Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes
PhD Gareth Davies, MD, PhD Attila R Garami, MBChB Joanna Byers
doi:10.1101/2020.05.01.20087965
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 wave. Timely implementation of vitamin D supplementation programmes worldwide is critical with initial priority given to those who are..
Footnotes
References
Alipio, Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus,
doi:10.2139/ssrn.3571484Aspelund, Grübler, Smith, Gudmundsson, Keppel et al., Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts, Nutrients,
doi:10.3390/nu11010074Chamsi-Pasha, Shao, Tang, Angiotensin-Converting Enzyme 2 as a Therapeutic Target for Heart Failure, Curr Heart Fail Rep,
doi:10.1007/s11897-013-0178-0Charytan, Padera, Helfand, Association of activated vitamin D use with myocardial fibrosis and capillary supply: results of an autopsy study, Renal Failure,
doi:10.3109/0886022X.2015.1040704Cia, Ethnic groups
Cook, Kursumovic, Lennane, Exclusive: deaths of NHS staff from covid-19 analysed, Health Service Journal
Dancer, Parekh, Lax, Souza, Zheng et al., Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS)
Davies, Garami, Byers, COVID-19 and Vitamin D Information -2 Page Summary
Dijkman, Jebbink, Deijs, Milewska, Pyrc et al., Replication-dependent downregulation of cellular angiotensin-converting enzyme 2, J Gen Virol,
doi:10.1099/vir.0.043919-0Frieden, Evidence for Health Decision Making -Beyond Randomized, Controlled Trials, N Engl J Med
Gandini, Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials
Garami, Re: Preventing a covid-19 pandemic -Is there a magic bullet to save COVID-19 patients? We can give it a try!
Gaunt, Hardie, Claas, Simmonds, Templeton, Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method, J Clin Microbiol,
doi:10.1128/JCM.00636-10Giustina, Adler, Binkley, Bollerslev, Bouillon et al., Consensus statement from 2nd International Conference on Controversies in Vitamin D, Rev Endocr Metab Disord,
doi:10.1007/s11154-019-09532-wGiustina, Adler, Binkley, Bouillon, Ebeling et al., None
Giustina, Re, Preventing a covid-19 pandemic Can high prevalence of severe hypovitaminosis D play a role in the high impact of Covid infection in Italy?
Glicio, Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report
Gruffdavies, gruffdavies/GD-COVID-19
Hamming, Timens, Bulthuis, Lely, Navis et al., Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis, J Pathol,
doi:10.1002/path.1570Hoffmann, Kleine-Weber, Krüger, Müller, Drosten et al., The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells,
doi:10.1101/2020.01.31.929042Holick, The Vitamin D Deficiency Pandemic: a Forgotten Hormone Important for Health, Public Health Rev,
doi:10.1007/BF03391602Hopkins, Novel Coronavirus COVID-19 (2019-nCoV) Data Repository by Johns Hopkins CSSE
Ilie, Stefanescu, Smith, The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality, Aging Clin Exp Res,
doi:10.1007/s40520-020-01570-8Imai, Kuba, Rao, Huan, Guo et al., Angiotensin-converting enzyme 2 protects from severe acute lung failure, Nature,
doi:10.1038/nature03712Isaia, Giorgino, Rini, Bevilacqua, Maugeri et al., Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors, Osteoporos Int,
doi:10.1007/s00198-003-1390-7Jiménez-Sousa, Martínez, Medrano, Fernández-Rodríguez, Resino, Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease, Front Immunol,
doi:10.3389/fimmu.2018.00458Kennedy-Martin, Curtis, Faries, Robinson, Johnston, A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results, Trials,
doi:10.1186/s13063-015-1023-4Keum, Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials
Kong, Zhu, Shi, Liu, Chen et al., VDR Attenuates Acute Lung Injury by Blocking Ang-2-Tie-2 Pathway and Renin-Angiotensin System, Mol Endocrinol,
doi:10.1210/me.2013-1146Lawlor, Triangulation in aetiological epidemiology. -PubMed -NCBI, International Journal of Epidemiology
Lucisano, Buemi, Passantino, Aloisi, Cernaro et al., New Insights on the Role of Vitamin D in the Progression of Renal Damage, KBR,
