Rare variant association testing by adaptive combination of P-values.
With the development of next-generation sequencing technology, there is a great demand for powerful statistical methods to detect rare variants (minor allele frequencies (MAFs)<1%) associated with diseases. Testing for each variant site individually is known to be underpowered, and therefore many methods have been proposed to test for the association of a group of variants with phenotypes, by pooling signals of the variants in a chromosomal region. However, this pooling strategy inevitably leads to the inclusion of a large proportion of neutral variants, which may compromise the power of association tests. To address this issue, we extend the [Formula: see text]-MidP method (Cheung et al., 2012, Genet Epidemiol 36: 675-685) and propose an approach (named 'adaptive combination of P-values for rare variant association testing', abbreviated as 'ADA') that adaptively combines per-site P-values with the weights based on MAFs. Before combining P-values, we first imposed a truncation threshold upon the per-site P-values, to guard against the noise caused by the inclusion of neutral variants. This ADA method is shown to outperform popular burden tests and non-burden tests under many scenarios. ADA is recommended for next-generation sequencing data analysis where many neutral variants may be included in a functional region.
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Wan-Yu
WY
Lin
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Xiang-Yang
XY
Lou
Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Guimin
G
Gao
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Nianjun
N
Liu
D000465:Algorithms; D016022:Case-Control Studies; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods*; D006331:Heart Diseases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016014:Linear Models; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012984:Software