{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T22:30:47Z","timestamp":1757457047666,"version":"3.37.3"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,7,27]],"date-time":"2019-07-27T00:00:00Z","timestamp":1564185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["090532\/Z\/09\/Z","203141\/Z\/16\/Z"],"award-info":[{"award-number":["090532\/Z\/09\/Z","203141\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/14\/55\/30806","RE\/13\/1\/30181, M.F. and J.C.H."],"award-info":[{"award-number":["FS\/14\/55\/30806","RE\/13\/1\/30181, M.F. and J.C.H."]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"European Union Seventh Framework programme","doi-asserted-by":"publisher","award":["HEALTH-F2-2013-60145"],"award-info":[{"award-number":["HEALTH-F2-2013-60145"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"name":"TriPartite Immunometabolism Consortium"},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF15CC0018486"],"award-info":[{"award-number":["NNF15CC0018486"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Common small-effect genetic variants that contribute to human complex traits and disease are typically identified using traditional fixed-effect (FE) meta-analysis methods. However, the power to detect genetic associations under FE models deteriorates with increasing heterogeneity, so that some small-effect heterogeneous loci might go undetected. A modified random-effects meta-analysis approach (RE2) was previously developed that is more powerful than traditional fixed and random-effects methods at detecting small-effect heterogeneous genetic associations, the method was updated (RE2C) to identify small-effect heterogeneous variants overlooked by traditional fixed-effect meta-analysis. Here, we re-appraise a large-scale meta-analysis of coronary disease with RE2C to search for small-effect genetic signals potentially masked by heterogeneity in a FE meta-analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our application of RE2C suggests a high sensitivity but low specificity of this approach for discovering small-effect heterogeneous genetic associations. We recommend that reports of small-effect heterogeneous loci discovered with RE2C are accompanied by forest plots and standardized predicted random-effects statistics to reveal the distribution of genetic effect estimates across component studies of meta-analyses, highlighting overly influential outlier studies with the potential to inflate genetic signals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Scripts to calculate standardized predicted random-effects statistics and generate forest plots are available in the getspres R package entitled from https:\/\/magosil86.github.io\/getspres\/.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz590","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T19:17:27Z","timestamp":1563995847000},"page":"552-557","source":"Crossref","is-referenced-by-count":3,"title":["Identifying small-effect genetic associations overlooked by the conventional fixed-effect model in a large-scale meta-analysis of coronary artery disease"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3388-9892","authenticated-orcid":false,"given":"Lerato E","family":"Magosi","sequence":"first","affiliation":[{"name":"Wellcome Centre for Human Genetics"},{"name":"Division of Cardiovascular Medicine , Radcliffe Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuj","family":"Goel","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics"},{"name":"Division of Cardiovascular Medicine , Radcliffe Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jemma C","family":"Hopewell","sequence":"additional","affiliation":[{"name":"Nuffield Department of Population Health, University of Oxford , Oxford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4564-2165","authenticated-orcid":false,"given":"Martin","family":"Farrall","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics"},{"name":"Division of Cardiovascular Medicine , Radcliffe Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,7,27]]},"reference":[{"key":"2023013112084563300_btz590-B1","doi-asserted-by":"crossref","first-page":"e1002822.","DOI":"10.1371\/journal.pcbi.1002822","article-title":"Chapter 11: genome-wide association studies","volume":"8","author":"Bush","year":"2012","journal-title":"PLoS Comput. Biol"},{"key":"2023013112084563300_btz590-B2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/ng.784","article-title":"Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease","volume":"43","year":"2011","journal-title":"Nat. Genet"},{"key":"2023013112084563300_btz590-B3","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/ng.3396","article-title":"A comprehensive 1000 genomes-based genome-wide association meta-analysis of coronary artery disease","volume":"47","year":"2015","journal-title":"Nat. Genet"},{"key":"2023013112084563300_btz590-B4","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2307\/3001666","article-title":"The combination of estimates from different experiments","volume":"10","author":"Cochran","year":"1954","journal-title":"Biometrics"},{"key":"2023013112084563300_btz590-B5","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ng.782","article-title":"A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease","volume":"43","year":"2011","journal-title":"Nat. Genet"},{"key":"2023013112084563300_btz590-B6","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.0006-341X.1999.00997.x","article-title":"Genomic