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Inheritance Model Introduces Differential Bias in CNV Calls Between Parents and Offspring
Author(s) -
Kim Sulgi,
Millard Steven P.,
Yu ChangEn,
Leong Lesley,
Radant Allen,
Dobie Dorcas,
Tsuang Debby W.,
Wijsman Ellen M.
Publication year - 2012
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.21643
Subject(s) - offspring , copy number variation , inference , pedigree chart , inheritance (genetic algorithm) , covariate , psychology , computer science , genetics , biology , gene , artificial intelligence , machine learning , pregnancy , genome
Copy Number Variation ( CNV ) is increasingly implicated in disease pathogenesis. CNV s 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 Penn CNV (the J oint‐call and P osterior‐call), which are some of the most well‐developed family‐based CNV calling methods, use a “ J oint‐model” as a main component. This models all family members’ CNV states together with M endelian inheritance. Methods based on the J oint‐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 J oint‐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 J oint‐model can introduce different CNV call rates among family members in the absence of a true difference. We show that the J oint‐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 P enn CNV 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 J oint‐model calls in CNV association studies with family‐based datasets. Genet. Epidemiol. 36:488‐498, 2012. © 2012 Wiley Periodicals, Inc.