotype using random forests. Genet Epidemiol 2005, 28: 171\u2013182. 10.1002\/gepi.20041","journal-title":"Genet Epidemiol"},{"key":"3024_CR32","doi-asserted-by":"publisher","first-page":"19199","DOI":"10.1073\/pnas.0709868104","volume":"104","author":"X Chen","year":"2007","unstructured":"Chen X, Liu CT, Zhang M, Zhang H: A forest-based approach to identifying gene and gene-gene interactions. Proc Natl Acad Sci USA 2007, 104: 19199\u201319203. 10.1073\/pnas.0709868104","journal-title":"Proc Natl Acad Sci USA"},{"key":"3024_CR33","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1471-2105-4-28","volume":"4","author":"MD Ritchie","year":"2003","unstructured":"Ritchie MD, White BC, Parker JS, Hahn LW, Moore JH: Optimization of neural network architecture using genetic programming improves detection and modeling of gene-gene interactions in studies of human diseases. BMC Bioinformatics 2003, 4: 28. 10.1186\/1471-2105-4-28","journal-title":"BMC Bioinformatics"},{"key":"3024_CR34","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1002\/gepi.20307","volume":"32","author":"AA Motsinger-Reif","year":"2008","unstructured":"Motsinger-Reif AA, Dudek SM, Hahn LW, Ritchie MD: Comparison of approaches for machine-learning optimization of neural networks for detecting gene-gene interactions in genetic epidemiology. Genet Epidemiol 2008, 32: 325\u2013340. 10.1002\/gepi.20307","journal-title":"Genet Epidemiol"},{"key":"3024_CR35","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1093\/hmg\/11.20.2463","volume":"11","author":"HJ Cordell","year":"2002","unstructured":"Cordell HJ: Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet 2002, 11: 2463\u20132468. 10.1093\/hmg\/11.20.2463","journal-title":"Hum Mol Genet"},{"key":"3024_CR36","first-page":"317","volume-title":"Nature Encyclopedia of the Human Genome","author":"SR Wilson","year":"2004","unstructured":"Wilson SR: Epistasis. In Nature Encyclopedia of the Human Genome. Volume 2. Edited by: Cooper DN. London: Nature Publishing Group; 2004:317\u2013320."},{"key":"3024_CR37","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/gepi.1370090506","volume":"9","author":"RJ Neuman","year":"1992","unstructured":"Neuman RJ, Rice JP: Two-locus models of disease. Genet Epidemiol 1992, 9: 347\u2013365. 10.1002\/gepi.1370090506","journal-title":"Genet Epidemiol"},{"key":"3024_CR38","first-page":"1127","volume":"53","author":"NJ Schork","year":"1993","unstructured":"Schork NJ, Boehnke M, Terwilliger JD, Ott J: Two-trait-locus linkage analysis: a powerful strategy for mapping complex genetic traits. Am J Hum Genet 1993, 53: 1127\u20131136.","journal-title":"Am J Hum Genet"},{"key":"3024_CR39","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1159\/000022939","volume":"50","author":"W Li","year":"2000","unstructured":"Li W, Reich J: A complete enumeration and classification of two-locus disease models. Hum Hered 2000, 50: 334\u2013349. 10.1159\/000022939","journal-title":"Hum Hered"},{"key":"3024_CR40","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/ng1537","volume":"37","author":"J Marchini","year":"2005","unstructured":"Marchini J, Donnelly P, Cardon LR: Genome-wide strategies for detecting multiple loci that influence complex diseases. Nat Genet 2005, 37: 413\u2013417. 10.1038\/ng1537","journal-title":"Nat Genet"},{"key":"3024_CR41","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/1471-2156-9-17","volume":"9","author":"IB Hallgr\u00edmsd\u00f3ttir","year":"2008","unstructured":"Hallgr\u00edmsd\u00f3ttir IB, Yuster DS: A complete classification of epistatic two-locus models. BMC Genet 2008, 9: 17. 10.1186\/1471-2156-9-17","journal-title":"BMC Genet"},{"key":"3024_CR42","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1086\/338759","volume":"70","author":"R Culverhouse","year":"2002","unstructured":"Culverhouse R, Suarez BK, Lin J, Reich T: A perspective on epistasis: limits of models displaying no main effect. Am J Hum Genet 2002, 70: 461\u2013471. 10.1086\/338759","journal-title":"Am J Hum Genet"},{"key":"3024_CR43","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s00125-004-1419-2","volume":"47","author":"YM Cho","year":"2004","unstructured":"Cho YM, Ritchie MD, Moore JH, Park JY, Lee KU, Shin HD, Lee HK, Park KS: Multifactor-dimensionality reduction shows a two-locus interaction associated with type 2 diabetes mellitus. Diabetologia 2004, 47: 549\u2013554. 