Identification of the Minimum Effective Dose for Normally Distributed Endpoints Using a Model Selection Approach

Abstract

When identifying the minimum effective dose (MED) or the lowest observed adverse event level (LOAEL), researchers usually employ multiple comparison procedures (MCPs). The ones preferred are the Dunnett-type difference-to-placebo and ratio-to-control test. In this article, we will use a model selection criterion, namely the generalized order-restricted information criterion (GORIC). The GORIC can evaluate a set of hypotheses regarding the response means directly and simultaneously, where in this case in each hypothesis a different dose is hypothesized to be the MED or LOAEL. It takes different patterns of increasing response with increasing dose into account without pooling response means, whereas MCPs with order restrictions do. The GORIC chooses the best hypothesis of the set leading to the identification of the MED and, depending on the set, to a specific pattern of response means. We will show, by simulation, that the GORIC has advantages in identifying the MED or LOAEL, besides theoretical ones. Supplementary materials for this article are available online.

Key Words:

• Analysis of variance
• GORIC
• LOAEL
• MED
• Optimal dose
• Order restrictions

Acknowledgments

The work of LAH was partly supported by the German Science Foundation grand HO-1687/9.