Weighted p-value adjustments for animal carcinogenicity trend test

A typical animal carcinogenicity experiment routinely analyzes approximatel y 10-30 tumor sites. Comparisons of tumor responses between dosed and contr ol groups and dose-related trend tests are often evaluated for each individ ual tumor site/type separately, p-Value adjustment approaches have been pro posed for controlling the overall Type I error rate or familywise error rat e (FWE). However, these adjustments often result in reducing the power to d etect a dose effect. This paper proposes using weighted adjustments bg assu ming that each tumor can be classified as either class A or class B based o n Drier considerations. The tumors in class A, which are considered as more critical endpoints, are given less adjustment. Two weighted methods of adj ustments are presented, the weighted p adjustment and weighted alpha adjust ment. A Monte Carlo simulation shows that both weighted adjustments control the FWE well. Further more, the power increases if a treatment-dependent t umor is analyzed as in class A tumors and the power decreases if it is anal yzed as in class B tumors. A data set front a National Toxicology Program ( NTP), 2-year animal carcinogenicity experiment with 13 tumor types:sites ob served in male mice was analyzed using the proposed methods. The modified p oly-3 test was used to test for increased carcinogenicity since it has been adopted by the NTP as a standard test for a dose-related trend. The unweig hted adjustment analysis concluded that there was no statistically signific ant dose-related trend. Using the Feed and Drug Administration classificati on scheme for the weighted adjustment analyses, two rare tumors (with backg round rates of 1% or less) were analyzed as class A tumors and 11 common tu mors (with background rates higher than 1%) as class B. Both weighted analy ses showed a significant dose-related trend for one rare tumor.