Bayesian Adaptive Designs for Early Phase Clinical Trials

My dissertation focuses mainly on Bayesian adaptive designs for phase I and phase II clinical trials. It includes three specific topics: (1) proposing a novel two-dimensional dose-finding algorithm for biological agents, (2) developing Bayesian adaptive screening designs to provide more efficient and ethical clinical trials, and (3) incorporating missing late-onset responses to make an early stopping decision. Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which toxicity and efficacy monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a phase I/II trial design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Simulation studies show that the proposed design substantially outperforms the conventional multi-arm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while at the same time allocating substantially more patients to efficacious treatments. The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while at the same time providing higher power to identify the best treatment at the end of the trial. Phase II trial studies usually are single-arm trials which are conducted to test the efficacy of experimental agents and decide whether agents are promising to be sent to phase III trials. Interim monitoring is employed to stop the trial early for futility to avoid assigning unacceptable number of patients to inferior treatments. We propose a Bayesian single-arm phase II design with continuous monitoring for estimating the response rate of the experimental drug. To address the issue of late-onset responses, we use a piece-wise exponential model to estimate the hazard function of time to response data and handle the missing responses using the multiple imputation approach. We evaluate the operating characteristics of the proposed method through extensive simulation studies. We show that the proposed method reduces the total length of the trial duration and yields desirable operating characteristics for different physician-specified lower bounds of response rate with different true response rates.

A systematic review of economic evaluations for interventions of cardiovascular diseases

Background. Cardiovascular disease (CVD) exhibits the most striking public health significance due to its high prevalence and mortality as well as huge economic burdens all over the world, especially in industrialized countries. Major risk factors of CVDs have been the targets of population-wide prevention in the United States. Economic evaluations provide structured information in regard to the efficiency of resource utilization which can inform decisions of resource allocation. The main purpose of this review is to investigate the pattern of study design of economic evaluations for interventions of CVDs. ^ Methods. Primary journal articles published during 2003-2008 were systematically retrieved via relevant keywords from Medline, NHS Economic Evaluation Database (NHS EED) and EBSCO Academic Search Complete. Only full economic evaluations for narrowly defined CVD interventions were included for this review. The methodological data of interest were extracted from the eligible articles and reorganized in Microsoft Access database. Chi-square tests in SPSS were used to analyze the associations between pairs of categorical data. ^ Results. One hundred and twenty eligible articles were reviewed after two steps of literature selection with explicit inclusion and exclusion criteria. Descriptive statistics were reported regarding the evaluated interventions, outcome measures, unit costing and cost reports. The chi-square test of the association between prevention level of intervention and category of time horizon showed no statistical significance. The chi-square test showed that sponsor type was significantly associated with whether new or standard intervention being concluded as more cost effective. ^ Conclusions. Tertiary prevention and medication interventions are the major interests for economic evaluators. The majority of the evaluations were claimed from either a provider’s or a payer’s perspective. Almost all evaluations adopted gross costing strategy for unit cost data rather than micro costing. EQ-5D is the most commonly used instrument for subjective outcome measurement. More than half of the evaluations used decision analytic modeling techniques. The lack of consistency in study design standards in published evaluations appears in several aspects. Prevention level of intervention is not likely to be a factor for evaluators to decide whether to design an evaluation in a lifetime horizon or not. Published evaluations sponsored by industry are more likely to conclude that new intervention is more cost effective than standard intervention.^

An interactive intervention to impact adherence to antiretroviral treatment among treatment-naive HIV-infected adults in Thailand: A pilot randomized controlled study

