Efficient Design of Biological Experiments for Dose-Response Modeling in Nanomaterial Toxicology Studies

West Virginia University Research Corporation, Morgantown WV

Investigators

Abstract

Proposal No: 1065931 PI Name: Feng Yang One of the most fundamental steps in assessing the risk of a nanomaterial is to understand and properly characterize its dose-response relationship based on biological experiments. Because of costs, ethics, or other limitations on resources or time, sample sizes are usually restricted and efficient use of available resources is critical. Thus, the design of experiments, i.e., the selection of experimental doses and the allocation of animals, plays an important role in the success of dose-response studies. Intellectual Merits: Efficient design for dose-response modeling is particularly challenging due to the special features of toxicity data. The objective of the proposed research is to develop an experimental design procedure, which accommodates the nonlinear nature of dose-response curves and variance heterogeneity of toxicity data, to guide the dose selection and animal allocation in biological experiments for the efficient generation of dose-response relationships. The proposed design procedure will be built in a two-stage Bayesian paradigm, which provides a statistically valid mechanism to utilize prior information for the design of future experiments. Most suitable dose-response as well as variance models will be identified to describe the toxicity data. Bootstrapping, a computationally intensive resampling method as opposed to conventional statistical inference methods, will be used to derive important information from the preliminary data required by the subsequent experimental design. To achieve practically useful designs, multiple design criteria will be considered simultaneously, and multi-objective metaheuristics will be adapted to search for a set of Pareto optimum designs, which allow for the evaluation of various trade-offs in practical experimental settings. Broader Impacts: The outcome of this research will result in an efficient experimental design procedure which is able to characterize substances by high-quality dose-response profiles using less experiments. The methods obtained from the proposed work will substantially reduce the experimental cost and time in toxicology studies, alleviate the rising concerns for animal ethics, and accelerate the progress toward quantifying the risk, safety and health effects of environmental and occupational exposure to nanomaterials. The implementation of the project will promote the fusion of different disciplines and the collaborative partnership between universities and federal labs. The broad data dissemination will directly impact the risk and safety assessment for human health and the environment. The educational objectives of this effort are to train graduate and undergraduate students, to recruit underrepresented (women, minority and low-income) students to participate in the proposed research. In addition, this work will provide a valuable resource for classroom case studies, and attract young talents into the multidisciplinary field interfacing industrial engineering (e.g., computer simulation, statistics, etc.) with biology and nanotechnology.