Overall Type I Error Rate and Power of Multiple Dunnett's Tests on Rodent Body Weights in Toxicology Studies

Abstract

Body weight data are routinely collected in in vivo general toxicology studies, including 2-year carcinogenicity studies, to help assess the overall health of animals. The effect of the compound on body weight is statistically evaluated for each sex separately using a linear trend test or a many-to-one test by Dunnett. These tests are performed either in the framework of a one-factor analysis of variance (ANOVA) or a repeated measures ANOVA. The one-factor ANOVA with Dunnett's test at each time point is a common practice in industry. Although each individual test is conducted at the 0.05 significance level, one wonders about the overall type I error rate and power for performing many individual Dunnett's tests. A simulation study is conducted to answer this question for general toxicology studies of durations 1 month, 3 months, and 2 years. These results provide guidance to managing multiplicity of body weight analysis of general toxicology studies.

Key Words:

• General toxicology studies
• Longitudinal data
• Multiplicity of testing
• Overall type I error rate and power
• Parallel design

ACKNOWLEDGMENT

The authors thank Dr. Karl Lin for motivating this research project and providing guidance throughout. We also thank Drs. Gerald Long, Robert vanLier, and Alex Dmitrienko for their valuable suggestions that helped improve this manuscript.

Notes

Note 1: Strong correlation refers to 0.97, 0.98, and 0.96 for a 4-week, 13-week, and 2-year study, respectively. Note 2: Based on 1000 simulations. Note 3: ARH(1) stands for heterogeneous first-order autoregressive.

Note 1: Strong correlation refers to 0.97, 0.98, and 0.96 for a 4-week, 13-week, and 2-year study, respectively. Note 2: Based on 1000 simulations. Note 3: ARH(1) stands for heterogeneous first-order autoregressive.

Note 1: Strong correlation refers to 0.97, 0.98 and 0.96 for a 4-week, 13-week, and 2-year study, respectively. Note 2: Based on 1000 simulations.

Note 1: Based on 1000 simulations.

Note 2: 15 animals per group and 4 groups including the control.

Note 1: Based on 1000 simulations. Note 2: 15 animals per group and 4 groups including the control. Note 3: ARH(1) stands for heterogeneous first-order autoregressive.

Note 1: Based on 1000 simulations. Note 2: 10 animals per group and 4 groups including the control. Note 3: ARH(1) stands for heterogeneous first-order autoregressive.