Background. Consistent adherence to antiretroviral treatment is necessary for a treatment success. Improving and maintaining adherence rate >95% are challenging for health care professionals. This pilot randomized controlled study aimed to evaluate the impact of the interactive intervention on adherence to GPO-VIR, to describe the feasibility of the interactive intervention in Thailand, and to illustrate the adherence self-efficacy concept among HIV treatment-naïve patients in Thailand who were starting antiretroviral treatment. ^ Methods. The study took place at three HIV clinics located in Phayao, Thailand. Twenty-three patients were randomly assigned into the experimental (n=11) and the control groups (n=12). Each participant in the experimental group and a significant person to the patient received 5 educational sessions with a nurse at the clinics and at their homes. They also received 3 follow-up evaluations during the 6-month period of the study. The participants in the control group received the standard of care provided by HIV clinical personnel plus three follow-up evaluations at the clinic. ^ Results. Seventeen patients (7 in the experimental and 10 in the control group) completed the study. The 4-day recall on the Thai ACTG Adherence Scale demonstrated adherence rate >95% for most participants from both groups. After the first measurement, no experimental group patients reporting missing ART, while one control group participant continuously skipped ART. Participants from both groups had significantly increased CD4 cell counts after the study (F(1, 15) = 29.30, p = .000), but no differences were found between two groups (F(1, 15) = .001, p = .98). Examination of the intervention showed limitations and possibilities to implement it in Thailand. Qualitative data demonstrated self-efficacy expectations, resignation and acceptance as related concepts to improve adherence outcomes. ^ Conclusions. This interactive intervention, after appropriate modifications, is feasible to apply for Thai HIV-treatment naïve patients. Because of limitations the study could not demonstrate whether the interactive intervention improved adherence to ART among HIV-treatment naïve in Thailand. A longitudinal study in a larger sample would be required to test the impact of the intervention. ^ Keyword: antiretroviral treatment, adherence, treatment-naïve, Thailand, randomized controlled study ^

Project Alpha: A culturally appropriate approach to adolescent male sex education

In the United States today, adolescents face unacceptably high rates of mortality and morbidity due to the contraction of HIV/AIDS, sexually transmitted diseases and teenage pregnancy. In view of these rates, there is a need for applied preventive interventions to delay adolescent sexual behavior until adulthood. Project Alpha was a school-adopted, quasi-experimental program for adolescent male students attending Sharpstown High School in Houston, Texas. This intervention used student newsletters to provide specific role-model stories on community and student role models who have changed attitudes or improved efficacy to abstain from sexual behavior until adulthood. It was hypothesized that teenagers exposed to the intervention would show improvements in knowledge, beliefs, avoidance skills, perceived norms, intentions and self-efficacy to delay sexual behavior compared to no-treatment reference teenagers in the same school.^ In total, the Project Alpha program had a significant effect on student knowledge, beliefs (towards abstinence and having sex with multiple partners), perceived risk (HIV/STD testing), self-efficacy (could avoid sex with attractive girl who wants to have sex), perceived social norms (friends believing in sexual abstinence) and sexual intentions. However, no significant intervention effects were found in student's beliefs (that it was OK to have sex with girlfriend), perceived risk of HIV/STD, self-efficacy (to avoid sex with girlfriend) and social norms (friends believe it is OK to have sex with a girlfriend and multiple partners in the same month). ^

Attributing inpatient care to diabetes: The case of Medicare for the elderly in Texas, 1995

Specific aims. This study estimated the accuracy of alternative numerator methods for attributing health care utilization and associated costs to diabetes by comparing findings from those methods with findings from a benchmark denominator method. ^ Methods. Using Medicare's 1995 inpatient and enrollment databases for the elderly in Texas, the researcher developed alternative estimates of costs attributable to diabetes. Among alternative numerator methods were selection of all records having diabetes as a principal or secondary diagnosis, and a complex ICD-9-CM sorting routine as previously developed for study of diabetes costs in Texas. Findings from numerator methods were compared with those from a benchmark denominator method based on attributable risk and adapted from a study of national diabetes costs by the American Diabetes Association. This study applied age, gender and ethnicity specific estimates of diabetes prevalence taken from the 1987–94 National Health Interview Surveys to person-months of Medicare Part A, non-HMO enrollment for Texas in 1995. Outcome measures were number of persons identified as having diabetes using alternative definitions of the disease; and number of hospital stays, patient days, and costs using alternative methods for attributing care and costs to diabetes. Cost estimates were based on Medicare payments plus deductibles, co-pays and third party payments. ^ Findings. Numerator methods for attributing costs to diabetes produced findings quite different than those from the benchmark denominator method. When attribution was based on diabetes as principal or secondary diagnosis, the resulting estimates were significantly higher than those obtained from the denominator method. The more complex sorting routine produced estimates near the lower boundary for the confidence interval associated with estimates from the benchmark method. ^ Conclusions. Numerator methods employed by previous researchers poorly estimate the costs of diabetes. While crude mathematical adjustment can be made to the respective numerator approaches, a more useful strategy would be to refine the complex sorting routine to include more hospitalizations. This report recommends approaches to improving methods previously employed in study of diabetes costs. ^

