Abstract
Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research.
Highlights
Reproducibility of results from preclinical animal research is alarmingly low, and various threats to reproducibility have been proposed, including a lack of scientific rigor, low statistical power, analytical flexibility, and publication bias [1,2,3,4,5,6,7,8]
Preclinical animal research is mostly based on studies conducted in a single laboratory and under highly standardized conditions
This entails the risk that the study results may only be valid under the specific conditions of the test laboratory, which may explain the poor reproducibility of preclinical animal research
Summary
Reproducibility of results from preclinical animal research is alarmingly low, and various threats to reproducibility have been proposed, including a lack of scientific rigor, low statistical power, analytical flexibility, and publication bias [1,2,3,4,5,6,7,8]. Contrary to the common belief that standardization guarantees reproducibility (e.g., [9]), both theoretical [10,11,12] and empirical [13,14,15,16,17] evidence indicate that rigorous standardization may generate spurious results that are idiosyncratic to the specific standardized conditions under which they were obtained, thereby causing poor reproducibility This is because the response of an animal to an experimental treatment (e.g., a drug) often depends on the phenotypic state of the animal, which is a product of the genotype and the environmental conditions. Phenotypic plasticity caused by gene-by-environment (G × E) interactions determines the range of variation (reaction norm) of an animal’s response [18] Instead of incorporating such natural biological variation in the experimental design, laboratory animal scientists consider this variation as a nuisance, which they aim to eliminate through rigorous standardization of both genotype and environmental conditions [9]. Rigorously standardized single-laboratory studies continue to be the gold standard approach to animal research from basic exploratory research to late-phase preclinical testing
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