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THE PENALIZED OPTIMAL EXPERIMENTAL DESIGN: THE PRECISE ESTIMATION OF AN INTERACTION THRESHOLD IN A MIXTURE OF EIGHTEEN POLYHALOGENATED AROMATIC HYDROCARBONS.
Citation:
YEATTS, S. D., C. GENNINGS, AND K. M. CROFTON. THE PENALIZED OPTIMAL EXPERIMENTAL DESIGN: THE PRECISE ESTIMATION OF AN INTERACTION THRESHOLD IN A MIXTURE OF EIGHTEEN POLYHALOGENATED AROMATIC HYDROCARBONS. Presented at Society of Toxicology, Charlotte, NC, March 25 - 29, 2007.
Description:
Crofton et al. (EHP, 2005) conducted a study of 18 polyhalogenated aromatic hydrocarbons (PHAHs) on serum total thyroxine (T4). Young female Long-Evans rats were dosed with the 18 single agents or a fixed-ratio mixture, and serum total T4 was measured via radioimmunoassay. The initial analysis found significant interaction among the chemicals, with evidence of synergy at high doses (Crofton et al., 2005). To address the subsequent question of dose-dependency, Gennings et al. (JABES, 2006) fit an interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, however, the corresponding confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, a Ds- optimal second stage design was determined, with the objective of minimizing the variance of the hypothesized interaction threshold. Substantial concerns regarding the practicality of this design led to the use of the penalized optimality criterion (Parker and Gennings, JABES, under review), which uses desirability functions to penalize impractical experimental designs. Results demonstrate that, while the Ds- optimal second stage design can be used to more precisely define the interaction threshold, the penalized Ds- optimal second stage design has the characteristics deemed important in practice, while allowing only a minimal increase in the variance of the interaction threshold. This abstract does not necessarily represent EPA policies.