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Weighted p ‐Value Adjustments for Animal Carcinogenicity Trend Test
Author(s) -
Chen James J.,
Lin Karl K.,
Huque Mohammad,
Arani Ramin B.
Publication year - 2000
Publication title -
biometrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.298
H-Index - 130
eISSN - 1541-0420
pISSN - 0006-341X
DOI - 10.1111/j.0006-341x.2000.00586.x
Subject(s) - statistics , mathematics , type i and type ii errors , carcinogen , medicine , toxicology , biology , genetics
Summary. 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 α 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.