Tracking of plasma lipids and lipoproteins, within-person and year-to-year variability in plasma cholesterol levels among participants from age 8 to 18 in Project HeartBeat!

Coronary heart disease remains the leading cause of death in the United States and increased blood cholesterol level has been found to be a major risk factor with roots in childhood. Tracking of cholesterol, i.e., the tendency to maintain a particular cholesterol level relative to the rest of the population, and variability in blood lipid levels with increase in age have implications for cholesterol screening and assessment of lipid levels in children for possible prevention of further rise to prevent adulthood heart disease. In this study the pattern of change in plasma lipids, over time, and their tracking were investigated. Also, within-person variance and retest reliability defined as the square root of within-person variance for plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides and their relation to age, sex and body mass index among participants from age 8 to 18 years were investigated. ^ In Project HeartBeat!, 678 healthy children aged 8, 11 and 14 years at baseline were enrolled and examined at 4-monthly intervals for up to 4 years. We examined the relationship between repeated observations by Pearson's correlations. Age- and sex-specific quintiles were calculated and the probability of participants to remain in the uppermost quintile of their respective distribution was evaluated with life table methods. Plasma total cholesterol, HDL-C and LDL-C at baseline were strongly and significantly correlated with measurements at subsequent visits across the sex and age groups. Plasma triglyceride at baseline was also significantly correlated with subsequent measurements but less strongly than was the case for other plasma lipids. The probability to remain in the upper quintile was also high (60 to 70%) for plasma total cholesterol, HDL-C and LDL-C. ^ We used a mixed longitudinal, or synthetic cohort design with continuous observations from age 8 to 18 years to estimate within person variance of plasma total cholesterol, HDL-C, LDL-C and triglycerides. A total of 5809 measurements were available for both cholesterol and triglycerides. A multilevel linear model was used. Within-person variance among repeated measures over up to four years of follow-up was estimated for total cholesterol, HDL-C, LDL-C and triglycerides separately. The relationship of within-person and inter-individual variance with age, sex, and body mass index was evaluated. Likelihood ratio tests were conducted by calculating the deviation of −2log (likelihood) within the basic model and alternative models. The square root of within-person variance provided the retest reliability (within person standard deviation) for plasma total cholesterol, HDL-C, LDL-C and triglycerides. We found 13.6 percent retest reliability for plasma cholesterol, 6.1 percent for HDL-cholesterol, 11.9 percent for LDL-cholesterol and 32.4 percent for triglycerides. Retest reliability of plasma lipids was significantly related with age and body mass index. It increased with increase in body mass index and age. These findings have implications for screening guidelines, as participants in the uppermost quintile tended to maintain their status in each of the age groups during a four-year follow-up. The magnitude of within-person variability of plasma lipids influences the ability to classify children into risk categories recommended by the National Cholesterol Education Program. ^

Latino perceptions of and barriers to preventive healthcare maintenance in the southwest United States

