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Transmission-based approaches provide robustness against population stratification, but the evaluation of the significance of test statistics based on asymptotic theory can be imprecise. Also, power will depend heavily on the choice of the test statistic and on the underlying genetic architecture of the locus, which will be generally unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In our proposed framework, we utilize the FBAT haplotype algorithm to obtain the conditional offspring genotype distribution under the null hypothesis given the sufficient statistic. Based on this conditional offspring genotype distribution, the significance of virtually any association test statistic can be evaluated based on simulations or exact computations, without the need for asymptotic approximations. Besides standard linear burden-type statistics, this enables our approach to also evaluate other test statistics such as variance components statistics, higher criticism approaches, and maximum-single-variant-statistics, where asymptotic theory might be involved or does not provide accurate approximations for rare variant data. Based on these P-values, combined test statistics such as the aggregated Cauchy association test (ACAT) can also be utilized. In simulation studies, we show that our framework outperforms existing approaches for family-based studies in several scenarios. We also applied our methodology to a TOPMed whole-genome sequencing dataset with 897 asthmatic trios from Costa Rica.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>FBAT software is available at https:\/\/sites.google.com\/view\/fbatwebpage. Simulation code is available at https:\/\/github.com\/julianhecker\/FBAT_rare_variant_test_simulations. Whole-genome sequencing data for \u2018NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica\u2019 is available at https:\/\/www.ncbi.nlm.nih.gov\/projects\/gap\/cgi-bin\/study.cgi?study_id=phs000988.v4.p1.<\/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\/btaa1055","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T01:56:16Z","timestamp":1607651776000},"page":"5432-5438","source":"Crossref","is-referenced-by-count":8,"title":["A unifying framework for rare variant association testing in family-based designs, including higher criticism approaches, SKATs, and burden tests"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-089X","authenticated-orcid":false,"given":"Julian","family":"Hecker","sequence":"first","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"F William","family":"Townes","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Princeton University , Princeton, NJ 08540-5233, USA"}]},{"given":"Priyadarshini","family":"Kachroo","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"Cecelia","family":"Laurie","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Washington , Seattle, WA 98195-1617, USA"}]},{"given":"Jessica","family":"Lasky-Su","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"John","family":"Ziniti","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"Michael H","family":"Cho","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"Scott T","family":"Weiss","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115, USA"}]},{"given":"Nan M","family":"Laird","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Harvard T.H. Chan School of Public Health , Boston, MA 02115, USA"}]},{"given":"Christoph","family":"Lange","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Harvard T.H. Chan School of Public Health , Boston, MA 02115, USA"}]}],"member":"286","published-online":{"date-parts":[[2020,12,26]]},"reference":[{"key":"2023062708444874800_btaa1055-B1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","year":"2015","journal-title":"Nature"},{"key":"2023062708444874800_btaa1055-B2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1080\/01621459.2016.1192039","article-title":"The generalized higher criticism for testing SNP-set effects in genetic association studies","volume":"112","author":"Barnett","year":"2017","journal-title":"J. Am. Stat. 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