Research with rodents is crucial for expanding our understanding of genetic and environmental risk factors for neurodevelopmental disorders (NDD). However, there is growing concern about the number of animal studies that are difficult to replicate, potentially undermining the validity of results. These concerns have prompted funding agencies and academic journals to implement more rigorous standards in an effort to increase reproducibility in research. However, these standards fail to address a major source of variability in rodent research brought on by the “litter effect,” the fact that rodents from the same litter are phenotypically more similar to one other than rodents from different litters of the same strain. We show that the litter effect accounts for 30–60% of the variability associated with commonly studied phenotypes, including brain, placenta, and body weight. Moreover, we show how failure to control for litter-to-litter variation can mask a phenotype in Chd8V986*/+ mice that model haploinsufficiency of CHD8, a high-confidence autism gene. Thus, if not properly controlled, the litter effect has the potential to negatively influence rigor and reproducibility of NDD research. While efforts have been made to educate scientists on the importance of controlling for litter effects in previous publications, our analysis of the recent literature (2015–2020) shows that the vast majority of NDD studies focused on genetic risks, including mutant mouse studies, and environmental risks, such as air pollution and valproic acid exposure, do not correct for litter effects or report information on the number of litters used. We outline best practices to help scientists minimize the impact of litter-to-litter variability and to enhance rigor and reproducibility in future NDD studies using rodent models.

中文翻译：

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控制垃圾影响以提高神经发育障碍啮齿动物模型的严谨性和可重复性

啮齿动物研究对于扩大我们对神经发育障碍 (NDD) 的遗传和环境风险因素的理解至关重要。然而，人们越来越担心难以复制的动物研究数量，这可能会破坏结果的有效性。这些担忧促使资助机构和学术期刊实施更严格的标准，以提高研究的可重复性。然而，这些标准未能解决由“垃圾效应”引起的啮齿动物研究变异的主要来源，即来自同一垃圾的啮齿动物在表型上与其他啮齿动物的表型更相似，而不是来自同一品系的不同垃圾的啮齿动物。我们表明，垃圾效应占与常用研究表型相关的变异的 30-60%，包括大脑、胎盘和体重。此外，我们展示了未能控制窝间变异如何掩盖 Chd8V986*/+ 小鼠的表型，该小鼠模型 CHD8 是一种高可信度自闭症基因的单倍体不足。因此，如果控制不当，垃圾效应有可能对 NDD 研究的严谨性和可重复性产生负面影响。虽然在以前的出版物中已经努力教育科学家控制垃圾影响的重要性，但我们对最近文献（2015-2020）的分析表明，绝大多数 NDD 研究都集中在遗传风险上，包括突变小鼠研究，以及环境风险，例如空气污染和丙戊酸暴露，不能纠正垫料影响或报告使用垫料数量的信息。