title: The admixture maximum likelihood test to test for association between rare variants and disease phenotypes.
abstract: BACKGROUND
  The development of genotyping arrays containing hundreds of thousands of rare variants across the genome and advances in high-throughput sequencing technologies have made feasible empirical genetic association studies to search for rare disease susceptibility alleles. As single variant testing is underpowered to detect associations, the development of statistical methods to combine analysis across variants - so-called "burden tests" - is an area of active research interest. We previously developed a method, the admixture maximum likelihood test, to test multiple, common variants for association with a trait of interest. We have extended this method, called the rare admixture maximum likelihood test (RAML), for the analysis of rare variants. In this paper we compare the performance of RAML with six other burden tests designed to test for association of rare variants.
  
  
  RESULTS
  We used simulation testing over a range of scenarios to test the power of RAML compared to the other rare variant association testing methods. These scenarios modelled differences in effect variability, the average direction of effect and the proportion of associated variants. We evaluated the power for all the different scenarios. RAML tended to have the greatest power for most scenarios where the proportion of associated variants was small, whereas SKAT-O performed a little better for the scenarios with a higher proportion of associated variants.
  
  
  CONCLUSIONS
  The RAML method makes no assumptions about the proportion of variants that are associated with the phenotype of interest or the magnitude and direction of their effect. The method is flexible and can be applied to both dichotomous and quantitative traits and allows for the inclusion of covariates in the underlying regression model. The RAML method performed well compared to the other methods over a wide range of scenarios. Generally power was moderate in most of the scenarios, underlying the need for large sample sizes in any form of association testing.
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. jpt34@medschl.cam.ac.uk
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Tyrer
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
mesh_terms: D004194:Disease / Q000235:genetics*; D004198:Disease Susceptibility; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D010641:Phenotype