The use of mechanistic reasoning in assessing coronavirus interventions

Abstract

Rationale Evidence‐based medicine (EBM), the dominant approach to assessing the effectiveness of clinical and public health interventions, focuses on the results of association studies. EBM+ is a development of EBM that systematically considers mechanistic studies alongside association studies. Aims and objectives To explore examples of the importance of mechanistic evidence to coronavirus research. Methods We have reviewed the mechanistic evidence in four major areas that are relevant to the management of COVID‐19. Results and conclusions (a) Assessment of combination therapy for MERS highlights the need for systematic assessment of mechanistic evidence. (b) That hypertension is a risk factor for severe disease in the case of SARS‐CoV‐2 suggests that altering hypertension treatment might alleviate disease, but the mechanisms are complex, and it is essential to consider and evaluate multiple mechanistic hypotheses. (c) Confidence that public health interventions will be effective requires a detailed assessment of social and psychological components of the mechanisms of their action, in addition to mechanisms of disease. (d) In particular, if vaccination programmes are to be effective, they must be carefully tailored to the social context; again, mechanistic evidence is crucial. We conclude that coronavirus research is best situated within the EBM+ evaluation framework.

Adapt or die: how the pandemic made the shift from EBM to EBM+ more urgent

“…13 This is because real-world circumstances often differ from the ones in which a probabilistic estimate (such as an effect size in an RCT) was demonstrated; evidence supporting a plausible mechanism affirms (or not) that the causal relationship is likely to be stable across settings. 13 The presence of high-quality and consistent mechanistic evidence greatly increases the external 2 Mechanistic evidence is inherently explanatory. It helps address the question 'how might this effect be produced?'…”

“…This paper explains why we need to go beyond lip-service to evidential pluralism to fully answer those questions. While acknowledging the primacy of randomised controlled trials (RCTs) and meta-analyses of RCTs for estimating the efficacy of drugs and vaccines, we highlight and extend the arguments made by some scholars within the evidence-based medicine (EBM) movement for ‘EBM+’,1 2 defined as an approach which systematically considers mechanistic evidence (studies which aim to explain which factors and interactions are responsible for a phenomenon3) on a par with probabilistic clinical and epidemiological studies. Our central argument is that for some aspects of the pandemic, especially those characterised by a combination of complexity (multiple variables interacting dynamically with a high degree of uncertainty), urgency (decisions needed in days not years) and threat (the consequences of not acting could be catastrophic), mechanistic evidence has been mission-critical and RCTs difficult or impossible.…”

Humans, machines and decisions: Clinical reasoning in the age of artificial intelligence, evidence‐based medicine and Covid‐19

“…Perhaps inevitably, given our recent history, this edition includes a section for papers addressing the issues of reasoning-epistemological and moral-in the context of the Covid-19 pandemic. [28][29][30][31] Following the discussion of EBM, causal explanation and mechanisms in the preceding section, this one opens with a discussion of the use of EBM and mechanistic reasoning in assessing coronavirus interventions. 28 The authors present several examples to illustrate the importance of mechanistic evidence in this context, defending 'EBM+', an approach to evaluating interventions combining mechanistic studies and association studies.…”

“…[28][29][30][31] Following the discussion of EBM, causal explanation and mechanisms in the preceding section, this one opens with a discussion of the use of EBM and mechanistic reasoning in assessing coronavirus interventions. 28 The authors present several examples to illustrate the importance of mechanistic evidence in this context, defending 'EBM+', an approach to evaluating interventions combining mechanistic studies and association studies. They argue that this approach has an important role in public health, in particular with regard to the prospects for success in the on-going vaccination programmes.…”

From “getting things right” to “getting things right now”: Developing COVID‐19 guidance under time pressure and knowledge uncertainty

“…† Guidance institutions tried to streamline guidance development but found the emergence of a new disease and the urgency of need compromised the requirement for basing recommendations on prevailing standards of robust “high quality” research evidence. 10 Instead, guidance developers needed to rely on other types of knowledge, 11 including observational studies, 11 mechanistic studies 5 , 12 and indirect evidence on the effects on transmission of other viruses in non‐pandemic conditions. 13 What is more, the urgency for guidance meant that developers could no longer aim to “get things right” but had to “get things right now”.…”