10.1007\/s00125-003-1321-3","journal-title":"Diabetologia"},{"key":"3024_CR44","doi-asserted-by":"publisher","first-page":"2701","DOI":"10.1093\/hmg\/ddl203","volume":"15","author":"CH Hsieh","year":"2006","unstructured":"Hsieh CH, Liang KH, Hung YJ, Huang LC, Pei D, Liao YT, Kuo SW, Bey MSJ, Chen JL, Chen EY: Analysis of epistasis for diabetic nephropathy among type 2 diabetic patients. Hum Mol Genet 2006, 15: 2701\u20132708. 10.1093\/hmg\/ddl203","journal-title":"Hum Mol Genet"},{"key":"3024_CR45","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1111\/j.1464-5491.2007.02255.x","volume":"24","author":"L Qi","year":"2007","unstructured":"Qi L, van Dam RM, Asselbergs FW, Hu FB: Gene-gene interactions between HNF4A and KCNJ11 in predicting type 2 diabetes in women. Diabet Med 2007, 24: 1187\u20131191. 10.1111\/j.1464-5491.2007.02255.x","journal-title":"Diabet Med"},{"key":"3024_CR46","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/gepi.20304","volume":"32","author":"Z Zhang","year":"2008","unstructured":"Zhang Z, Zhang S, Wong MY, Wareham NJ, Sha Q: An ensemble learning approach jointly modeling main and interaction effects in genetic association studies. Genet Epidemiol 2008, 32: 285\u2013300. 10.1002\/gepi.20304","journal-title":"Genet Epidemiol"},{"key":"3024_CR47","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1038\/oby.2007.343","volume":"15","author":"M Fiorito","year":"2007","unstructured":"Fiorito M, Torrente I, De Cosmo S, Guida V, Colosimo A, Prudente S, Flex E, Menghini R, Miccoli R, Penno G, Pellegrini F, Tassi V, Federici M, Trischitta V, Dallapiccola B: Interaction of DIO2 T92A and PPAR\u03b32 P12A polymorphisms in the modulation of metabolic syndrome. Obesity 2007, 15: 2889\u20132895. 10.1038\/oby.2007.343","journal-title":"Obesity"},{"key":"3024_CR48","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1534\/genetics.107.071696","volume":"176","author":"A Albrechtsen","year":"2007","unstructured":"Albrechtsen A, Castella S, Andersen G, Hansen T, Pedersen O, Nielsen R: A Bayesian multilocus association method: allowing for higher-order interaction in association studies. Genetics 2007, 176: 1197\u20131208. 10.1534\/genetics.107.071696","journal-title":"Genetics"},{"key":"3024_CR49","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1038\/ng2110","volume":"39","author":"Y Zhang","year":"2007","unstructured":"Zhang Y, Liu JS: Bayesian inference of epistatic interactions in case-control studies. Nat Genet 2007, 39: 1167\u20131173. 10.1038\/ng2110","journal-title":"Nat Genet"},{"key":"3024_CR50","doi-asserted-by":"publisher","first-page":"e157","DOI":"10.1371\/journal.pgen.0020157","volume":"2","author":"DM Evans","year":"2006","unstructured":"Evans DM, Marchini J, Morris AP, Cardon LR: Two-stage two-locus models in genome-wide association. PLoS Genet 2006, 2: e157. 10.1371\/journal.pgen.0020157","journal-title":"PLoS Genet"},{"key":"3024_CR51","first-page":"39","volume":"7","author":"I Ionita","year":"2006","unstructured":"Ionita I, Man M: Optimal two-stage strategy for detecting interacting genes in complex diseases. BMC Genet 2006, 7: 39.","journal-title":"BMC Genet"},{"key":"3024_CR52","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/1471-2164-9-360","volume":"9","author":"J Gay\u00e1n","year":"2008","unstructured":"Gay\u00e1n J, Gonz\u00e1lez-P\u00e9rez A, Bermudo F, S\u00e1ez ME, Royo JL, Quintas A, Galan JJ, Mor\u00f3n FJ, Ramirez-Lorca R, Real LM, Ruiz A: A method for detecting epistasis in genome-wide studies using case-control multi-locus association analysis. BMC Genomics 2008, 9: 360. 10.1186\/1471-2164-9-360","journal-title":"BMC Genomics"},{"key":"3024_CR53","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/gepi.20251","volume":"31","author":"AG Heidema","year":"2007","unstructured":"Heidema AG, Feskens EJM, Doevendans PAFM, Ruven HJT, van Houwelingen HC, Mariman ECM, Boer JMA: Analysis of multiple SNPs in genetic association studies: comparison of three multi-locus methods to prioritize and select SNPs. Genet Epidemiol 2007, 31: 910\u2013921. 