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The main research topic in this dissertation is the development of the closure method of multiple testing procedures. Considering a general procedure that allows the underlying test statistics as well as the associated parameters to be dependent, we first propose a step-down procedure controlling the FWER, which is defined as the probability of committing at least one false discovery. Holm (1979) first proposed a step-down procedure for multiple hypothesis testing with a control of the familywise error rate (FWER) under any kind of dependence. Under the normal distributional setup, Seneta and Chen (2005) sharpened the Holm procedure by taking into account the correlations between the test statistics. In this dissertation, the Seneta-Chen procedure is further modified yielding a more powerful FWER controlling procedure. We then advance our research and propose another step-down procedure to control the generalized FWER (k-FWER), which is defined as the probability of making at least k false discoveries. We compare our proposed k-FWER procedure with the Lehmann and Romano (2005) procedure. The proposed k-FWER procedure is more powerful, particularly when there is a strong dependence in the tests. When the proportion of true null hypotheses is expected to be small, the traditional tests are usually conservative by a factor associated with pi0, which is the proportion of true null hypotheses among all null hypotheses. Under independence, two procedures controlling the FWER and the k-FWER are proposed in this dissertation. Simulations are carried out to show that our procedures often provide much better FWER or k-FWER control and power than the traditional procedures. / Statistics

With increased pressures from governmental and insurance agencies, today's physician devotes less time to patient care and more time to administration. To alleviate this problem, Biological & Popular Culture, Inc. (Biopop) proposed the building of partnerships with healthcare professionals to provide high-quality, cost-effective medical care in a physician network setting. To assist Biopop in evaluating potential operating procedures, a discrete-event simulation model has been constructed. The model is built in an object-oriented, visual manner utilizing the Visual Simulation Environment (VSE). The model examines both internal Biopop operations and external clinic operations. The research presented herein describes the design of the simulation model and details the analysis of the clinical environment. A methodology for determining appropriate staffing and physical resources in a clinical environment is presented. This methodology takes advantage of several simulation-based statistical techniques, including batch means; fractional factorial design; and simultaneous ranking, selection, and multiple comparisons. An explanation of the experimental design is provided and results of the experimentation are presented. Based upon the experimental results, conclusions are drawn and recommendations are made for an appropriate staffing and facility size for a two-physician family practice healthcare clinic. / Master of Science

The problem of this study was to determine the differences in experimentwise and comparisonwise Type I error rate among six multiple comparison procedures when applied to twenty-eight combinations of normally distributed data. These were the Least Significant Difference, the Fisher-protected Least Significant Difference, the Student Newman-Keuls Test, the Duncan Multiple Range Test, the Tukey Honestly Significant Difference, and the Scheffe Significant Difference. The Spjøtvoll-Stoline and Tukey—Kramer HSD modifications were used for unequal n conditions. A Monte Carlo simulation was used for twenty-eight combinations of k and n. The scores were normally distributed (µ=100; σ=10). Specified multiple comparison procedures were applied under two conditions: (a) all experiments and (b) experiments in which the F-ratio was significant (0.05). Error counts were maintained over 1000 repetitions. The FLSD held experimentwise Type I error rate to nominal alpha for the complete null hypothesis. The FLSD was more sensitive to sample mean differences than the HSD while protecting against experimentwise error. The unprotected LSD was the only procedure to yield comparisonwise Type I error rate at nominal alpha. The SNK and MRT error rates fell between the FLSD and HSD rates. The SSD error rate was the most conservative. Use of the harmonic mean of the two unequal sample n's (HSD-TK) yielded uniformly better results than use of the minimum n (HSD-SS). Bernhardson's formulas controlled the experimentwise Type I error rate of the LSD and MRT to nominal alpha, but pushed the HSD below the 0.95 confidence interval. Use of the unprotected HSD produced fewer significant departures from nominal alpha. The formulas had no effect on the SSD.

Two-arm group sequential designs have been widely used for over forty years, especially for studies with mortality endpoints. The natural generalization of such designs to trials with multiple treatment arms and a common control (MAMS designs) has, however, been implemented rarely. While the statistical methodology for this extension is clear, the main limitation has been an efficient way to perform the computations. Past efforts were hampered by algorithms that were computationally explosive. With the increasing interest in adaptive designs, platform designs, and other innovative designs that involve multiple comparisons over multiple stages, the importance of MAMS designs is growing rapidly. This dissertation proposes a group sequential approach to design MAMS trial where the test statistic is the maximum of the cumulative score statistics for each pair-wise comparison, and is evaluated at each analysis time point with respect to efficacy and futility stopping boundaries while maintaining strong control of the family wise error rate (FWER). In this dissertation we start with a break-through algorithm that will enable us to compute MAMS boundaries rapidly. This algorithm will make MAMS design a practical reality. For designs with efficacy-only boundaries, the computational effort increases linearly with number of arms and number of stages. For designs with both efficacy and futility boundaries the computational effort doubles with successive increases in number of stages. Previous attempts to obtain MAMS boundaries were confined to smaller problems because their computational effort grew exponentially with number of arms and number of stages. We will next extend our proposed group sequential MAMS design to permit adaptive changes such as dropping treatment arms and increasing the sample size at each interim analysis time point. In order to control the FWER in the presence of these adaptations the early stopping boundaries must be re-computed by invoking the conditional error rate principle and the closed testing principle. This adaptive MAMS design is immensely useful in phase~2 and phase~3 settings. An alternative to the group sequential approach for MAMS design is the p-value combination approach. This approach has been in place for the last fifteen years.This alternative MAMS approach is based on combining independent p-values from the incremental data of each stage. Strong control of the FWER for this alternative approach is achieved by closed testing. We will compare the operating characteristics of the two approaches both analytically and empirically via simulation. In this dissertation we will demonstrate that the MAMS group sequential approach dominates the traditional p-value combination approach in terms of statistical power.

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