Evaluation of Toxicological Studies Using a Nonparametric Shirley-Type Trend Test for Comparing Several Dose Levels with a Control Group

Abstract

The U.S. National Toxicology Program uses Shirley's test for the evaluation of endpoints in hematology, clinical chemistry, and urinalysis, which are assumed to be skewed distributed. Until now, no algorithm for Shirley's test for general unbalanced designs has been devised. A Shirley-type procedure is provided for estimating multiplicity-adjusted p-values or simultaneous confidence intervals for any continuous or discrete distributions and possible heterogeneous variances. Routine evaluation can be performed using the open-source R package nparcomp. The use of simultaneous confidence intervals for the relative effect is recommended, since these scale-invariant intervals allow one to claim the statistical significance of multiple endpoints as well as their biological relevance.

Key Words:

• Nonparametric test
• Shirley test
• Simultaneous confidence intervals
• Trend test

Acknowledgments

The authors are grateful to an Associate Editor of the journal and several anonymous referees for helpful comments which considerably improved the article. This work was supported in part by the German Science Foundation projects Br-655/16-1 and HO 1687/9-1.