Abstract: medRxiv preprint doi: https://doi.org/10.1101/2020.05.01.20087965; this version posted June 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 9th June 2020 Evidence Supports a Causal Role for Vitamin D Status in Global COVID-19 Outcomes Evidence Supports a Causal Role for Vitamin D Status in Global COVID-19 Outcomes Gareth Davies (PhD), Attila R Garami (MD, PhD), Joanna Byers (MBChB) Version: 9th June 2020 Abstract Background: The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 seemed to affect locations in the northern hemisphere most severely appearing to overlap with the pattern of seasonal vitamin D deficiency. Integrating available knowledge, we hypothesised that vitamin D status could play a causal role in COVID-19 outcomes. Objectives: We set out to analyse the relationship between COVID-19 severity and latitude, and construct a causal inference framework to validate this hypothesis. Methods: We analysed global daily reports of fatalities and recoveries from 239 locations from 22nd Jan 2020 to 9th April 2020. We quantified local COVID-19 outbreak severity to clearly distinguish the latitude relationship and identify any outliers breaking this pattern, and analysed the timeline of spread. We then used a causal inference framework to distinguish correlation from cause using observational data with a hypothetico-deductive method of proof. We constructed two contrasting directed acyclic graph (DAG) models, one causal and one acausal with respect to vitamin D and COVID-19 severity, allowing us to make 19 verifiable and falsifiable predictions for each. Results: ​Our analysis confirmed a striking correlation between COVID-19 severity and latitude, and ruled out the temporal spread of infection as an explanation. We compared observed severity for 239 locations with our contrasting model. In the causal model, 16 predictions matched observed data and 3 predictions were untestable; in the acausal model, 14 predictions strongly contradicted observed data, 2 appeared to contradict data, and 3 were untestable. Discussion: We show in advance of RCTs that observed data strongly match predictions made by the causal model but contradict those of the acausal model. We present historic evidence that vitamin D supplementation prevented past respiratory virus pandemics. We discuss how molecular mechanisms of vitamin D action can prevent respiratory viral infections and protect against ARDS. We highlight vitamin D's direct effect on the renin-angiotensin-system (RAS), which in concert with additional effects, can modify host responses thus preventing a cytokine storm and SARS-CoV-2-induced pathological changes. Emerging clinical research confirms striking correlations between hypovitaminosis D and COVID-19 severity, in full alignment with our study. Conclusions: Our novel causal inference analysis of global data verifies that vitamin D status plays a key role in COVID-19 outcomes. The data set size, supporting historical, biomolecular, and emerging clinical research evidence altogether suggest that a very high level of confidence is justified. Vitamin D prophylaxis potentially offers a widely available, low-risk, highly-scalable, and cost-effective pandemic management strategy including the mitigation of local outbreaks and a second..