Lancaster Environment Centre, Lancaster University, Lancaster, UK; Evidence-based Toxicology Collaboration at Johns Hopkins Bloomberg School of Public Health (EBTC), Washington, DC, USA.
Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St West, Hamilton, Onatario L8N 3Z5, Canada.
J Clin Epidemiol. 2022 Jun;146:32-46. doi: 10.1016/j.jclinepi.2022.02.011. Epub 2022 Feb 24.
"Biological plausibility" is a concept frequently referred to in environmental and public health when researchers are evaluating how confident they are in the results and inferences of a study or evidence review. Biological plausibility is not, however, a domain of one of the most widely used approaches for assessing the certainty of evidence (CoE) which underpins the findings of a systematic review, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) CoE Framework.
Whether the omission of biological plausibility is a potential limitation of the GRADE CoE Framework is a topic that is regularly discussed, especially in the context of environmental health systematic reviews.
We analyze how the concept of "biological plausibility," as applied in the context of assessing certainty of the evidence that supports the findings of a systematic review, is accommodated under the processes of systematic review and the existing GRADE domains.
We argue that "biological plausibility" is a concept which primarily comes into play when direct evidence about the effects of an exposure on a population of concern (usually humans) is absent, at high risk of bias, inconsistent, or limited in other ways. In such circumstances, researchers look toward evidence from other study designs to draw conclusions. In this respect, we can consider experimental animal and in vitro evidence as "surrogates" for the target populations, exposures, comparators, and outcomes of actual interest. Through discussion of 10 examples of experimental surrogates, we propose that the concept of biological plausibility consists of two principal aspects: a "generalizability aspect" and a "mechanistic aspect."
The "generalizability aspect" concerns the validity of inferences from experimental models to human scenarios, and asks the same question as does the assessment of external validity or indirectness in systematic reviews. The "mechanistic aspect" concerns certainty in knowledge of biological mechanisms and would inform judgments of indirectness under GRADE, and thus the overall CoE. Although both aspects are accommodated under the indirectness domain of the GRADE CoE Framework, further research is needed to determine how to use knowledge of biological mechanisms in the assessment of indirectness of the evidence in systematic reviews.
“生物学合理性”是研究人员在评估对研究或证据综述结果和推论的置信度时，在环境和公共卫生领域经常提到的一个概念。然而，“生物学合理性”并不是评估证据确定性（CoE）的最广泛使用方法之一的领域，该方法是系统综述、推荐评估、发展和评价（GRADE）CoE 框架的发现的基础。
在环境健康系统评价的背景下，经常讨论省略“生物学合理性”是否是 GRADE CoE 框架的潜在局限性。
我们分析了在评估支持系统综述发现的证据确定性的过程中，如何适应“生物学合理性”这一概念，以及现有的 GRADE 领域。
我们认为，“生物学合理性”是一个概念，主要在缺乏直接证据、存在高偏倚风险、不一致或其他方面有限的情况下，当涉及到对关注人群（通常是人类）的暴露影响的证据时发挥作用。在这种情况下，研究人员会寻找其他研究设计的证据来得出结论。在这方面，我们可以将实验动物和体外证据视为实际目标人群、暴露、比较和结果的“替代物”。通过讨论 10 个实验替代物的例子，我们提出“生物学合理性”概念包括两个主要方面：“可推广性方面”和“机制方面”。
“可推广性方面”涉及从实验模型到人类场景的推断的有效性，并提出了与系统综述中外部有效性或间接性评估相同的问题。“机制方面”涉及对生物机制知识的确定性，并将为 GRADE 中对间接性的判断提供信息，从而影响总体 CoE。尽管这两个方面都在 GRADE CoE 框架的间接性领域中得到了适应，但需要进一步研究如何在系统综述证据的间接性评估中利用对生物机制的知识。
