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A central but challenging problem in genetic studies is to test for (usually weak) associations between a complex trait (e.g., a disease status) and sets of multiple genetic variants. Due to the lack of a uniformly most powerful test, data‐adaptive tests, such as the adaptive sum of powered score (aSPU) test, are advantageous in maintaining high power against a wide range of alternatives. However, there is often no closed‐form to accurately and analytically calculate thep‐values of many adaptive tests like aSPU, thus Monte Carlo (MC) simulations are often used, which can be time consuming to achieve a stringent significance level (e.g., 5e‐8) used in genome‐wide association studies (GWAS). To estimate such a smallp‐value, we need a huge number of MC simulations (e.g., 1e+10). As an alternative, we propose using importance sampling to speed up such calculations. We develop some theory to motivate a proposed algorithm for the aSPU test, and show that the proposed method is computationally more efficient than the standard MC simulations. Using both simulated and real data, we demonstrate the superior performance of the new method over the standard MC simulations.

 

Panel count data arise when the number of recurrent events experienced by each subject is observed intermittently at discrete examination times. The examination time process can be informative about the underlying recurrent event process even after conditioning on covariates. We consider a semiparametric accelerated mean model for the recurrent event process and allow the two processes to be correlated through a shared frailty. The regression parameters have a simple marginal interpretation of modifying the time scale of the cumulative mean function of the event process. A novel estimation procedure for the regression parameters and the baseline rate function is proposed based on a conditioning technique. In contrast to existing methods, the proposed method is robust in the sense that it requires neither the strong Poisson-type assumption for the underlying recurrent event process nor a parametric assumption on the distribution of the unobserved frailty. Moreover, the distribution of the examination time process is left unspecified, allowing for arbitrary dependence between the two processes. Asymptotic consistency of the estimator is established, and the variance of the estimator is estimated by a model-based smoothed bootstrap procedure. Numerical studies demonstrated that the proposed point estimator and variance estimator perform well with practical sample sizes. The methods are applied to data from a skin cancer chemoprevention trial.

 

Abstract Wilk’s theorem, which offers universal chi-squared approximations for likelihood ratio tests, is widely used in many scientific hypothesis testing problems. For modern datasets with increasing dimension, researchers have found that the conventional Wilk’s phenomenon of the likelihood ratio test statistic often fails. Although new approximations have been proposed in high dimensional settings, there still lacks a clear statistical guideline regarding how to choose between the conventional and newly proposed approximations, especially for moderate-dimensional data. To address this issue, we develop the necessary and sufficient phase transition conditions for Wilk’s phenomenon under popular tests on multivariate mean and covariance structures. Moreover, we provide an in-depth analysis of the accuracy of chi-squared approximations by deriving their asymptotic biases. These results may provide helpful insights into the use of chi-squared approximations in scientific practices.