control for association studies","volume":"55","author":"Devlin","year":"1999","journal-title":"Biometrics"},{"key":"2023013112084563300_btz590-B7","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.ajhg.2011.04.014","article-title":"Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies","volume":"88","author":"Han","year":"2011","journal-title":"Am. J. Hum. Genet"},{"key":"2023013112084563300_btz590-B8","doi-asserted-by":"crossref","first-page":"17921.","DOI":"10.1038\/s41598-017-18214-z","article-title":"Genome-wide association study identifies a missense variant at APOA5 for coronary artery disease in Multi-Ethnic Cohorts from Southeast Asia","volume":"7","author":"Han","year":"2017","journal-title":"Sci. Rep"},{"key":"2023013112084563300_btz590-B9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1177\/1536867X0800800403","article-title":"Meta-regression in Stata","volume":"8","author":"Harbord","year":"2008","journal-title":"Stata J"},{"key":"2023013112084563300_btz590-B10","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat. Med"},{"key":"2023013112084563300_btz590-B11","doi-asserted-by":"crossref","first-page":"i379","DOI":"10.1093\/bioinformatics\/btx242","article-title":"Increasing the power of meta-analysis of genome-wide association studies to detect heterogeneous effects","volume":"33","author":"Lee","year":"2017","journal-title":"Bioinformatics"},{"key":"2023013112084563300_btz590-B12","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1093\/eurheartj\/ehx254","article-title":"UK Biobank: opportunities for cardiovascular research","volume":"40","author":"Littlejohns","year":"2019","journal-title":"Eur. Heart J."},{"key":"2023013112084563300_btz590-B13","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/ng.2337","article-title":"Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease","volume":"44","author":"Lu","year":"2012","journal-title":"Nat. Genet"},{"key":"2023013112084563300_btz590-B14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1161\/CIRCGENETICS.115.001096","article-title":"Genetic susceptibility to lipid levels and lipid change over time and risk of incident hyperlipidemia in Chinese populations","volume":"9","author":"Lu","year":"2016","journal-title":"Circ. Cardiovasc. Genet"},{"key":"2023013112084563300_btz590-B15","doi-asserted-by":"crossref","first-page":"e1006755","DOI":"10.1371\/journal.pgen.1006755","article-title":"Identifying systematic heterogeneity patterns in genetic association meta-analysis studies","volume":"13","author":"Magosi","year":"2017","journal-title":"PLoS Genet"},{"key":"2023013112084563300_btz590-B16","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ejhg.2012.75","article-title":"Meta-analysis of genetic association studies under heterogeneity","volume":"20","author":"Neupane","year":"2012","journal-title":"Eur. J. Hum. Genet"},{"key":"2023013112084563300_btz590-B17","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/humrep\/deu267","article-title":"Association between endometriosis and the interleukin 1A (IL1A) locus","volume":"30","author":"Sapkota","year":"2015","journal-title":"Hum. Reprod"},{"key":"2023013112084563300_btz590-B18","doi-asserted-by":"crossref","first-page":"15539.","DOI":"10.1038\/ncomms15539","article-title":"Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism","volume":"8","author":"Sapkota","year":"2017","journal-title":"Nat. Commun"},{"key":"2023013112084563300_btz590-B19","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1093\/hmg\/ddx062","article-title":"Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels","volume":"26","author":"Spracklen","year":"2017","journal-title":"Hum. Mol. Genet"},{"key":"2023013112084563300_btz590-B100","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med"},{"key":"2023013112084563300_btz590-B20","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","article-title":"Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease","volume":"122","author":"van der Harst","year":"2018","journal-title":"Circ. Res"},{"key":"2023013112084563300_btz590-B21","doi-asserted-by":"crossref","first-page":"2976.","DOI":"10.1038\/s41467-018-05369-0","article-title":"Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function","volume":"9","author":"Wyss","year":"2018","journal-title":"Nat. Commun"},{"key":"2023013112084563300_btz590-B22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/ng.823","article-title":"Genome partitioning of genetic variation for complex traits using common SNPs","volume":"43","author":"Yang","year":"2011","journal-title":"Nat. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz590\/29192353\/btz590.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/2\/552\/48991744\/btz590.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/2\/552\/48991744\/btz590.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T21:28:45Z","timestamp":1675200525000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/2\/552\/5539865"}},"subtitle":[],"editor":[{"given":"Alfonso","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,7,27]]},"references-count":23,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,1,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz590","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2020,1,15]]},"published":{"date-parts":[[2019,7,27]]}}}