Biostatistical Assessment of Mutagenicity Studies: A Stepwise Confidence Procedure

Michael Jackson Adjabui ,Mathias Akamba,Nathaniel Howard

doi:10.1155/2019/3249097

Abstract

The paper addresses the issue of identifying the maximum safe dose in the context of noninferiority trials where several doses of toxicological compounds exist. Statistical methodology for identifying the maximum safe dose is available for three-arm noninferiority designs with only one experimental drug treatment. Extension of this methodology for several experimental groups exists but with multiplicity adjustment. However, if the experimental or the treatment groups can be ordered a priori according to their treatment effect, then multiplicity adjustment is unneeded. Assuming homogeneity of variances across dose group in normality settings, we employed the generalized Fieller’s confidence interval method in a multiple comparison stepwise procedure by incorporating the partitioning principle in order to control the familywise error rate (FWER). Simulation results revealed that the procedure properly controlled the FWER in strong sense. Also, the power of our procedure increases with increasing sample size and the ratio of mean differences. We illustrate our procedure with mutagenicity dataset from a clinical study.

Highlights

Assessing an investigational substance for mutagenic activity is one of the vital concerns of genetic toxicologists
The objective of mutagenicity assay in regulatory toxicology is the decision on mutagenicity or nonmutagenicity of an investigational substance (Hothorn et al, [1])
We simultaneously compare each of the k treatments with the negative control. Statistical decision in this settings involves multiple comparison and stepwise procedures: that is, individual inferences are made in stepwise manner if the sequence of individual inferences is in a specific order, as used in Stefensson et al [2], Cao et al [3], Chen [4], and Adjabui et al [5]

Summary

Introduction

Assessing an investigational substance for mutagenic activity is one of the vital concerns of genetic toxicologists. A typical experimental design used in this assay for genotoxicity assessment in one-way model in k + 2 groups is as follows: In this setup, we have two objectives to achieve. We simultaneously compare each of the k treatments with the negative control Statistical decision in this settings involves multiple comparison and stepwise procedures: that is, individual inferences are made in stepwise manner if the sequence of individual inferences is in a specific order, as used in Stefensson et al [2], Cao et al [3], Chen [4], and Adjabui et al [5].

Preliminaries

The Proposed Procedure

Simulation Studies

Example

Conclusion