title: Blindly using Wald's test can miss rare disease-causal variants in case-control association studies.
abstract: There are four tests--the likelihood ratio (LR) test, Wald's test, the score test and the exact test--commonly employed in genetic association studies. On comparison of the four tests, we found that Wald's test, popular in genome-wide screens due to its low computational demands, exhibited a paradoxical behaviour in that the test statistic decreased as the effect size of the variant increased, resulting in a loss of power. The LR test always achieved the most significant P-values, followed by the exact test. We further examined the results in a real data set composed of high- and low-cholesterol subjects from the Dallas Heart Study (DHS). We also compared the single-variant LR test with two multi-variant analysis approaches--the burden test and the C-alpha test--in analysing the sequencing data by simulation. Our results call for caution in using Wald's test in genome-wide case-control association studies and suggest that the LR test is a better alternative in spite of its computational demands.
authors.affiliation: Bristol-Myers Squibb Company, Pennington, NJ, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Xing
authors.forename: Chang-Yun
authors.initials: CY
authors.lastname: Lin
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wooding
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
mesh_terms: D016022:Case-Control Studies; D056726:Genetic Association Studies / Q000379:methods*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D035583:Rare Diseases / Q000235:genetics*; D054928:Validation Studies as Topic