{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:14Z","timestamp":1772138054833,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-LM012535"],"award-info":[{"award-number":["R01-LM012535"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HG008773"],"award-info":[{"award-number":["R01-HG008773"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brain Pool Plus"},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT","doi-asserted-by":"crossref","award":["2020H1D3A2A03100666"],"award-info":[{"award-number":["2020H1D3A2A03100666"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>In the genome-wide association analysis of population-based biobanks, most diseases have low prevalence, which results in low detection power. One approach to tackle the problem is using family disease history, yet existing methods are unable to address type I error inflation induced by increased correlation of phenotypes among closely related samples, as well as unbalanced phenotypic distribution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We propose a new method for genetic association test with family disease history, mixed-model-based Test with Adjusted Phenotype and Empirical saddlepoint approximation, which controls for increased phenotype correlation by adopting a two-variance-component mixed model, accounts for case\u2013control imbalance by using empirical saddlepoint approximation, and is flexible to incorporate any existing adjusted phenotypes, such as phenotypes from the LT-FH method. We show through simulation studies and analysis of UK Biobank data of white British samples and the Korean Genome and Epidemiology Study of Korean samples that the proposed method is robust and yields better calibration compared to existing methods while gaining power for detection of variant\u2013phenotype associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The summary statistics and code generated in this study are available at https:\/\/github.com\/styvon\/TAPE.<\/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\/btac459","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T10:59:17Z","timestamp":1658746757000},"page":"4337-4343","source":"Crossref","is-referenced-by-count":2,"title":["Incorporating family disease history and controlling case\u2013control imbalance for population-based genetic association studies"],"prefix":"10.1093","volume":"38","author":[{"given":"Yongwen","family":"Zhuang","sequence":"first","affiliation":[{"name":"Center for Statistical Genetics, University of Michigan School of Public Health , Ann Arbor, MI, USA"},{"name":"Department of Biostatistics, University of Michigan School of Public Health , Ann Arbor, MI, USA"}]},{"given":"Brooke N","family":"Wolford","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI, USA"}]},{"given":"Kisung","family":"Nam","sequence":"additional","affiliation":[{"name":"Graduate School of Data Science, Seoul National University , Seoul, Korea"}]},{"given":"Wenjian","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences, Peking University , Beijing, China"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7719-0859","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Broad Institute , Boston, MA, USA"}]},{"given":"Cristen J","family":"Willer","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI, USA"},{"name":"Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School , Ann Arbor, MI, USA"},{"name":"Department of Human Genetics, University of Michigan Medical School , Ann Arbor, MI, USA"}]},{"given":"Bhramar","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan School of Public Health , Ann Arbor, MI, USA"},{"name":"Department of Epidemiology, University of Michigan School of Public Health , Ann Arbor, MI, USA"},{"name":"Michigan Institute of Data Science, University of Michigan , Ann Arbor, MI, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8097-3878","authenticated-orcid":false,"given":"Seunggeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of Data Science, Seoul National University , Seoul, Korea"}]}],"member":"286","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ajhg.2020.06.003","article-title":"A fast and accurate method for genome-wide time-to-event data analysis and its application to UK Biobank","volume":"107","author":"Bi","year":"2020","journal-title":"Am. J. Hum. Genet"},{"key":"2023041408242939500_","article-title":"Genome-wide genetic data on \u223c500,000 UK Biobank participants","author":"Bycroft","year":"2017","journal-title":"preprint at"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1214\/aoms\/1177728652","article-title":"Saddlepoint approximations in statistics","volume":"25","author":"Daniels","year":"1954","journal-title":"Ann. Math. Stat"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/biomet\/75.3.417","article-title":"Saddlepoint approximations in resampling methods","volume":"75","author":"Davison","year":"1988","journal-title":"Biometrika"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"eaay5525","DOI":"10.1126\/sciadv.aay5525","article-title":"Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer","volume":"6","author":"Du","year":"2020","journal-title":"Sci. Adv"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/biomet\/76.3.457","article-title":"On the empirical saddlepoint approximation","volume":"76","author":"Feuerverger","year":"1989","journal-title":"Biometrika"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/ng.3404","article-title":"Partitioning heritability by functional annotation using genome-wide association summary statistics","volume":"47","author":"Finucane","year":"2015","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.2307\/2533274","article-title":"Average information REML: an efficient algorithm for variance parameter estimation in linear mixed models","volume":"51","author":"Gilmour","year":"1995","journal-title":"Biometrics"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/ng.122","article-title":"Many