Using Historical Controls in the Analysis of Developmental Toxicity Data

Abstract

Historical control data can often aid in the interpretation of the results from laboratory dose-response experiments. For example, formal statistical methods for using historical data are well established for carcinogenicity studies. In that case, a score test derived from a beta-binomial model yields a simple modification of the standard Cochran-Armitage test for trend. However, this test cannot be used for developmental toxicity studies since it does not allow for the additional correlation structure induced by the presence of litter effects. In this paper, quasi-likelihood methods are used to incorporate historical control information into a trend test for the types of correlated binary outcomes that typically arise in developmental toxicity studies. The proposed test is asymptotically equivalent to the beta-binomial score test in the special case when all the litter sizes are equal to 1. Malformation data from a series of developmental toxicity studies illustrate the results.