10.1002\/gepi.20251","journal-title":"Genet Epidemiol"},{"key":"3024_CR54","volume-title":"Multivariate Permutation Tests with Applications to Biostatistics","author":"F Pesarin","year":"2001","unstructured":"Pesarin F: Multivariate Permutation Tests with Applications to Biostatistics. Chichester: Wiley; 2001."},{"key":"3024_CR55","volume-title":"Statistical Methods for Research Workers","author":"RA Fisher","year":"1932","unstructured":"Fisher RA: Statistical Methods for Research Workers. 4th edition. London: Oliver and Boyd; 1932.","edition":"4"},{"key":"3024_CR56","volume-title":"Resampling-Based Multiple Testing: Examples and Methods for p-value Adjustment","author":"PH Westfall","year":"1993","unstructured":"Westfall PH, Young SS: Resampling-Based Multiple Testing: Examples and Methods for p-value Adjustment. New York: John Wiley and Sons; 1993."},{"key":"3024_CR57","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/gepi.20096","volume":"29","author":"T Becker","year":"2005","unstructured":"Becker T, Schumacher J, Cichon S, Baur MP, Knapp M: Haplotype interaction analysis of unlinked regions. Genet Epidemiol 2005, 29: 313\u2013322. 10.1002\/gepi.20096","journal-title":"Genet Epidemiol"},{"key":"3024_CR58","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1093\/bioinformatics\/btn581","volume":"25","author":"C Herold","year":"2009","unstructured":"Herold C, Becker T: Genetic association analysis with FAMHAP: a major program update. Bioinformatics 2009, 25: 134\u2013136. 10.1093\/bioinformatics\/btn581","journal-title":"Bioinformatics"},{"key":"3024_CR59","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1126\/science.28.706.49","volume":"28","author":"GH Hardy","year":"1908","unstructured":"Hardy GH: Mendelian proportions in a mixed population. Science 1908, 28: 49\u201350. 10.1126\/science.28.706.49","journal-title":"Science"},{"key":"3024_CR60","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1142\/9789812701626_0046","volume-title":"Proceedings of the Pacific Symposium on Biocomputing 2006: 3-7 January 2006; Maui","author":"SM Dudek","year":"2006","unstructured":"Dudek SM, Motsinger AA, Velez DR, Williams SM, Ritchie MD: Data simulation software for whole-genome association and other studies in human genetics. In Proceedings of the Pacific Symposium on Biocomputing 2006: 3\u20137 January 2006; Maui. Edited by: Altman RB, Dunker AK, Hunter L, Murray T, Klein TE. Singapore: World Scientific; 2006:499\u2013510."},{"key":"3024_CR61","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1162\/153244303322753616","volume":"3","author":"I Guyon","year":"2003","unstructured":"Guyon I, Elisseeff A: An introduction to variable and feature selection. J Mach Learn Res 2003, 3: 1157\u20131182. 10.1162\/153244303322753616","journal-title":"J Mach Learn Res"},{"key":"3024_CR62","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/ng0208-124","volume":"40","author":"W Yu","year":"2008","unstructured":"Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ: A navigator for human genome epidemiology. Nat Genet 2008, 40: 124\u2013125. 10.1038\/ng0208-124","journal-title":"Nat Genet"},{"key":"3024_CR63","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1471-2105-7-60","volume":"7","author":"KW Carter","year":"2006","unstructured":"Carter KW, McCaskie PA, Palmer LJ: JLIN: a java based linkage disequilibrium plotter. BMC Bioinformatics 2006, 7: 60. 10.1186\/1471-2105-7-60","journal-title":"BMC Bioinformatics"},{"key":"3024_CR64","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/genetics\/49.1.49","volume":"49","author":"RC Lewontin","year":"1964","unstructured":"Lewontin RC: The interaction of selection and linkage. I. general considerations; heterotic models. Genetics 1964, 49: 49\u201367.","journal-title":"Genetics"},{"key":"3024_CR65","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/BF01245622","volume":"38","author":"WG Hill","year":"1968","unstructured":"Hill WG, Robertson A: Linkage disequilibrium in finite populations. Theor Appl Genet 1968, 38: 226\u2013231. 