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Statistical analysis of in vivo rodent micronucleus assay

Cited 9 time in Web of Science Cited 11 time in Scopus
Authors
Kim, Byung Soo; Cho, Myung-Haing; Kim, Hyun Jung
Issue Date
2000-09
Citation
Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol.469 No.2, pp.233-241
Keywords
Cochran-Armitage trend testDunnett type testmicronucleus assayMonte Carlo simulationsize of a teststatistical proceduresstatistical software program
Abstract
The in vivo rodent micronucleus assay (MNC) is widely used as a cytogenetic assay to detect the clastogenic activity of a chemical in vivo. MNC is one of three tests in a battery recommended by the fourth International Conference on Harmonization (ICH4) of Genotoxicity Guidelines. As such it has been accepted by many regulatory authorities. However, the determination of a positive result in a genotoxicity test, including MNC, has been an issue of debate among toxicologists and biometricians. In this presentation we compare several statistical procedures that have been suggested for the analysis of MNC data and indicate which one is the most powerful. The standard protocol of MNC has at least three dose levels plus the control dose and uses at least four animals per group. For each animal, 2000 polychromatic erythrocytes (PCE) are counted. Two statistical procedures can be employed, either alone or jointly, for the analysis of the MNC dose-response curve. These are the Cochran-Armitage (C-A) trend test and the Dunnett type test. For performing Dunnett type tests, toxicologists often use negative historical control rate for the estimate of the concurrent negative control rate. Some toxicologists emphasize the reproducibility of assay results instead of the dose-response relationship for the important criterion [J. Ashby, H. Tinwell, Mutat. Res. 327 (1995) 49-55; for the rebuttal see M. Hayashi, T. Sofuni, Mutat. Res. 331 (1995) 173-174]. The following three procedures are currently employed in toxicology labs for the evaluation of MNC result. The assay response is deemed positive if it is detected by (i) the C-A trend test alone, (ii) both the C-A trend test and the Dunnett type test and (iii) either the C-A trend test or the Dunnett type test. Using Monte Carlo simulation, we first find for each procedure, sizes of tests which yield the experiment-wise type I error rate of 0.05 and show that the procedure (ii) is the most powerful against the alternatives of monotone increase. The procedure (ii) which originated from Hayashi's three-step procedure was coded in C and termed 'MNC'. The MNC software program is available in the public domain through the ftp. (C) 2000 Elsevier Science B.V. All rights reserved.
ISSN
1383-5718
URI
https://hdl.handle.net/10371/172478
DOI
https://doi.org/10.1016/S1383-5718(00)00085-1
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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