Variation and its implications for the design of experiments in toxicological research

Abstract

The controlled experiment is one of the most powerful tools available in biomedical research, and thousands of such experiments are conducted annually. However, the basic principles of designing such experiments do not seem to be widely understood. If the experimental material is heterogeneous, then the treated and control groups may not be identical at the start of the experiment, even if large sample sizes are used. Yet genetically heterogeneous ‘outbred’ stocks of laboratory mice and rats are widely used in the pharmaceutical industry in spite of the availability of more homogeneous inbred strains. The use of such stocks is justified on two grounds: that humans are also heterogeneous, and that such stocks offer a wide range of phenotypes for toxicological screening. Both arguments are spurious. It is not necessary for atoxicological model of humans to be a goodgenetic model. Models do not have to resemble their target in every respect. Were they to do so they would no longer be models. The genetic heterogeneity within an outbred stock simply creates ‘noise’ when comparing treated and control groups, and prevents more exact matching of groups before the experiment starts. Phenotypic heterogeneity can be achieved without this disadvantage using a factorial experimental design involving more than one strain, with groups exactly matched genetically, but without increasing total numbers.

The lack of understanding of good experimental design seems to extend to other areas, with few research workers using techniques such as blocking and factorial experimental designs which have been known for over 60 years, and which are widely used in other disciplines. Experiments are often unnecessarily large and surveys suggest that more than half have obvious statistical errors. Better training in experimental design would be cost effective in making better use of scarce resources, and would help to reduce the use of laboratory animals, which is an ethically desirable goal.