Issues in the Experimental Design and Statistical Analysis of In Vitro Mutagenicity Tests

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0092-8615/97 Copyright 0 1997 Drug Information Association Inc.

ISSUES IN THE EXPERIMENTAL DESIGN AND STATISTICAL ANALYSIS OF IN VITRO MUTAGENICITY TESTS DAVIDP. LOVELL,BSc, PHD, FSS, MIBIoL, CBIOL,CSTAT Head of Biostatistics and Computer Services, BIBRA International, Carshalton, Surrey, United Kingdom

This paper discusses issues related to the statistical analysis of in vitro testsfor mutagenicity. The range of methods available from bacterial tests such as the Ames/Salmonella assay to the use of human lymphocyte culture assays for in vitro mutagenicity tests are outlined. Aspects of experimental designs associated with the direrent in vitro tests are compared and contrasted. The relative power of the direrent in vitro tests is discussed and contrasted with the power associated with the comparable in vivo tests. The use of techniques such as randomization, replication, and blocking to minimize the introduction of biases is stressed. The need for independent repeats of the experiment is emphasized. The purpose of statistical analysis of the data and the relative importance of hypothesis testing and estimation is discussed in the context of the choice of analytical methods, the power of the designs, and the Type I and 2 errors associated with the tests. The potential to incorporate historical control data into the assessments is considered. Actual data are used to illustrate some of the problems encountered in the analysis of in vitro mutagenicity data. It is argued that statistical analysis is only one aspect of the assessment of in vitro mutagenicity tests. Guidelines for the choice of experimental design and statistical analysis should not be overprescriptive but rather should be flexible enough to allow the full power of the two disciplines of statistics and genetic toxicology to be utilized. Key Words: In vitro testing; Genotoxicity; Statistics; Guidelines; Mutagenesis

INTRODUCTION “A little onward lend thy guiding hand to these dark steps a little further on.” John Milton (1608-1674)

THE OBJECTIVE OF this paper is two-fold:

Presented at the DIA Workshop “Statistical Methodology in Non-clinical and Toxicological Studies,” March 25-27, 1996, Bruges, Belgium. Reprint address: Dr, David p, Lovell, B I B U International, Woodmansterne Road, Carshalton, Surrey, SM5 4DS, United Kingdom.

1. To assess the appropriateness of biostatistical methods described in genetic toxicology guidelines and related International Conference on Harmonisation (ICH) documents or drafts, and 2. To discuss important issues of interest to statisticians involved in nonclinical and toxicology phases of drug development. A key question is: “is there a need for new ,@delines for statistical analysis?, this ‘Ontext it is perhaps surprising how strong definitions of guideline are. For instance, the Wordperfect Thesaurus gives the

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David P. Love11

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following synonyms for guideline: direction, instruction, rule, stricture, regulation; while the Concise Oxf