Weighted p-value adjustments for animal carcinogenicity trend test.
A typical animal carcinogenicity experiment routinely analyzes approximately 10-30 tumor sites. Comparisons of tumor responses between dosed and control groups and dose-related trend tests are often evaluated for each individual tumor site/type separately. p-Value adjustment approaches have been proposed for controlling the overall Type I error rate or familywise error rate (FWE). However, these adjustments often result in reducing the power to detect a dose effect. This paper proposes using weighted adjustments by assuming that each tumor can be classified as either class A or class B based on prior considerations. The tumors in class A, which are considered as more critical endpoints, are given less adjustment. Two weighted methods of adjustments are presented, the weighted p adjustment and weighted alpha adjustment. A Monte Carlo simulation shows that both weighted adjustments control the FWE well. Furthermore, the power increases if a treatment-dependent tumor is analyzed as in class A tumors and the power decreases if it is analyzed as in class B tumors. A data set from a National Toxicology Program (NTP) 2-year animal carcinogenicity experiment with 13 tumor types/sites observed in male mice was analyzed using the proposed methods. The modified poly-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 unweighted adjustment analysis concluded that there was no statistically significant dose-related trend. Using the Food and Drug Administration classification scheme for the weighted adjustment analyses, two rare tumors (with background rates of 1% or less) were analyzed as class A tumors and 11 common tumors (with background rates higher than 1%) as class B. Both weighted analyses showed a significant dose-related trend for one rare tumor.
Chen
J J
JJ
Division of Biometry and Risk Assessment, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, USA. jchen@nctr.fda.gov
Lin
K K
KK
Huque
M
M
Arani
R B
RB
D000818:Animals; D015197:Carcinogenicity Tests / Q000706:statistics & numerical data*; D002273:Carcinogens / Q000633:toxicity; D003627:Data Interpretation, Statistical; D008297:Male; D051379:Mice; D015233:Models, Statistical; D009010:Monte Carlo Method; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000145:classification
D002273:Carcinogens