Between the 1990 and 2000 Censuses, the Latino population accounted for 40% of the increase in the nation’s total population. The growing population of Latinos underscores the importance for understanding factors that influence whether and how Latinos take care of their health. According to the U.S. Department of Human Health Service’s Office of Minority Health (OMH), Latinos are at greater risk for health disparities (2003). Factors such as lack of health insurance and access to preventive care play a major role in limiting Latino use of primary health care (Institute of Medicine, 2005). Other significant barriers to preventive health care maintenance behaviors have been identified in current literature such as primary care physician interaction, self-perceived health status, and socio-cultural beliefs and traditions (Rojas-Guyler, King, Montieth and 2008; Meir, Medina, and Ory, 2007; Black, 1999). Despite these studies, there remains less information regarding interpersonal perceptions, environmental dynamics and individual and cultural attitudes relevant to utilization of healthcare (Rojas-Guyler, King, Montieth and 2008; Aguirre-Molina, Molina and Zambrana, 2001). Understanding the perceptions of Latinos and the barriers to health care could directly affect healthcare delivery. Improved healthcare utilization among Latinos could reduce the long term health consequences of many preventable and manageable diseases. The purpose of this study was to explore Latino perceptions of U.S. health care and desired changes by Latinos in the U.S. healthcare system. The study had several objectives, including to explore perceived barriers to healthcare utilization and the resulting effects on health among Latinos, to describe culturally influenced attitudes about health care and use of health care services among Latinos, and to make recommendations for reducing disparities by improving healthcare and its utilization. The current study utilized data that were collected as part of a larger study to examine multidimensional, cross-cultural issues relevant to interactions between healthcare consumers and providers. Qualitative methods were used to analyze four Spanish-language focus group transcripts to interpret cultural influences on perceptions and beliefs among Latinos. Direct coding of transcript content was carried out by two reviewers, who conducted independent reviews of each transcript. Team members developed and refined thematic categories, positive and negative cases, and example text segments for each theme and sub-theme. Incongruities of interpretations were resolved through extensive discussion. Study participants included 44 self-identified Latino adults (16 male, 28 female) between age 18 and 64 years. Thirty seven (84.1%) of the participants were immigrants. The study population comprised eight ethnic subgroups. While 31% of the participants reported being employed on a full-time basis, only 18.4% had medical insurance that was private or employee sponsored. Five major themes regarding the perceptions and healthcare utilization behaviors of Latinos were consistent across all focus groups and were identified during the analysis. These were: (1) healthcare utilization, experience, and access; (2) organizational and institutional systems; (3) communication and interpersonal interactions between healthcare provider, staff, and patient; (4) Latinos’ perception of their own health status; (5) cultural influences on healthcare utilization, which included an innovation termed culturally-bound locus of control. Healthcare utilization was directly influenced by healthcare experience, access, current health status, and cultural factors and indirectly influenced by organizational systems. There was a strong interdependence among the main themes. The ability to communicate and interact effectively with healthcare providers and navigate healthcare systems (organizational and institutional access) significantly influenced the participant’s health care experience, most often (indirectly) impacting utilization negatively. ^ Research such as this can help to identify those perceptions and attitudes held by Latinos concerning utilization or underutilization of healthcare systems. These data suggest that for healthcare utilization to improve among Latinos, healthcare systems must create more culturally competent environments by providing better language services at the organizational level and more culturally sensitive providers at the interpersonal level. Better understanding of the complex interactions between these impediments can aid intervention developments, and help health providers and researchers in determining appropriate, adequate, and effective measurers of care to better increase overall health of Latinos.^

Campaign contributions to congressional candidates by the healthcare sector from 1990 to 2008

Stakeholder groups with special interests as donors to finance congressional campaigns have been a controversial issue in the United Sates. While previous studies concentrated on whether a connection existed between the campaign contributions provided by stakeholder groups and the voting behavior of congressional members, there is little evidence to show the trend of allocation of their campaign contributions to their favorite candidates during the elections. This issue has become increasingly important in the health sector since the health care reform bill was passed in early 2010.^ This study examined the long-term trend of campaign contributions offered by various top healthcare stakeholder groups to particular political parties (i.e. Democrat and Republican). The main focus of this paper was to observe and describe the financial donations provided by these healthcare stakeholder groups in the congressional election cycles from 1990 to 2008 in order to obtain an overview of their patterns of campaign contributions. Their contributing behaviors were characterized based on the campaign finance data collected by the Center for Responsive Politics (CRP). Specifically, I answered the questions: (1) to which political party did specific healthcare stakeholder groups give money and (2) what was the pattern of their campaign contributions from 1990 to 2008?^ The findings of my study revealed that the healthcare stakeholder groups had different political party preferences and partisanship orientations regarding the Democratic or Republican Party. These differences were obvious throughout the election cycles from 1990 to 2008 and their distinct patterns of financial contribution were evident across industries in the health sector as well. Among all the healthcare stakeholder groups in this study, physicians were the top contributors in the congressional election. The pharmaceutical industry was the only group where the majority of contribution funds were allocated to Republicans in every election period studied. This study found that no interest group has succeeded in electing the preferred congressional candidate by giving the majority of its financial support to the winning party in every election. Chiropractors, hospitals/nursing homes, and health services/HMOs performed better than other healthcare stakeholder groups by supporting the electoral winner 8 out of 9 election cycles.^

