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This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g., within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affected is required. Here, we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene\u2010based analyses, a partial sharing test based on RV sharing probabilities for subsets of affected relatives and a haplotype\u2010based RV definition. RVS also has the desirable feature of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome\u2010wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared with alternative methods (RareIBD and the Gene\u2010Based Segregation Test), and had superior power compared with the pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests.<\/jats:p>","DOI":"10.1002\/gepi.22155","type":"journal-article","created":{"date-parts":[[2018,9,24]],"date-time":"2018-09-24T05:14:49Z","timestamp":1537766089000},"page":"37-49","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-9999","authenticated-orcid":false,"given":"Alexandre","family":"Bureau","sequence":"first","affiliation":[{"name":"D\u00e9partement de M\u00e9decine Sociale et Pr\u00e9ventive Universit\u00e9 Laval Qu\u00e9bec City Qu\u00e9bec Canada"},{"name":"Centre de recherche CERVO Qu\u00e9bec City Qu\u00e9bec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferdouse","family":"Begum","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret A.","family":"Taub","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Johns Hopkins Bloomberg School of Public Health Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline B.","family":"Hetmanski","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret M.","family":"Parker","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hasan","family":"Albacha\u2010Hejazi","sequence":"additional","affiliation":[{"name":"Prime Health Clinic\u202f Jeddah Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan F.","family":"Scott","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine Johns Hopkins Medical Institutions Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics School of Medicine, University of Iowa Iowa City Iowa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[{"name":"Department of Oral Biology School of Dental Medicine, University of Pittsburgh Pittsburgh Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-2920","authenticated-orcid":false,"given":"Joan E.","family":"Bailey\u2010Wilson","sequence":"additional","affiliation":[{"name":"Inherited Disease Research Branch National Human Genome Research Institute Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingo","family":"Ruczinski","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Johns Hopkins Bloomberg School of Public Health Baltimore 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