title: Inheritance model introduces differential bias in CNV calls between parents and offspring.
abstract: Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a "Joint-model" as a main component. This models all family members' CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases vs. controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. We show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents and offspring in one multimarker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA.
authors.forename: Sulgi
authors.initials: S
authors.lastname: Kim
authors.forename: Steven P
authors.initials: SP
authors.lastname: Millard
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
authors.forename: Lesley
authors.initials: L
authors.lastname: Leong
authors.forename: Allen
authors.initials: A
authors.lastname: Radant
authors.forename: Dorcas
authors.initials: D
authors.lastname: Dobie
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
mesh_terms: D000465:Algorithms; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D005192:Family Health; D005819:Genetic Markers; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D015233:Models, Statistical; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D005819:Genetic Markers