STRATEGIES FOR THE TRANSFER OF APPROPRIATE TECHNOLOGY TO DEVELOPING COUNTRIES: THE IMPLEMENTATION AND DEVELOPMENT OF ENVIRONMENTAL HEALTH PROGRAMS IN TUNISIA

This dissertation focuses on Project HOPE, an American medical aid agency, and its work in Tunisia. More specifically this is a study of the implementation strategies of those HOPE sponsored projects and programs designed to solve the problems of high morbidity and infant mortality rates due to environmentally related diarrheal and enteric diseases. Several environmental health programs and projects developed in cooperation with Tunisian counterparts are described and analyzed. These include (1) a paramedical manpower training program; (2) a national hospital sanitation and infection control program; (3) a community sewage disposal project; (4) a well reconstruction project; and (5) a solid-waste disposal project for a hospital.^ After independence, Tunisia, like many developing countries, encountered several difficulties which hindered progress toward solving basic environmental health problems and prompted a request for aid. This study discusses the need for all who work in development programs to recognize and assess those difficulties or constraints which affect the program planning process, including those latent cultural and political constraints which not only exist within the host country but within the aid agency as well. For example, failure to recognize cultural differences may adversely affect the attitudes of the host staff towards their work and towards the aid agency and its task. These factors, therefore, play a significant role in influencing program development decisions and must be taken into account in order to maximize the probability of successful outcomes.^ In 1969 Project HOPE was asked by the Tunisian government to assist the Ministry of Health in solving its health manpower problems. HOPE responded with several programs, one of which concerned the training of public health nurses, sanitary technicians, and aids at Tunisia's school of public health in Nabeul. The outcome of that program as well as the strategies used in its development are analyzed. Also, certain questions are addressed such as, what should the indicators of success be, and when is the time right to phase out?^ Another HOPE program analyzed involved hospital sanitation and infection control. Certain generic aspects of basic hospital sanitation procedures were documented and presented in the form of a process model which was later used as a "microplan" in setting up similar programs in other Tunisian hospitals. In this study the details of the "microplan" are discussed. The development of a nation-wide program without any further need of external assistance illustrated the success of HOPE's implementation strategies.^ Finally, although it is known that the high incidence of enteric disease in developing countries is due to poor environmental sanitation and poor hygiene practices, efforts by aid agencies to correct these conditions have often resulted in failure. Project HOPE's strategy was to maximize limited resources by using a systems approach to program development and by becoming actively involved in the design and implementation of environmental health projects utilizing "appropriate" technology. Three innovative projects and their implementation strategies (including technical specifications) are described.^ It is advocated that if aid agencies are to make any progress in helping developing countries basic sanitation problems, they must take an interdisciplinary approach to progrm development and play an active role in helping counterparts seek and identify appropriate technologies which are socially and economically acceptable. ^

Client Home or Agency Office? How Do We Decide Where to See Our Clients?

Decisions about location of services sometimes appear to be made more on the basis of agency preference than assessment of need. Today the profession has enough experience with service locations that it is possible to develop more clear guidelines for the decision about where work with clients should take place, in the client’s home or nearby community or in the practitioner’s office. This study was conducted with two purposes; 1) to identify at a higher level of evidence the various reasons for seeing clients in their own homes and nearby community setting; and 2) to demonstrate how readily available information can be used to gradually increase the level of evidence by which practice decisions are made.

Journeying Beyond the Balcony to the Block Party and Up to 50,000 Feet: Disparities in Children’s Health and Healthcare

Invited Commentary on “Observations from the Balcony: Directions for Pediatric Health Disparities Research and Policy".