A Computational Tool for Testing Dose-Related Trend Using an Age-Adjusted Bootstrap-Based Poly-kTest

Abstract

A computational tool for testing for a dose-related trend and/or a pairwise difference in the incidence of an occult tumor via an age-adjusted bootstrap-based poly-k test and the original poly-k test is presented in this paper. The poly-k test (Bailer and Portier 1988) is a survival-adjusted Cochran-Armitage test, which achieves robustness to effects of differential mortality across dose groups. The original poly-k test is asymptotically standard normal under the null hypothesis. However, the asymptotic normality is not valid if there is a deviation from the tumor onset distribution that is assumed in this test. Our age-adjusted bootstrap-based poly-k test assesses the significance of assumed asymptotic normal tests and investigates an empirical distribution of the original poly-k test statistic using an age-adjusted bootstrap method. A tumor of interest is an occult tumor for which the time to onset is not directly observable. Since most of the animal carcinogenicity studies are designed with a single terminal sacrifice, the present tool is applicable to rodent tumorigenicity assays that have a single terminal sacrifice. The present tool takes input information simply from a user screen and reports testing results back to the screen through a user-interface. The computational tool is implemented in C/C++ and is applied to analyze a real data set as an example. Our tool enables the FDA and the pharmaceutical industry to implement a statistical analysis of tumorigenicity data from animal bioassays via our age-adjusted bootstrap-based poly-k test and the original poly-k test which has been adopted by the National Toxicology Program as its standard statistical test.

Carcinogenicity and testicular toxicity of 2-bromopropane in a 26-week inhalation study using the rasH2 mouse model

“…jstat soft. org/ artic le/ view/ v016i 07 33 . The incidences of non-neoplastic lesions were analyzed using the chi-square test, and the severity was defined as 1, slight; 2, moderate; 3, marked; and 4, severe.…”

“…All statistical analysis, except for the Poly-k test, was carried out by the BAIS system (Hitachi Social Information Services Ltd., Tokyo, Japan) and GraphPad Prism 5 (GraphPad Software, San Diego, CA). The incidence of neoplastic lesions was statistically analyzed by Fisher’s exact test and incidence trend was analyzed by Peto mortality-prevalence test (Peto’s trend test) and the Poly-k (k = 3) test (Poly-3 trend test) using the age-adjusted Poly-k testing software available at http://www.jstatsoft.org/article/view/v016i07 33 . The incidences of non-neoplastic lesions were analyzed using the chi-square test, and the severity was defined as 1, slight; 2, moderate; 3, marked; and 4, severe.…”

Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats

“…The Kaplan-Meir method and log-rank test was used for survival analysis. Incidences of neoplastic lesions were analyzed for a dose-response relationship by the Poly-k (k=3) test (Poly-3 trend test) using the age-adjusted Poly-k testing software available at https://www.jstatsoft.org/article/view/v016i07 (Moon et al 2006). Differences in the incidences of histopathological lesions and urinalysis parameters between control and treatment groups were evaluated by 2-tailed Fisher's exact test.…”