10.1007\/BF01245622","journal-title":"Theor Appl Genet"},{"key":"3024_CR66","first-page":"921","volume":"12","author":"L Excoffier","year":"1995","unstructured":"Excoffier L, Slatkin M: Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995, 12: 921\u2013927.","journal-title":"Mol Biol Evol"},{"key":"3024_CR67","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1086\/380204","volume":"73","author":"MP Epstein","year":"2003","unstructured":"Epstein MP, Satten GA: Inference on haplotype effects in case-control studies using unphased genotype data. Am J Hum Genet 2003, 73: 1316\u20131329. 10.1086\/380204","journal-title":"Am J Hum Genet"},{"key":"3024_CR68","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-3-540-39907-0_32","volume-title":"Artificial Intelligence in Medicine","author":"A Jakulin","year":"2003","unstructured":"Jakulin A, Bratko I, Smrke D, Dem\u0161ar J, Zupan B: Attribute interactions in medical data analysis. In Artificial Intelligence in Medicine. Edited by: Dojat M, Keravnou E, Barahona P. Berlin, Heidelberg: Springer; 2003:229\u2013238. [Carbonell JG, Siekmann J (Series Editors): Lecture Notes in Artificial Intelligence, vol 2780]. [Carbonell JG, Siekmann J (Series Editors): Lecture Notes in Artificial Intelligence, vol 2780]."},{"key":"3024_CR69","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-3-540-39804-2_22","volume-title":"Knowledge Discovery in Databases: PKDD 2003","author":"A Jakulin","year":"2003","unstructured":"Jakulin A, Bratko I: Analyzing attribute dependencies. In Knowledge Discovery in Databases: PKDD 2003. Edited by: Lavra\u010d N, Gamberger D, Todorovski L, Blockeel H. Berlin, Heidelberg: Springer; 2003:229\u2013240. [Carbonell JG, Siekmann J (Series Editors): Lecture Notes in Artificial Intelligence, vol 2838]. [Carbonell JG, Siekmann J (Series Editors): Lecture Notes in Artificial Intelligence, vol 2838]."},{"key":"3024_CR70","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa M, Goto S: KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 2000, 28: 27\u201330. 10.1093\/nar\/28.1.27","journal-title":"Nucleic Acids Res"},{"key":"3024_CR71","doi-asserted-by":"publisher","first-page":"D354","DOI":"10.1093\/nar\/gkj102","volume":"34","author":"M Kanehisa","year":"2006","unstructured":"Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita K, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M: From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 2006, 34: D354-D357. 10.1093\/nar\/gkj102","journal-title":"Nucleic Acids Res"},{"key":"3024_CR72","doi-asserted-by":"publisher","first-page":"D480","DOI":"10.1093\/nar\/gkm882","volume":"36","author":"M Kanehisa","year":"2008","unstructured":"Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, Katayama T, Kawashima S, Okuda S, Tokimatsu T, Yamanishi Y: KEGG for linking genomes to life and the environment. Nucleic Acids Res 2008, 36: D480-D484. 10.1093\/nar\/gkm882","journal-title":"Nucleic Acids Res"},{"key":"3024_CR73","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/S0378-1119(02)00582-6","volume":"290","author":"F Thameem","year":"2002","unstructured":"Thameem F, Wolford JK, Wang J, German MS, Bogardus C, Prochazka M: Cloning, expression and genomic structure of human LMX1A , and variant screening in Pima Indians. Gene 2002, 290: 217\u2013225. 10.1016\/S0378-1119(02)00582-6","journal-title":"Gene"},{"key":"3024_CR74","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1086\/302061","volume":"63","author":"RL Hanson","year":"1998","unstructured":"Hanson RL, Ehm MG, Pettitt DJ, Prochazka M, Thompson DB, Timberlake D, Foroud T, Kobes S, Baier L, Burns DK, Almasy L, Blangero J, Garvey WT, Bennett PH, Knowler WC: An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 1998, 63: 1130\u20131138. 10.1086\/302061","journal-title":"Am J Hum Genet"},{"key":"3024_CR75","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s00439-008-0523-7","volume":"124","author":"TS Leak","year":"2008","unstructured":"Leak TS, Mychaleckyj JC, Smith SG, Keene KL, Gordon CJ, Hicks PJ, Freedman BI, Bowden DW, Sale MM: Evaluation of a SNP map of 6q24\u201327 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population. Hum Genet 2008, 124: 63\u201371. 10.1007\/s00439-008-0523-7","journal-title":"Hum Genet"},{"key":"3024_CR76","doi-asserted-by":"publisher","first-page":"830","DOI":"10.2337\/diabetes.53.3.830","volume":"53","author":"MM Sale","year":"2004","unstructured":"Sale MM, Freedman BI, Langefeld CD, Williams AH, Hicks PJ, Colicigno CJ, Beck SR, Brown WM, Rich SS, Bowden DW: A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q. Diabetes 2004, 53: 830\u2013837. 