Dose–Response and Thresholds in Mutagenicity Studies: A Statistical Testing Approach

Abstract

The analysis of dose–response relationships is an important objective in toxicology, and one in which both modelling and testing approaches are used. One particular question is whether a threshold exists at low doses. The concept of a pragmatic threshold is used, i.e. low doses with biologically unimportant effects are assumed to be threshold doses. “Biologically unimportant” means, in statistical terms, a lower effect than the effect of the negative control, or at least a just-tolerable margin δ higher than the effect of the negative control. Therefore, threshold doses can be tested in terms of a one-sided hypothesis of equivalence. A new approach is proposed, assuming, at the least, that the low dose is a threshold dose, and the highest dose is superior to the negative control. By analogy to the k-fold rule commonly used in mutagenicity studies, tests on ratio-to-control are used. The a priori definition of the threshold margin is inherently needed. A further approach proposes the analysis of dose–response relationships by means of order-restricted inference (the so-called trend test). A modification of a multiple-contrast test is used, in which only those contrasts are included that are sensitive for no effects at low doses. A further modification treats the complicated, but real, problem of simultaneous existence of a threshold, a monotonic increase, and a downturn effect at high dose(s). A parametric procedure is considered, together with an extension for proportions. The important problem of a priori sample size definition is discussed. The approaches are demonstrated by means of examples based on real data.

Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials

“…In this retrospective analysis, patients were diagnosed with B-cell precursor acute lymphoblastic leukaemia by standard flow-cytometric criteria and were treated in the UKALL97/99 (between Jan 1, 1997, and June 15, 2002) or UKALL2003 (between Oct 1, 2003, and June 30, 2001) treatment trials, as previously described (appendix pp [22][23]. All patients aged 1-18 years (in UKALL97/99) and 1-24 years (in UKALL2003) from the UK and Ireland who were newly diagnosed with B-cell precursor acute lymphoblastic leukaemia were eligible for the trials.…”

Selected Biostatistical Aspects of the Validation of In Vitro Toxicological Assays

“…Complex statistical software is needed, but is available (18). This protected trend test approach can also be used for the identification of empirical threshold doses (6), by using J-shapesensitive contrasts only (19).…”

Biostatistical Assessment of Mutagenicity Studies: A Stepwise Confidence Procedure

“…Some simultaneous inferences remit multiplicity adjustments by invoking the partition principle proposed by Finner and Strassburger [6]: where the parameter space is partitioned into many disjoint subsets and only one of these nonempty disjoint subsets contains the true parameter of interest, so that the FWER will be properly controlled. In literature, mutagenicity dataset has been assessed according to the proof of safety by utilizing the concept of the maximum safe dose (Hothorn and Hauschke [7], by numerous authors, among them Hauschke and Hothorn [8], Hauschke et al [9], Hothorn and Bretz [10]). As a result, this article discusses statistical aspects in terms of design and analysis using stepwise confidence set-based procedure for identification of maximum safe dose: that is, the highest experiment dose with no biological relevant increase in safety effect in comparison with negative control (Hothorn amd Hauschke [9]).…”