The chapters of this thesis focus two different issues that arise in clinical trials and propose novel methods to address them. The first issue arises in the analysis of data with non-ignorable missing observations. The second issue concerns the development of methods that provide physicians better tools to understand and treat diseases efficiently by using each patient's characteristics and personal biomedical profile. Inherent to most clinical trials is the issue of missing data, specially those that arise when patients drop out the study without further measurements. Proper handling of missing data is crucial in all statistical analyses because disregarding missing observations can lead to biased results. In the first two chapters of this thesis, we deal with the "worst-rank score" missing data imputation technique in pretest-posttest clinical trials. Subjects are randomly assigned to two treatments and the response is recorded at baseline prior to treatment (pretest response), and after a pre-specified follow-up period (posttest response). The treatment effect is then assessed on the change in response from baseline to the end of follow-up time. Subjects with missing response at the end of follow-up are assign values that are worse than any observed response (worst-rank score). Data analysis is then conducted using Wilcoxon-Mann-Whitney test. In the first chapter, we derive explicit closed-form formulas for power and sample size calculations using both tied and untied worst-rank score imputation, where the worst-rank scores are either a fixed value (tied score) or depend on the time of withdrawal (untied score). We use simulations to demonstrate the validity of these formulas. In addition, we examine and compare four different simplification approaches to estimate sample sizes. These approaches depend on whether data from the literature or a pilot study are available. In second chapter, we introduce the weighted Wilcoxon-Mann-Whitney test on un-tied worst-rank score (composite) outcome. First, we demonstrate that the weighted test is exactly the ordinary Wilcoxon-Mann-Whitney test when the weights are equal. Then, we derive optimal weights that maximize the power of the corresponding weighted Wilcoxon-Mann-Whitney test. We prove, using simulations, that the weighted test is more powerful than the ordinary test. Furthermore, we propose two different step-wise procedures to analyze data using the weighted test and assess their performances through simulation studies. Finally, we illustrate the new approach using data from a recent randomized clinical trial of normobaric oxygen therapy on patients with acute ischemic stroke. The third and last chapter of this thesis concerns the development of robust methods for treatment groups identification in personalized medicine. As we know, physicians often have to use a trial-and-error approach to find the most effective medication for their patients. Personalized medicine methods aim at tailoring strategies for disease prevention, detection or treatment by using each individual subject's personal characteristics and medical profile. This would result to (1) better diagnosis and earlier interventions, (2) maximum therapeutic benefits and reduced adverse events, (3) more effective therapy, and (4) more efficient drug development. Novel methods have been proposed to identify subgroup of patients who would benefit from a given treatment. In the last chapter of this thesis, we develop a robust method for treatment assignment for future patients based on the expected total outcome. In addition, we provide a method to assess the incremental value of new covariate(s) in improving treatment assignment. We evaluate the accuracy of our methods through simulation studies and illustrate them with two examples using data from two HIV/AIDS clinical trials.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/10288942 |
| Date | January 2012 |
| Creators | Matsouaka, Roland Albert |
| Contributors | Betensky, Rebecca Aubrey, Cai, Tianxi |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | closed access |
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