Causal mediation analysis and the promise of αDEspR, a preclinical potential COVID-19 treatment in the ICU

Music City Center 

Mediation analysis, which started in the mid-1980s, is used extensively by applied researchers. Indirect and direct effects are the parts of a treatment effect that are mediated by a covariate (indirect effect) and the part that is not (direct effect). Subsequent work on natural and pure indirect and direct effects provides a formal causal interpretation, based on cross-worlds counterfactuals: outcomes under treatment with the mediator set to its value without treatment. Organic indirect and direct effects avoid cross-worlds counterfactuals, using so-called organic interventions on the mediator while keeping the initial treatment fixed. We argue that pure and organic indirect effects are very relevant for drug development: 1] They are often the effect of a treatment through its intended pathway, and 2] they can be estimated without on-treatment outcome data. We illustrate our approach by estimating the pure/organic indirect effect of αDEspR in COVID-19 patients in the ICU. αDEspR targets elimination of circulating DEspR+ neutrophils extruding neutrophil-extracellular traps (NET+Ns) to attenuate or prevent multi-organ failure in critical COVID-19 in the ICU. Thus, we estimate the pure/organic indirect effect of αDEspR mediated by DEspR+[NET+Ns]. Using the sequential organ failure assessment (SOFA)-score as a measure of multi-organ failure, we estimated the pure/organic indirect effect of αDEspR using outcome data from patients with COVID-19 in the ICU not treated with αDEspR. Our analysis illustrates the pre-clinical promise of αDEspR, to be used as an argument to fund an early-stage randomized clinical trial to collect on-treatment outcomes and estimate αDEspR's overall effect – thus giving insight into clinical trial design. Causal mediation analysis can also be used as a way to evaluate DEspR+[NET+Ns] as a clinical trial stratifying and monitoring biomarker in critical COVID-19. This illustrates how causal mediation analysis can be used as a much-needed translational bridge from animal model testing towards clinical trial testing.

mediation

causal

COVID

ICU