10.2337\/diabetes.53.3.830","journal-title":"Diabetes"},{"key":"3024_CR77","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S0009-9236(03)00014-6","volume":"73","author":"I Watanabe","year":"2003","unstructured":"Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, Koishi R, Takahashi T, Miyoshi K, Nakamura K, Izumi T, Matsushita Y, Furukawa H, Haruyama H, Koga T: A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2003, 73: 435\u2013455. 10.1016\/S0009-9236(03)00014-6","journal-title":"Clin Pharmacol Ther"},{"key":"3024_CR78","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1097\/MAJ.0b013e3180a5e934","volume":"334","author":"F Gloria-Bottini","year":"2007","unstructured":"Gloria-Bottini F, Magrini A, Antonacci E, La Torre M, Di Renzo L, De Lorenzo A, Bergamaschi A, Bottini E: Phosphoglucomutase genetic polymorphism and body mass. Am J Med Sci 2007, 334: 421\u2013425. 10.1097\/MAJ.0b013e3180a5e934","journal-title":"Am J Med Sci"},{"key":"3024_CR79","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/204742a0","volume":"204","author":"N Spencer","year":"1964","unstructured":"Spencer N, Hopkinson DA, Harris H: Phosphoglucomutase polymorphism in man. Nature 1964, 204: 742\u2013745. 10.1038\/204742a0","journal-title":"Nature"},{"key":"3024_CR80","doi-asserted-by":"publisher","first-page":"10730","DOI":"10.1073\/pnas.90.22.10730","volume":"90","author":"RE March","year":"1993","unstructured":"March RE, Putt W, Hollyoake M, Ives JH, Lovegrove JU, Hopkinson DA, Edwards YH, Whitehouse DB: The classical human phosphoglucomutase (PGM1) isozyme polymorphism is generated by intragenic recombination. Proc Natl Acad Sci USA 1993, 90: 10730\u201310733. 10.1073\/pnas.90.22.10730","journal-title":"Proc Natl Acad Sci USA"},{"key":"3024_CR81","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/ng.120","volume":"40","author":"E Zeggini","year":"2008","unstructured":"Zeggini E, Scott LJ, Saxena R, Voight BF: Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008, 40: 638\u2013645. 10.1038\/ng.120","journal-title":"Nat Genet"},{"key":"3024_CR82","volume-title":"Numerical Recipes in C: The Art of Scientific Computing","author":"WH Press","year":"1992","unstructured":"Press WH, Teukolsky SA, Vetterling WT, Flannery BP: Numerical Recipes in C: The Art of Scientific Computing. 2nd edition. Cambridge: Cambridge University Press; 1992.","edition":"2"},{"key":"3024_CR83","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.asoc.2003.08.003","volume":"4","author":"JH Moore","year":"2004","unstructured":"Moore JH, Hahn LW, Ritchie MD, Thornton TA, White BC: Routine discovery of complex genetic models using genetic algorithms. Appl Soft Comput 2004, 4: 79\u201386. 10.1016\/j.asoc.2003.08.003","journal-title":"Appl Soft Comput"},{"key":"3024_CR84","unstructured":"S Statistic in Gene Mapping[http:\/\/www.genemapping.cn\/sumstat.html]"},{"key":"3024_CR85","volume-title":"Data Mining: Practical Machine Learning Tools and Techniques","author":"IH Witten","year":"2005","unstructured":"Witten IH, Frank E: Data Mining: Practical Machine Learning Tools and Techniques. 2nd edition. San Francisco: Morgan Kaufmann; 2005.","edition":"2"},{"key":"3024_CR86","unstructured":"Weka 3: Data Mining Software in Java[http:\/\/www.cs.waikato.ac.nz\/ml\/weka\/]"},{"key":"3024_CR87","unstructured":"Multifactor Dimensionality Reduction[http:\/\/www.multifactordimensionalityreduction.org\/]"},{"key":"3024_CR88","unstructured":"JLIN: A Java Based Linkage Disequilibrium Plotter[http:\/\/www.genepi.org.au\/jlin.html]"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-10-294.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T21:34:00Z","timestamp":1630445640000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-10-294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,17]]},"references-count":88,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["3024"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-10-294","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,17]]},"assertion":[{"value":"5 March 2009","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"294"}}