A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

Consumer satisfaction with primary care provider choice and associated trust

Trust is important in medical relationships and for the achievement of better health outcomes. Developments in managed care in the recent years are believed to affect the quality of healthcare services delivery and to undermine trust in the healthcare provider. Physician choice has been identified as a strong predictor of provider trust but has not been studied in detail. Consumer satisfaction with primary care provider (PCP) choice includes having or not having physician choice. This dissertation developed a conceptual framework that guided the study of consumer satisfaction with PCP choice as a predictor of provider trust, and conducted secondary data analyses examining the association between PCP choice and trust, by identifying factors related to PCP choice satisfaction, and their relative importance in predicting provider trust. The study specific aims were: (1) to determine variables related to the factors: consumer characteristics and health status, information and consumer decision-making, consumer trust in providers in general and trust in the insurer, health plan financing and plan characteristics, and provider characteristics that may relate to PCP choice satisfaction; (2) to determine if the factors in aim one are related to PCP choice satisfaction; and (3) to analyze the association between PCP choice satisfaction and provider trust, controlling for potential confounders. Analyses were based on secondary data from a random national telephone survey in 1999, of residential households in the United States which included respondents aged over 20 and who had at least two visits with a health professional in the past two years. Among 1,117 eligible households interviewed (response rate 51.4%), 564 randomly selected to respond to insurer related questions made up the study sample. Analyses using descriptive statistics, and linear and logistic regressions found continual effective care and interaction with the PCP beyond the medical setting most predictive of PCP choice satisfaction. Four PCP choice satisfaction factors were also predictive of provider trust. Findings highlighted the importance of the PCP's professional and interpersonal competencies for the development of sustainable provider trust. Future research on the access, utilization, cognition, and helpfulness of provider specific information will further our understanding of consumer choice and trust. ^

Introduction to public health preparedness for disaster and emergency response

The unprecedented attacks of September 11, 2001, and the subsequent anthrax-related events thrust our nation's often forgotten public health system into the forefront of public attention. A strong public health system with a well-prepared workforce plays a critical role in preparing for and responding to the threat of bioterrorism and other disasters and emergencies. Technical expertise is critical as is a basic awareness and understanding of core public health competencies especially as they relate to disaster and emergency response is also imperative for a public health agency to function as a vital Emergency Response team member. Ideally this training should begin at the Public Health graduate level so as to provide the baseline core tools to be able to function as a vital team member when they are practicing out in the real world. Online learning is an efficient and effective method for providing public health education to in a flexible format to meet the needs of busy student-professions. This Public Health Disaster Preparedness online course developed during an Emergency Response state program practicum is a practical and proficient approach to accomplish this endeavor. ^

Role of T cell response during vaccine immunity to tuberculosis

Tuberculosis remains one of the leading causes of death in man due to a single infectious agent. An estimated one-third of the world's population is infected with the causative agent, Mycobacterium tuberculosis (Mtb), despite the availability of the widely used vaccine, BCG. BCG has significantly varying protection rates with the lowest level of protection seen with the most common form of TB, adult pulmonary TB. Thus, numerous studies are being conducted to develop a more efficient vaccine. The ideal candidate vaccine would possess the ability to induce a solid and strong Th1 response, as this is the subset of T cells primarily involved in clearance of the infection. A novel vaccine should also induce such a response that may be recalled and expanded upon subsequent infection. Our group has introduced a mutant of a virulent strain of Mtb which lacks a component of the immunogenic antigen 85 complex (Ag85). Our vaccine, ΔfbpA, does not secrete the fibronectin binding protein Ag85A, and this has shown to lead to its attenuation in both murine macrophages and mice. Previous studies have also proven that ΔfbpA is more protective in mice than BCG against virulent aerosol challenge with Mtb. This study addresses the mechanisms of protection observed with ΔfbpA by phenotyping responding T cells. We first evaluated the ability of dendritic cells to present the mycobacteria to naïve T cells, an in vitro mock of primary immunization. We also measured the response of primed T cells to macrophage-presented mycobacteria to interpret the possible response of a vaccinated host to a boost. We concluded that ΔfbpA can elicit a stronger Th1 response compared to BCG in vitro, and further observed that this enhanced response is at least partly due to the presence of proteins encoded by a region of the genome absent in all strains of BCG. Finally, we observed this heightened Th1 response in the mouse model after primary vaccination and a virulent aerosol challenge. The cytolytic T cell response was also measured after virulent challenge and was found to be superior in the ΔfbpA-treated group when compared to the BCG group. ^