Indiana University-Purdue University Indianapolis (IUPUI) / Adverse drug events (ADEs) are injuries resulting from drug-related medical interventions. ADEs can be either induced by a single drug or a drug-drug interaction (DDI). In order to prevent unnecessary ADEs, many regulatory agencies in public health maintain pharmacovigilance databases for detecting novel drug-ADE associations. However, pharmacovigilance databases usually contain a significant portion of false associations due to their nature structure (i.e. false drug-ADE associations caused by co-medications). Besides pharmacovigilance studies, the risks of ADEs can be minimized by understating their mechanisms, which include abnormal pharmacokinetics/pharmacodynamics due to genetic factors and synergistic effects between drugs. During the past decade, pharmacogenomics studies have successfully identified several predictive markers to reduce ADE risks. While, pharmacogenomics studies are usually limited by the sample size and budget. In this dissertation, we develop statistical methods for pharmacovigilance and pharmacogenomics studies. Firstly, we propose an empirical Bayes mixture model to identify significant drug-ADE associations. The proposed approach can be used for both signal generation and ranking. Following this approach, the portion of false associations from the detected signals can be well controlled. Secondly, we propose a mixture dose response model to investigate the functional relationship between increased dimensionality of drug combinations and the ADE risks. Moreover, this approach can be used to identify high-dimensional drug combinations that are associated with escalated ADE risks at a significantly low local false discovery rates. Finally, we proposed a cost-efficient design for pharmacogenomics studies. In order to pursue a further cost-efficiency, the proposed design involves both DNA pooling and two-stage design approach. Compared to traditional design, the cost under the proposed design will be reduced dramatically with an acceptable compromise on statistical power. The proposed methods are examined by extensive simulation studies. Furthermore, the proposed methods to analyze pharmacovigilance databases are applied to the FDA’s Adverse Reporting System database and a local electronic medical record (EMR) database. For different scenarios of pharmacogenomics study, optimized designs to detect a functioning rare allele are given as well.

Traditional single stage design optimality procedures can be used to efficiently generate data for an assumed model y = f(x^(m),b) + ε. The model assumptions include the form of f, the set of regressors, x^(m) , and the distribution of ε. The nature of the response, y, often provides information about the model form (f) and the error distribution. It is more difficult to know, apriori, the specific set of regressors which will best explain the relationship between the response and a set of design (control) variables x. Misspecification of x^(m) will result in a design which is efficient, but for the wrong model. A Bayesian two stage design approach makes it possible to efficiently design experiments when initial knowledge of x^(m) is poor. This is accomplished by using a Bayesian optimality criterion in the first stage which is robust to model uncertainty. Bayesian analysis of first stage data reduces uncertainty associated with x^(m), enabling the remaining design points (second stage design) to be chosen with greater efficiency. The second stage design is then generated from an optimality procedure which incorporates the improved model knowledge. Using this approach, numerous two stage design procedures have been developed for the normal linear model. Extending this concept, a Bayesian design augmentation procedure has been developed for the purpose of efficiently obtaining data for variance modeling, when initial knowledge of the variance model is poor. / Ph. D.

Bayesian optimal designs have received increasing attention in recent years, especially in biomedical and clinical trials. Bayesian design procedures can utilize the available prior information of the unknown parameters so that a better design can be achieved. However, a difficulty in dealing with the Bayesian design is the lack of efficient computational methods. In this research, a hybrid computational method, which consists of the combination of a rough global optima search and a more precise local optima search, is proposed to efficiently search for the Bayesian D-optimal designs for multi-variable generalized linear models. Particularly, Poisson regression models and logistic regression models are investigated. Designs are examined for a range of prior distributions and the equivalence theorem is used to verify the design optimality. Design efficiency for various models are examined and compared with non-Bayesian designs. Bayesian D-optimal designs are found to be more efficient and robust than non-Bayesian D-optimal designs. Furthermore, the idea of the Bayesian sequential design is introduced and the Bayesian two-stage D-optimal design approach is developed for generalized linear models. With the incorporation of the first stage data information into the second stage, the two-stage design procedure can improve the design efficiency and produce more accurate and robust designs. The Bayesian two-stage D-optimal designs for Poisson and logistic regression models are evaluated based on simulation studies. The Bayesian two-stage optimal design approach is superior to the one-stage approach in terms of a design efficiency criterion. / Ph. D.

The design of clinical trials is one of the important problems in medical statistics. Its main purpose is to determine the methodology and the sample size required of a testing study to examine the safety and efficacy of drugs. It is also a part of the Food and Drug Administration approval process. In this thesis, we first study the comparison of the efficacy of drugs in clinical trials. We focus on the two-sample comparison of proportions to investigate testing strategies based on two-stage design. The properties and advantages of the procedures from the proposed testing designs are demonstrated by numerical results, where comparison with the classical method is made under the same sample size. A real example discussed in Cardenal et al. (1999) is provided to explain how the methods may be used in practice. Some figures are also presented to illustrate the pattern changes of the power functions of these methods. In addition, the proposed procedure is also compared with the Pocock (1997) and O¡¦Brien and Fleming (1979) tests based on the standardized statistics. In the second part of this work, the operating room scheduling problem is considered, which is also important in medical studies. The national health insurance system has been conducted more than ten years in Taiwan. The Bureau of National Health Insurance continues to improve the national health insurance system and try to establish a reasonable fee ratio for people in different income ranges. In accordance to the adjustment of the national health insurance system, hospitals must pay more attention to control the running cost. One of the major hospital's revenues is generated by its surgery center operations. In order to maintain financial balance, effective operating room management is necessary. For this topic, this study focuses on the model fitting of operating times and operating room scheduling. Log-normal and mixture log-normal distributions are identified to be acceptable statistically in describing these operating times. The procedure is illustrated through analysis of thirteen operations performed in the gynecology department of a major teaching hospital in southern Taiwan. The best fitting distributions are used to evaluate performances of some operating combinations on daily schedule, which occurred in real data. The fitted distributions are selected through certain information criteria and bootstrapping the log-likelihood ratio test. Moreover, we also classify the operations into three different categories as well as three stages for each operation. Then based on the classification, a strategy of efficient scheduling is proposed. The benefits of rescheduling based on the proposed strategy are compared with the original scheduling observed.

The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.