An Age-Adjusted Trend Test for the Tumor Incidence Rate for Single-Sacrifice Experiments
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0092-8615/97 Copyright 0 1997 Drug Information Association Inc.
AN AGE-ADJUSTED TREND TEST FOR THE TUMOR INCIDENCE RATE FOR SINGLE-SACRIFICE EXPERIMENTS RALPHL. KODELL,BRUCEA. PEARCE, AND ANGELOTURTURRO Division of Biometry and Risk Assessment, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas
HONGSHIKAHN Department of Applied Mathematics and Statistics, State University of New York at Stony Brook, Stony Brook, New York
The nonparametric age-adjusted test proposed by Kodell and Ahn ( 1 )for assessing doserelated trend with respect to the tumor incidence rate in animal experiments is extended from the case of multiple sacrifices to the case of a single (terminal)sacrifice. The tumor incidence rate is made identifiable for time intervals preceding the final time interval by assuming constant proportionality of the tumor prevalences in live and dead animals. Information on cause of death is not required. A Monte Carlo simulation study is conducted to assess size and power of the test. Key Words: Bioassay; Constrained maximization; Delta method; Power; Proportional prevalences; Single Sacrifice; Size
INTRODUCTION THIS PAPER DESCRIBES a nonparametric test for dose-related trend in the age-specific tumor incidence rate of a tumorigenesis bioassay that has no cause-of-death information and that has only a single sacrifice at the termination of the study. Without cause-of-death information or interval sacrifices, simplifying assumptions are necessary in order for tumor incidence rates for occult tumors to be identifiable from bioassay data (2). When cause-ofdeath data are available, the combined fatal-incidental tumor analysis of Pet0 et al. (3) is widely used to test for dose-related trend in preclinical studies, especially in the pharmaceutical industry. When cause-of-death information is not available on a case-by-case basis, but an assumption can be made about the likely lethality of the tumor of interest, either the incidental-tumor component or the fatal-tumor component of the test of Pet0 et al. (3) can be used (4). For data from studies that include interval sacrifices, but no cause-of-death data and no information about the likely lethality of tumors, statistical methods for analyzing tumor incidence rates have been proposed by a number of authors, including Dewanji and Kalbfleisch (3, Portier and Dinse (6), Malani and Van Ryzin (7), Williams and Portier (8), Malani and Lu (9), Ahn and Kodell (lo), and Kodell and Ahn (1,ll). Reprint address: Ralph L. Kodell, Division of Biometry and Risk Assessment, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079.
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R. L. Kodell. R. A. Peurce. A. Turturro. and H.Ahn
For data from bioassays with no information (or assumptions) regarding tumor lethality or cause-of-death, and no interval sacrifices. only Dinse (12) and Lindsey and Ryan (13) have proposed statistical tests for dose-related trend. Dinse's test
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