title: Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study.
abstract: A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (http://zhaocenter.org/software/).
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Hou
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Fred
authors.initials: F
authors.lastname: Sayward
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Nallakkandi
authors.initials: N
authors.lastname: Rajeevan
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Kei-Hoi
authors.initials: KH
authors.lastname: Cheung
authors.affiliation: Massachusetts Area Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Cho
authors.affiliation: Massachusetts Area Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Saiju
authors.initials: S
authors.lastname: Pyarajan
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Aslan
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Center for Medical Informatics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Perry
authors.initials: P
authors.lastname: Miller
authors.affiliation: Bruce W. Carter Miami Veterans Affairs (VA) Medical Center, Miami, Florida, United States of America.|Department of Psychiatry, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Harvey
authors.affiliation: Massachusetts Area Veterans Epidemiology Research and Information Center (MAVERIC), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts, United States of America.|Department of Medicine, Harvard University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Concato
authors.affiliation: Clinical Epidemiology Research Center (CERC), Veterans Affairs (VA) Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America.|Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000465:Algorithms; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D023281:Genomics / Q000379:methods*; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000592:standards*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011786:Quality Control; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D005819:Genetic Markers
keywords: genome wide association test; genotyping; genotyping error; sequencing; statistical power