Abstract
This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), “…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not.” Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)–based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.
Highlights
POSSIBLE SYSTEMATIC APPROACHES?To begin systematically structuring the rapidly accumulating information on COVID-19 (Triggle et al, 2021)—in the hopes of clarifying and reconciling the discrepancies, and eventually maturing the information into clinically-actionable knowledge and understanding—let us view this topic along three “axes” implied by our opening sentence: namely, we consider 1) a context-of-disease (COD) axis, 2) a degree-of-(therapeutic)benefit (DOB) axis, and 3) a mechanism-of-action (MOA) axis
We only note that a recent study (Malone et al, 2021) offers a detailed and insightful analysis of possible on–/off–target properties of famotidine, as regards 1) hypothesis testing of its mechanism/mode of action (MOA), and 2) discrepancies that can arise among different studies because of differences in dosage, single- and multi-agent treatment regimes, pharmacokinetic–related properties (e.g., ADME), and so on; notably, that work concluded that off-target pathways likely do not play a major role in the case of famotidine as a potential COVID-19 therapeutic
Perhaps some inconsistencies can be resolved by viewing famotidine and its potential roles in COVID-19 through a more mechanistic, molecular-level lens? Alongside the observational, patient-based studies, the potential MOA for a therapeutic role of famotidine has been explored in a few publications
Summary
To begin systematically structuring the rapidly accumulating information on COVID-19 (Triggle et al, 2021)—in the hopes of clarifying and reconciling the discrepancies, and eventually maturing the information into clinically-actionable knowledge and understanding—let us view this topic along three “axes” implied by our opening sentence: namely, we consider 1) a context-of-disease (COD) axis, 2) a degree-of-(therapeutic)benefit (DOB) axis, and 3) a mechanism-of-action (MOA) axis. There exists the possibility of spurious links (or, inversely, masked associations) because of underlying physiological factors, e.g., Sethia et al.’s (2020a) description of the impacts of 1) potentially great differences in disease severity on treatment outcomes (without adequately accounting for such in case-matching and stratification methods to obtain sub-cohorts), FIGURE 1 | An ontological perspective on famotidine and COVID-19. This diagram (A) illustrates the types of RDF triple associations, consisting of a (subject, predicate, object) triplet, that express the relations between entities that underlie an ontology. Regardless, Etminan et al highlight several improvements that can be made in future approaches to statistically elucidate famotidine ↔ COVID-19 relationships
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