This dissertation presents novel sequential dose-finding designs that adjust for inter-individual pharmacokinetic variability in phase I cancer clinical trials. Unlike most traditional dose-finding designs whose primary goals are the determination of a maximum safe dose, the goal of our proposed designs is to estimate a patient-specific dosing function such that the responses of patients can achieve a target safety level. Extending from a single compartment model in the pharmacokinetic theory, we first postulate a linear model to describe the relationship between the area under concentration-time curve, dose and predicted clearance. We propose a repeated least squares procedure that aims to sequentially determine dose according to individual ability of metabolizing the drug. To guarantee consistent estimation of the individualized dosing function at the end of a trial, we apply repeated least squares subject to a consistency constraint based on an eigenvalue theory for stochastic linear regression. We empirically determine the convergence rate of the eigenvalue constraint using a real data set from an irinotecan study in colorectal carcinoma patients, and calibrate the procedure to minimize a loss function that accounts for the dosing costs of study subjects and future patients. When compared to the traditional body surface area and an equation based dosing methods, the simulation results demonstrate that the repeated least squares procedure control the dosing cost and allow for precise estimation of the dosing function. Furthermore, in order to enhance the generality and robustness of the dose-finding designs, we generalize the linear association to a nonlinear relationship between the response and a linear combination of dose and predicted clearance. We propose a two-stage sequential design, the semiparametric link-adapted recursion, which targets at individualizing dose assignments meanwhile adapting for an unknown nonlinear link function connecting the response and dose along with predicted clearance. The repeat least squares with eigenvalue constraint design is utilized as the first stage, and the second stage recursively applies an iterative semiparametric least squares approach to estimate the dosing function and determine dosage for next patient. The simulation results demonstrate that: at first, the performance of repeated least squares with eigenvalue constraint design is acceptably robust to model misspecifications; at second, as its performance is close to that of repeated least squares procedure under parametric models, the semiparametric link-adapted recursion does not sacrifice much estimation accuracy to gain robustness against model misspecifications; at last, compared to the repeated least squares procedure, the semiparametric link-adapted recursion can significantly improve the dosing costs and estimation precision under the semiparametric models.

In collaboration with the United States Environmental Protection Agency (USEPA), the University of South Florida Health Risk Methodology Group has developed dose-time-response models to characterize neurobehavioral response to chemical exposure. The application of dose-time-response models to neurobehavioral screening tests on laboratory animals allows for benchmark dose estimation to establish exposure limits in environmental risk assessment. This thesis has advanced dose-time-response modeling by generalizing a published toxico diffusion model to allow for dose dependent time of peak effects. To accomplish this, a biphasic model was developed which adopted the effect compartment model paradigm used in pharmacokinetics/pharmacodynamics to estimate a distributional rate constant to account for dose related variation in the time of peak effect. The biphasic model was able to describe dose-dependent time of peak effects as observed in the data on acute exposure to parathion and adequately predicted the observed response. However, the experimental design appeared insufficient in statistical power to confirm statistical significance for each parameter of interest. Motivated by the question of what design requirement might be necessary to validate the biphasic model, Monte Carlo simulation was adopted. Simulations were performed to assess the efficacy and efficiency of various experimental designs for detecting and evaluating some critical characteristics of the biphasic model, including the TOPE. The results of simulation suggest that the location of measurement times around the TOPE have important implications for assessing the statistical significance of the parameter that describes dose-dependent TOPE and that the mean squared error of the parameter estimator was improved most when testing times were chosen to bracket the TOPE. While dose dependent time of peak effects has underlying physiological mechanisms such as synergistic or capacity limited kinetics, the biphasic model estimates these physiological properties through a mathematical function which may be physiologically relevant but does not necessarily define physiological mechanisms underlying the response. However, if verified through further testing, the biphasic model may contribute to the USEPA’s aim of developing physiologically relevant dose-response models for assessing risk of neurotoxicity with repeated measurements of response.

Tn5 mutagenesis of apdA (for antibiotic production) and deletion of gacA (for global antibiotic and cyanide) resulted in the same pleiotropic phenotype in Pseudomonas fluorescens (i.e. production of an array of secondary metabolites including the antibiotics pyrrolnitrin, pyoluteorin, and 2,4-diacetylphloroglucinol as well as a tryptophan-side-chain oxidase, hydrogen cyanide, and an extracellular protease was abolished). The apdA and gacA loci were identified and cloned from the genome of Pf-5. Nucleotide sequencing of the apdA and gacA loci was used to identify the open reading frames for these genes. The deduced amino acid sequences for apdA and gacA exhibited similarity to sensor kinase (ApdA) and response regulator (GacA) proteins that comprise two-component regulatory systems. The C-terminal domain of GacA containing the putative helix-turn-helix DNA-binding motif was fused to the glutathione S-transferase protein. The glutathione S-transferase GacA C-terminal fusion protein was used in a cycle selection procedure that was designed to identify GacA binding sites from a complex pool of DNA fragments. Although a putative binding site for GacA was identified using the cycle selection procedure, the results were inconclusive due to several inconsistencies in the DNA-binding assay. The upstream region of one gene, which codes for a putative porin, was identified as a putative binding site for GacA by the cycle selection procedure. Studies initiated to determine whether gacA regulates transcription of this putative porin gene have been unsuccessful, so it remains unclear whether this gene is regulated by GacA. Also, asymptotic limits to biological control of Rhizoctonia damping-off of cotton were observed with the biological control agent P. fluorescens Pf-5. / Graduation date: 1999

Graduation date: 1999

No description available.

Thesis (M.S.)--James Madison University, 2009. / Includes bibliographical references.

No description available.

No description available.

A wealth of studies have examined the impact of alcohol on violence; however, only a small number have addressed differences elicited by different doses of alcohol. Such studies are seriously limited by mixed findings, small sample sizes, inconsistent alcohol doses and control conditions, a bias toward studying only male participants, and the predominant use of only one particular measure to assess aggression. The present laboratory investigation was designed to elucidate and advance this literature by improving upon these limitations. Participants were 187 (95 men and 92 women) social drinkers. Following the consumption of one of 6 alcohol doses (i.e., 0.0g/kg; 0.125g/kg; 0.25g/kg; 0.5g/kg; 0.75g/kg; and 1.0g/kg), participants were tested on a laboratory task in which electric shocks were received from, and administered to, a fictitious opponent under the guise of a competitive reaction-time task. Aggression was operationalized as the intensity of shocks administered to their opponent. Analyses revealed that higher alcohol doses clearly elicited greater aggression in both genders consistent with a linear non-threshold dose-response model. Our data help to clarify a body of literature that has been afflicted with numerous limitations and will also help in the selection of alcohol doses for researchers conducting future laboratory-based aggression studies.

国立情報学研究所で電子化したコンテンツを使用している。