In the context of large-scale multiple testing, hypotheses are often accompanied with certain prior information. In chapter 2, we present a single-index modulated multiple testing procedure, which maintains control of the false discovery rate while incorporating prior information, by assuming the availability of a bivariate p-value for each hypothesis. To find the optimal rejection region for the bivariate p-value, we propose a criteria based on the ratio of probability density functions of the bivariate p-value under the true null and non-null. This criteria in the bivariate normal setting further motivates us to project the bivariate p-value to a single index p-value, for a wide range of directions. The true null distribution of the single index p-value is estimated via parametric and nonparametric approaches, leading to two procedures for estimating and controlling the false discovery rate. To derive the optimal projection direction, we propose a new approach based on power comparison, which is further shown to be consistent under some mild conditions. Multiple testing based on chi-squared test statistics is commonly used in many scientific fields such as genomics research and brain imaging studies. However, the challenges associated with designing a formal testing procedure when there exists a general dependence structure across the chi-squared test statistics have not been well addressed. In chapter 3, we propose a Factor Connected procedure to fill in this gap. We first adopt a latent factor structure to construct a testing framework for approximating the false discovery proportion (FDP) for a large number of highly correlated chi-squared test statistics with finite degrees of freedom k. The testing framework is then connected to simultaneously testing k linear constraints in a large dimensional linear factor model involved with some observable and unobservable common factors, resulting in a consistent estimator of FDP based on the associated unadjusted p-values.

This book establishes the theoretical foundations of a general methodology for multiple hypothesis testing and discusses its software implementation in R and SAS. These are applied to a range of problems in biomedical and genomic research, including identification of differentially expressed and co-expressed genes in high-throughput gene expression experiments; tests of association between gene expression measures and biological annotation metadata; sequence analysis; and genetic mapping of complex traits using single nucleotide polymorphisms. The procedures are based on a test statistics joint null distribution and provide Type I error control in testing problems involving general data generating distributions, null hypotheses, and test statistics.

This thesis aims to develop some new and novel methods in advancing multivariate testing and multiple testing for high-dimensional small sample size data. In Chapter 2, we propose a likelihood ratio test framework for testing normal mean vectors in high-dimensional data under two common scenarios: the one-sample test and the two-sample test with equal covariance matrices. We derive the test statistics under the assumption that the covariance matrices follow a diagonal matrix structure. In comparison with the diagonal Hotelling's tests, our proposed test statistics display some interesting characteristics. In particular, they are a summation of the log-transformed squared t-statistics rather than a direct summation of those components. More importantly, to derive the asymptotic normality of our test statistics under the null and local alternative hypotheses, we do not need the requirement that the covariance matrices follow a diagonal matrix structure. As a consequence, our proposed test methods are very flexible and readily applicable in practice. Monte Carlo simulations and a real data analysis are also carried out to demonstrate the advantages of the proposed methods. In Chapter 3, we propose a pairwise Hotelling's method for testing high-dimensional mean vectors. The new test statistics make a compromise on whether using all the correlations or completely abandoning them. To achieve the goal, we perform a screening procedure, pick up the paired covariates with strong correlations, and construct a classical Hotelling's statistic for each pair. While for the individual covariates without strong correlations with others, we apply squared t statistics to account for their respective contributions to the multivariate testing problem. As a consequence, our proposed test statistics involve a combination of the collected pairwise Hotelling's test statistics and squared t statistics. The asymptotic normality of our test statistics under the null and local alternative hypotheses are also derived under some regularity conditions. Numerical studies and two real data examples demonstrate the efficacy of our pairwise Hotelling's test. In Chapter 4, we propose a regularized t distribution and also explore its applications in multiple testing. The motivation of this topic dates back to microarray studies, where the expression levels of thousands of genes are measured simultaneously by the microarray technology. To identify genes that are differentially expressed between two or more groups, one needs to conduct hypothesis test for each gene. However, as microarray experiments are often with a small number of replicates, Student's t-tests using the sample means and standard deviations may suffer a low power for detecting differentially expressed genes. To overcome this problem, we first propose a regularized t distribution and derive its statistical properties including the probability density function and the moments. The noncentral regularized t distribution is also introduced for the power analysis. To demonstrate the usefulness of the proposed test, we apply the regularized t distribution to the gene expression detection problem. Simulation studies and two real data examples show that the regularized t-test outperforms the existing tests including Student's t-test and the Bayesian t-test in a wide range of settings, in particular when the sample size is small.

Useful Statistical Approaches for Addressing Multiplicity IssuesIncludes practical examples from recent trials Bringing together leading statisticians, scientists, and clinicians from the pharmaceutical industry, academia, and regulatory agencies, Multiple Testing Problems in Pharmaceutical Statistics explores the rapidly growing area of multiple c

Combines recent developments in resampling technology (including the bootstrap) with new methods for multiple testing that are easy to use, convenient to report and widely applicable. Software from SAS Institute is available to execute many of the methods and programming is straightforward for other applications. Explains how to summarize results using adjusted p-values which do not necessitate cumbersome table look-ups. Demonstrates how to incorporate logical constraints among hypotheses, further improving power.

Multiple comparison tests are quite prevalent in clinical trials to increase efficiency and the chance of finding treatment or drug effects. However, making multiple comparisons will lead to the potential inflation of the Type I error rate. How well one test procedure controls the rate of false-positive conclusions becomes the main concern nowadays. A novel method named Covering Principle has been proposed recently. It provides a new approach to designing multiple testing procedures from the angle of rejection regions in the sample space, rather than in the parameter space, which uses in the methods based on the closed testing and partitioning principle. This paper presented several cases studies and a simulation study using Holm's, Fixed and Fallback based on the Covering Principle. Meanwhile, the power comparison results between the Covering Principle and the graphical method are exhibited and analyzed in this paper.