title: gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels.
abstract: Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Larson
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: McDonnell
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cannon Albright
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Teerlink
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Janet
authors.initials: J
authors.lastname: Stanford
authors.affiliation: National Human Genome Research Institute, Bethesda, Maryland, United States of America.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Brady Urological Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: NorthShore University HealthSystem Research Institute, Chicago, Illinois, United States of America.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.|Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Ethan
authors.initials: E
authors.lastname: Lange
authors.affiliation: Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
authors.affiliation: Department of Translational Genomics, University of Southern California, Los Angeles, California, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.affiliation: Department of Urology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Isaac
authors.initials: I
authors.lastname: Powell
authors.affiliation: Statistical Genetics Section, National Human Genome Research Institute, Bethesda, Maryland, United States of America.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: CeRePP, Hopital Tenon, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cussenot
authors.affiliation: CeRePP, Hopital Tenon, Paris, France.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cancel-Tassin
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: MacInnis
authors.affiliation: Department of Urology, University of Ulm, Ulm, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.affiliation: Department of Health Research and Policy, Stanford University, Stanford, California, United States of America.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.affiliation: Department of Urology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Hsieh
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Catalona
authors.affiliation: Department of Oncology, Montreal General Hospital, Montreal, Quebec, Canada.|Department of Human Genetics, Montreal General Hospital, Montreal, Quebec, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Foulkes
authors.affiliation: Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Diptasri
authors.initials: D
authors.lastname: Mandal
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: The Institute of Cancer Research, London, UK.|The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
authors.affiliation: Department of Laboratory Medicine/Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D018401:Sample Size; D018709:Statistics, Nonparametric
keywords: gene set; next-generation sequencing; pathway; rare variation