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DETERMINING A ROBUST D-OPTIMAL DESIGN FOR TESTING FOR DEPARTURE FROM ADDITIVITY IN A MIXTURE OF FOUR PFAAS
Citation:
Carr, C., C. Gennings, B. D. ABBOTT, J. E. SCHMID, W. Wan, L. BURGOON, C. J. WOLF, AND C. LAU. DETERMINING A ROBUST D-OPTIMAL DESIGN FOR TESTING FOR DEPARTURE FROM ADDITIVITY IN A MIXTURE OF FOUR PFAAS. Presented at International Biometric Society Eastern North American Region (ENAR) meeting, Miami, FL, March 20 - 23, 2011.
Impact/Purpose:
Of particular focus to this research project is whether an environmentally relevant mixture of four PFAAs with long half-lives (PFOA, PFOS, PFNA, and PFHxS) acts synergistically.
Description:
Our objective was to determine an optimal experimental design for a mixture of perfluoroalkyl acids (PFAAs) that is robust to the assumption of additivity. Of particular focus to this research project is whether an environmentally relevant mixture of four PFAAs with long half-lives (PFOA, PFOS, PFNA, and PFHxS) acts synergistically. The first phase involved an in vitro study with a transfected-cell model to evaluate the ability of PFAAs to activate PPARa. Using the resulting data, a non-linear logistic additivity model was employed to predict relative luciferase units (RLU) at an environmentally relevant mixing ratio that was estimated from NHANES (2005-2006) data. This model was used in the design stage which used a maximin D-optimal design criterion to select an optimal design from a large set of specified designs. The candidate seven point designs (including one control) were generated by varying the totaldose locations and shape of the dose-response curve with the additivity curve used as a reference. A total of 6,006 designs and 13 dose-response shapes were considered. A D-optimal design robust to misspecification of the resulting dose-response shape was found with a minimum D-efficiency of 92%. The final stage of this research determined the necessary sample size to test for additivity. (This research was partially supported by NIEHS T32ES007334 and does not reflect USEPA policy.)