Reproducibility in biomedical research, and more specifically in preclinical animal research, has been seriously questioned. Several cases of spectacular failures to replicate findings published in the primary scientific literature have led to a perceived reproducibility crisis. Diverse threats to reproducibility have been proposed, including lack of scientific rigour, low statistical power, publication bias, analytical flexibility and fraud. An important aspect that is generally overlooked is the lack of external validity caused by rigorous standardization of both the animals and the environment. Here, we argue that a reaction norm approach to phenotypic variation, acknowledging gene-by-environment interactions, can help us seeing reproducibility of animal experiments in a new light. We illustrate how dominating environmental effects can affect inference and effect size estimates of studies and how elimination of dominant factors through standardization affects the nature of the expected phenotype variation through the reaction norms of small effect. Finally, we discuss the consequences of reaction norms of small effect for statistical analysis, specifically for random effect latent variable models and the random lab model.

生物医学研究，尤其是临床前动物研究中的可重复性受到严重质疑。几起复制主要科学文献中发表的研究结果的重大失败案例导致了可感知的可重复性危机。已经提出了对可重复性的多种威胁，包括缺乏科学严谨性、统计能力低、发表偏倚、分析灵活性和欺诈。通常被忽视的一个重要方面是由于动物和环境的严格标准化导致缺乏外部有效性。在这里，我们认为表型变异的反应规范方法，承认基因与环境的相互作用，可以帮助我们以新的眼光看待动物实验的可重复性。我们说明了主导环境效应如何影响研究的推断和效应大小估计，以及通过标准化消除主导因素如何通过小效应的反应规范影响预期表型变异的性质。最后，我们讨论了统计分析中小效应的反应范数的后果，特别是对于随机效应潜在变量模型和随机实验室模型。