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D-OPTIMAL EXPERIMENTAL DESIGNS TO TEST FOR DEPARTURE FROM ADDITIVITY IN A FIXED-RATIO MIXTURE RAY.
Citation:
COFFEY, T., C. GENNINGS, J. E. SIMMONS, AND D. W. HERR. D-OPTIMAL EXPERIMENTAL DESIGNS TO TEST FOR DEPARTURE FROM ADDITIVITY IN A FIXED-RATIO MIXTURE RAY. . Presented at Building the Scientific Foundation for Mixtures Joint Toxicity and Risk Assessment, Atlanta, GA, February 16 - 17, 2005.
Description:
Traditional factorial designs for evaluating interactions among chemicals in a mixture are prohibitive when the number of chemicals is large. However, recent advances in statistically-based experimental design have made it easier to evaluate interactions involving many chemicals. Using a fixed-ratio mixture ray with chemicals in relevant proportions results in an economical design that allows estimation of additivity or non-additive interaction for a mixture of interest. This methodology is easily extended to a mixture with a large number of chemicals. Further, optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are widely used for linear models, optimal designs for nonlinear threshold models are less known. As a new application in toxicology, we demonstrate the use of D-optimal designs for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated using data collected on a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. We show that using a D-optimal criterion produces experimental designs with increased power while standard, non-optimal designs with equally-spaced dose groups may result in low power if the active range or threshold is missed. Supported by T32 ES07334-01A1 (NIEHS, NIH) and CR-828-11401 (U.S. EPA). This is an abstract of a proposed presentation and does not necessarily reflect EPA policy or the official views of the NIEHS, NIH.