title: Testing for an unusual distribution of rare variants.
abstract: Technological advances make it possible to use high-throughput sequencing as a primary discovery tool of medical genetics, specifically for assaying rare variation. Still this approach faces the analytic challenge that the influence of very rare variants can only be evaluated effectively as a group. A further complication is that any given rare variant could have no effect, could increase risk, or could be protective. We propose here the C-alpha test statistic as a novel approach for testing for the presence of this mixture of effects across a set of rare variants. Unlike existing burden tests, C-alpha, by testing the variance rather than the mean, maintains consistent power when the target set contains both risk and protective variants. Through simulations and analysis of case/control data, we demonstrate good power relative to existing methods that assess the burden of rare variants in individuals.
authors.affiliation: The Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States of America. bneale@broadinstitute.org
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D000465:Algorithms; D000704:Analysis of Variance; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical