Type of Document	Dissertation
Author	Abebe, Kaleab Zenebe
URN	etd-06222009-134007
Title	A Study of Treatment-by-Site Interaction in Multisite Clinical Trials
Degree	Doctor of Philosophy
Program	Statistics
School	School of Arts and Sciences
Advisory Committee	Advisor Name Title Satish Iyengar Committee Chair Allan R. Sampson Committee Member David A. Brent Committee Member Leon J. Gleser Committee Member
Keywords	mediation interaction site differences mediated moderation moderation clinical trials
Date of Defense	2009-06-25
Availability	restricted
Abstract Currently, there is little discussion about methods to explain treatment-by-site interaction in multisite clinical trials, so investigators are left to explain these differences post-hoc with no formal statistical tests in the literature. Using mediated moderation techniques, three significance tests used to detect mediation are extended to the multisite setting. Explicit power functions are derived and compared. In the two-site case, the mediated moderation framework is utilized to test two difference-in-coefficients and one product-of-coefficients type tests. The test in the latter group is based on the product of two independent standard normal variables, which is a modified Bessel function of the second kind. Because the alternative distribution does not have a closed form expression, power is approximated using Gauss-Hermite quadrature. This test suffers from an inflated type I error, so two modifications are proposed: a combination of intersection-union and union-intersection tests; and one based on a variance stabilizing transformation. In addition, a modification of one of the difference-in-coefficients tests is proposed. The tests are also extended to deal with multiple sites in the ANOVA and logistic regres- sion models, and the groundwork has been laid to account for multiple mediators as well. The contribution of this is a group of formal significance tests for explaining treatment- by-site interaction in the multisite clinical trial setting. This will serve to inform the design of future clinical trials by accounting for this site-level variability. The proposed methodol- ogy is illustrated in the analysis of the Treatment of SSRI-Resistant Depression in Adolescents study conducted across six sites coordinated at the University of Pittsburgh.
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