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Alternatives to Laboratory Animals - ATLA

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Weighted p-value adjustments for animal carcinogenicity trend test.

Chen, J.J., Lin, K.K., Huque, M. and Arani, R.B.

Biometrics, 56(2), 586-592 (2000).

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 bg assuming that each tumor can be classified as either class A or class B based on Drier 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. Further more, 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 front 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 Feed 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.