sequence variants affecting diversity of adult human height","volume":"40","author":"Gudbjartsson","year":"2008","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"409","DOI":"10.6028\/jres.049.044","article-title":"Methods of conjugate gradients for solving linear systems","volume":"49","author":"Hestenes","year":"1952","journal-title":"J. Res. Natl. Bur. Stand"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41588-020-0613-6","article-title":"Liability threshold modeling of case\u2013control status and family history of disease increases association power","volume":"52","author":"Hujoel","year":"2020","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198522959.001.0001","volume-title":"Saddlepoint Approximations","author":"Jensen","year":"1995"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/s41588-019-0530-8","article-title":"A resource-efficient tool for mixed model association analysis of large-scale data","volume":"51","author":"Jiang","year":"2019","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1093\/ije\/dyv316","article-title":"Cohort profile: the Korean Genome and Epidemiology Study (KoGES) consortium","volume":"46","author":"Kim","year":"2017","journal-title":"Int. J. Epidemiol"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/nature08625","article-title":"Parental origin of sequence variants associated with complex diseases","volume":"462","author":"Kong","year":"2009","journal-title":"Nature"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1093\/biomet\/86.4.929","article-title":"Saddlepoint approximations for distributions of quadratic forms in normal variables","volume":"86","author":"Kuonen","year":"1999","journal-title":"Biometrika"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/ng.3766","article-title":"Case-control association mapping by proxy using family history of disease","volume":"49","author":"Liu","year":"2017","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/ng.3190","article-title":"Efficient Bayesian mixed-model analysis increases association power in large cohorts","volume":"47","author":"Loh","year":"2015","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","article-title":"Robust relationship inference in genome-wide association studies","volume":"26","author":"Manichaikul","year":"2010","journal-title":"Bioinformatics"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/ng.3643","article-title":"A reference panel of 64,976 haplotypes for genotype imputation","volume":"48","author":"McCarthy","year":"2016","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.je.2016.12.005","article-title":"Overview of the BioBank Japan project: study design and profile","volume":"27","author":"Nagai","year":"2017","journal-title":"J. Epidemiol"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1101\/gr.169375.113","article-title":"MultiBLUP: improved SNP-based prediction for complex traits","volume":"24","author":"Speed","year":"2014","journal-title":"Genome Res"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/ng.2410","article-title":"Rapid variance components\u2013based method for whole-genome association analysis","volume":"44","author":"Svishcheva","year":"2012","journal-title":"Nat. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1111\/cas.13815","article-title":"Genome-wide association study identifies gastric cancer susceptibility loci at 12q24. 11-12 and 20q11. 21","volume":"109","author":"Tanikawa","year":"2018","journal-title":"Cancer Sci"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1086\/519497","article-title":"Case-control association testing with related individuals: a more powerful quasi-likelihood score test","volume":"81","author":"Thornton","year":"2007","journal-title":"Am. J. Hum. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.ajhg.2015.10.002","article-title":"Two-variance-component model improves genetic prediction in family datasets","volume":"97","author":"Tucker","year":"2015","journal-title":"Am. J. Hum. Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep06874","article-title":"Further improvements to linear mixed models for genome-wide association studies","volume":"4","author":"Widmer","year":"2014","journal-title":"Sci. Rep"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/gutjnl-2019-318760","article-title":"Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations","volume":"69","author":"Yan","year":"2020","journal-title":"Gut"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"e1003520","DOI":"10.1371\/journal.pgen.1003520","article-title":"Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits","volume":"9","author":"Zaitlen","year":"2013","journal-title":"PLoS Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"e1006329","DOI":"10.1371\/journal.pgen.1006329","article-title":"CERAMIC: case-control association testing in samples with related individuals, based on retrospective mixed model analysis with adjustment for covariates","volume":"12","author":"Zhong","year":"2016","journal-title":"PLoS Genet"},{"key":"2023041408242939500_","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btac459\/45083034\/btac459.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/18\/4337\/49885422\/btac459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/38\/18\/4337\/49885422\/btac459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T18:10:36Z","timestamp":1700849436000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/38\/18\/4337\/6649715"}},"subtitle":[],"editor":[{"given":"Russell","family":"Schwartz","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":33,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2022,9,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btac459","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.07.04.21259997","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9,15]]},"published":{"date-parts":[[2022,7,25]]}}}