Interpreting global variations in the toll of COVID-19: The case for context and nuance in hypothesis generation and testing.

Key points: As of January 2022, the COVID-19 pandemic was on-going, affecting populations worldwide. The potential risks of the Omicron variant (and future variants) still remain an area of active investigation. Thus, the ultimate human toll of SARS-CoV-2, and, by extension, the variations in that toll among diverse populations, remain unresolved. Nonetheless, an extensive literature on causal factors in the observed patterns of COVID-19 morbidity and cause-specific mortality has emerged-particularly at the aggregate level of analysis. This article explores potential pitfalls in the attribution of COVID outcomes to specific factors in isolation by examining a diverse set of potential factors and their interactions. Methods: We sourced published data to establish a global database of COVID-19 outcomes for 68 countries and augmented these with an array of potential explanatory covariates from a diverse set of sources. We sought population-level aggregate factors from both health- and (traditionally) non-health domains, including: (a) Population biomarkers (b) Demographics and infrastructure (c) Socioeconomics (d) Policy responses at the country-level. We analyzed these data using (OLS) regression and more flexible non-parametric methods such as recursive partitioning, that are useful in examining both potential joint factor contributions to variations in pandemic outcomes, and the identification of possible interactions among covariates across these domains. Results: Using the national obesity rates of 68 countries as an illustrative predictor covariate of COVID-19 outcomes, we observed marked inconsistencies in apparent outcomes by population. Importantly, we also documented important variations in outcomes, based on interactions of health factors with covariates in other domains that are traditionally not related to biomarkers. Finally, our results suggest that single-factor explanations of population-level COVID-19 outcomes (e.g., obesity vs. cause-specific mortality) appear to be confounded substantially by other factors. Conclusions/implications: Our methods and findings suggest that a full understanding of the toll of the COVID-19 pandemic, as would be central to preparing for similar future events, requires analysis within and among diverse variable domains, and within and among diverse populations. While this may seem apparent, the bulk of the recent literature on the pandemic has focused on one or a few of these drivers in isolation. Hypothesis generation and testing related to pandemic outcomes will benefit from accommodating the nuance of covariate interactions, in an epidemiologic context. Finally, our results add to the literature on the ecological fallacy: the attempt to infer individual drivers and outcomes from the study of population-level aggregates.