Reproducible preclinical research-Is embracing variability the answer?

Abstract

Translational failures and replication issues of published research are undermining preclinical research and, if the outcomes are questionable, raise ethical implications over the continued use of animals. Standardization of procedures, environmental conditions, and genetic background has traditionally been proposed as the gold standard approach, as it reduces variability, thereby enhancing sensitivity and supporting reproducibility when the environment is defined precisely. An alternative view is that standardization can identify idiosyncratic effects and hence decrease reproducibility. In support of this alternative view, Voelkl and colleagues present evidence from resampling a large quantity of research data exploring a variety of treatments. They demonstrate that by implementing multi-laboratory experiments with as few as two sites, we can increase reproducibility by embracing variation without increasing the sample size.

Fig 1. Visualization of phenotypic plasticity.

A schematic to demonstrate the effect of phenotypic plasticity on an outcome measure. Each line with a unique color represents a different genotype. (A) Behavior when there is no phenotypic plasticity showing an outcome that depends on the genotype but is independent of the environment. (B) Behavior when there is phenotypic plasticity showing that the outcome depends on the genotype, environment, and an interaction between the genotype and environment. The observed phenotype for an organism, for the majority of traits, is a function of the environment and the genotype. G, genotype; E, environment; temp, temperature.

Fig 2. Treatment effect can depend on the environment.

The response of an organism to a treatment not only depends on the treatment but also on the state of the organism, which is a function of the current and historic environment. (A) Visualizes a treatment effect that is idiosyncratic to a particular environment. (B) Visualizes a treatment effect that is more generalizable. Whilst idiosyncratic findings are biologically relevant and can give insight to biological function and mechanism, a treatment effect that is more generalizable may be more likely to translate.