doi:10.1159/000355747Maeda, Saraiva, Kunii, Hayashi, Cendoroglo et al., Factors affecting vitamin D status in different populations in the city of São Paulo, Brazil: the São PAulo vitamin D Evaluation Study (SPADES), BMC Endocr Disord,
doi:10.1186/1472-6823-13-14Mithal, Wahl, Bonjour, Burckhardt, Hughes, on behalf of the IOF Committee of Scientific Advisors (CSA) Nutrition Working Group,
doi:10.1007/s00198-009-1030-yMoore, Zhang, Anderson, Alexander, Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016, JAMA Intern Med,
doi:10.1001/jamainternmed.2018.3931Nair, Vitamin D: The 'sunshine' vitamin, J Pharmacol Pharmacother
Nakamura, Vitamin D insufficiency in Japanese populations: from the viewpoint of the prevention of osteoporosis, Journal of Bone and Mineral Metabolism,
doi:10.1007/s00774-005-0637-0Oudit, The role of ACE2 in cardiovascular physiology
Pacurari, Kafoury, Tchounwou, Ndebele, The Renin-Angiotensin-aldosterone system in vascular inflammation and remodeling, Int J Inflam,
doi:10.1155/2014/689360Parva, Tadepalli, Singh, Qian, Joshi et al., Prevalence of Vitamin D Deficiency and Associated Risk Factors in the US Population, Cureus,
doi:10.7759/cureus.2741Pearl, Causal Inference in the Health Sciences: A Conceptual Introduction, Health Serv Outcomes Res Methodol,
doi:10.1023/A:1020315127304Pearl, Causality, None
Pubmeddev, Hoge, Vitamin D deficiency is common among adults in Wallonia (Belgium, 51°30' North): findings from the Nutrition, Environment and Cardio-Vascular Healt
Rabenberg, Scheidt-Nave, Busch, Rieckmann, Hintzpeter et al., Vitamin D status among adults in Germany -results from the German Health Interview and Examination Survey for Adults (DEGS1), BMC Public Health,
doi:10.1186/s12889-015-2016-7Rabenberg, Scheidt-Nave, Busch, Thamm, Rieckmann et al., Implications of standardization of serum 25-hydroxyvitamin D data for the evaluation of vitamin D status in Germany, including a temporal analysis, BMC Public Health,
doi:10.1186/s12889-018-5769-yRaharusun, Priambada, Budiarti, Agung, Budi, Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study,
doi:10.2139/ssrn.3585561Romagnoli, Caravella, Scarnecchia, Martinez, Minisola, Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients, British Journal of Nutrition,
doi:10.1017/s0007114599000264Schmucker, Schell, Portalupi, Oeller, Cabrera et al., Extent of Non-Publication in Cohorts of Studies Approved by Research Ethics Committees or Included in Trial Registries, PLoS One,
doi:10.1371/journal.pone.0114023Shi, Liu, Yao, Xing, Zhao et al., Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system, Sci Rep,
doi:10.1038/s41598-017-03474-6Speich, Von Niederhäusern, Schur, Hemkens, Fürst et al., Systematic Review on Costs and Resource Use of Randomized Clinical Trials Shows a Lack of Transparent and Comprehensive Data, J Clin Epidemiol,
doi:10.1016/j.jclinepi.2017.12.018Stagi, Rigante, Lepri, Cerinic, Falcini, Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?, Clin Rheumatol,
doi:10.1007/s10067-015-2970-6Tabrizi, Moosazadeh, Akbari, Dabbaghmanesh, Mohamadkhani et al., High Prevalence of Vitamin D Deficiency among Iranian Population: A Systematic Review and Meta-Analysis, Iran J Med Sci
Tikellis, Thomas, Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease, International Journal of Peptides,
doi:10.1155/2012/256294Tzilasa, Bourosa, Barbayianni, Karampitsakos, Kourtidou et al., Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis, Pulm Pharmacol Ther,
doi:10.1016/j.pupt.2019.01.003Website, Pregnancy supplements 'don't help, just take vit D and folic acid
Wösten-Van Asperen, Lutter, Specht, Moll, Van Woensel et al., Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist, J Pathol,
doi:10.1002/path.2987Xu, Yang, Chen, Luo, Zhang et al., Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system, Mol Med Rep,
doi:10.3892/mmr.2017.7546Yu, Castillo-Carandang, Sison, Uy, Villarante et al., Development and validation of a sunlight exposure questionnaire for urban adult Filipinos, Epidemiol Health,
doi:10.4178/epih.e2018050Yuan, 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter
Zhang, Kong, Deb, Chang, Li, Vitamin D Receptor Attenuates Renal Fibrosis by Suppressing the Renin-Angiotensin System, J Am Soc Nephrol,
doi:10.1681/ASN.2009080872Zhao, Hobbs, Ma, Jiang, Carlin, Combining Non-randomized and Randomized Data in Clinical Trials Using Commensurate Priors, Health Serv Outcomes Res Methodol,
doi:10.1007/s10742-016-0155-7DOI record:
{
"DOI": "10.1101/2020.05.01.20087965",
"URL": "http://dx.doi.org/10.1101/2020.05.01.20087965",
"abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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 could play a causal role in COVID-19 outcomes.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>We set out to analyse the relationship between COVID-19 severity and latitude, and construct a causal inference framework to validate this hypothesis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>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 its other 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our novel causal inference analysis of global data supports the hypothesis that vitamin D levels play 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 offers a widely available, low-risk, highly-scalable, and cost-effective pandemic management strategy including the mitigation of local outbreaks and a second wave. Timely implementation of vitamin D supplementation programmes worldwide is critical; initial priority should be given to those who are at the highest risk, including the elderly, immobile, homebound, BAME and healthcare professionals. Population-wide vitamin D sufficiency could prevent seasonal respiratory epidemics, decrease our dependence on pharmaceutical solutions, reduce hospitalisations, and thus greatly lower healthcare costs while significantly increasing quality of life.</jats:p></jats:sec>",
"accepted": {
"date-parts": [
[
2020,
6,
5
]
]
},
"author": [
{
"ORCID": "http://orcid.org/0000-0002-8901-0680",
"affiliation": [],
"authenticated-orcid": false,
"family": "Davies",
"given": "Gareth",
"sequence": "first"
},
{
"ORCID": "http://orcid.org/0000-0001-5920-8760",
"affiliation": [],
"authenticated-orcid": false,
"family": "Garami",
"given": "Attila R",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-8979-1835",
"affiliation": [],
"authenticated-orcid": false,
"family": "Byers",
"given": "Joanna",
"sequence": "additional"
}
],
"container-title": [],
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2020,
5,
6
]
],
"date-time": "2020-05-06T19:09:36Z",
"timestamp": 1588792176000
},
"deposited": {
"date-parts": [
[
2022,
10,
23
]
],
"date-time": "2022-10-23T05:58:32Z",
"timestamp": 1666504712000
},
"group-title": "Epidemiology",
"indexed": {
"date-parts": [
[
2023,
11,
6
]
],
"date-time": "2023-11-06T06:49:29Z",
"timestamp": 1699253369225
},
"institution": [
{
"name": "medRxiv"
}
],
"is-referenced-by-count": 16,
"issued": {
"date-parts": [
[
2020,
5,
6
]
]
},
"link": [
{
"URL": "https://syndication.highwire.org/content/doi/10.1101/2020.05.01.20087965",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "246",
"original-title": [],
"posted": {
"date-parts": [
[
2020,
5,
6
]
]
},
"prefix": "10.1101",
"published": {
"date-parts": [
[
2020,
5,
6
]
]
},
"publisher": "Cold Spring Harbor Laboratory",
"reference": [
{
"DOI": "10.1128/JCM.00636-10",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.1"
},
{
"DOI": "10.1098/rsif.2009.0227.focus",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.2"
},
{
"DOI": "10.1136/bmj.m810",
"doi-asserted-by": "crossref",
"key": "2021010407251895000_2020.05.01.20087965v2.3",
"unstructured": "Garami AR . Re: Preventing a covid-19 pandemic - Is there a magic bullet to save COVID-19 patients? We can give it a try! Published Online First: 12 March 2020. https://www.bmj.com/content/368/bmj.m810/rr-24 (accessed 12 Mar 2020)."
},
{
"DOI": "10.1136/bmj.m810",
"doi-asserted-by": "crossref",
"key": "2021010407251895000_2020.05.01.20087965v2.4",
"unstructured": "Giustina A . Re: Preventing a covid-19 pandemic Can high prevalence of severe hypovitaminosis D play a role in the high impact of Covid infection in Italy? Published Online First: 20 March 2020. https://www.bmj.com/content/368/bmj.m810/rr-36 (accessed 20 Mar 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.5",
"unstructured": "Davies G , Garami AR , Byers J . COVID-19 and Vitamin D Information - 2 Page Summary. 2020. https://bit.ly/VitDCovid19SummaryShort"
},
{
"article-title": "Vitamin D: The ‘sunshine’ vitamin",
"first-page": "118",
"journal-title": "J Pharmacol Pharmacother",
"key": "2021010407251895000_2020.05.01.20087965v2.6",
"volume": "3",
"year": "2012"
},
{
"DOI": "10.4161/derm.24494",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.7"
},
{
"DOI": "10.1007/s00198-003-1390-7",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.8"
},
{
"DOI": "10.1007/s00198-009-1030-y",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.9"
},
{
"DOI": "10.7759/cureus.2741",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.10"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.11",
"unstructured": "Are more black, Asian and minority ethnic people dying with Covid-19 than might be expected? The Nuffield Trust. 2020. https://www.nuffieldtrust.org.uk/news-item/are-more-black-asian-and-minority-ethnic-people-dying-with-covid-19-than-might-be-expected (accessed 1 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.12",
"unstructured": "Website. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)30922-3.pdf (accessed 1 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.13",
"unstructured": "Cook T , Kursumovic E , Lennane S . Exclusive: deaths of NHS staff from covid-19 analysed. Health Service Journal. https://www.hsj.co.uk/exclusive-deaths-of-nhs-staff-from-covid-19-analysed/7027471.article (accessed 1 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.14",
"unstructured": "New York Department of Health and Mental Hygiene. Age-adjusted rates of lab confirmed COVID-19 nonhospitalized cases, estimated non-fatal hospitalized cases, and patients known to have died as of Aprill 6,2020. NYC.gov. https://www1.nyc.gov/assets/doh/downloads/pdf/imm/covid-19-deaths-race-ethnicity-04162020-1.pdf (accessed 1 May 2020)."
},
{
"DOI": "10.1097/med.0b013e3283372859",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.15"
},
{
"DOI": "10.1186/s12883-019-1500-6",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.16"
},
{
"DOI": "10.1155/2019/3652894",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.17"
},
{
"DOI": "10.3390/nu11010074",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.18"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.19",
"unstructured": "And Gandini AP . Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/17846391 (accessed 29 Mar 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.20",
"unstructured": "Keum N et al. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/30796437 (accessed 29 Mar 2020)."
},
{
"DOI": "10.1007/s10742-016-0155-7",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.21"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.22",
"unstructured": "Johns Hopkins CSSE. 2019 Novel Coronavirus COVID-19 (2019-nCoV) Data Repository by Johns Hopkins CSSE. https://github.com/CSSEGISandData/COVID-19 (accessed 26 Apr 2020)."
},
{
"DOI": "10.7927/H4JW8BX5",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.23"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.24",
"unstructured": "gruffdavies. gruffdavies/GD-COVID-19. GitHub. https://github.com/gruffdavies/GD-COVID-19 (accessed 7 May 2020)."
},
{
"DOI": "10.1101/2020.04.23.20077685",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.25"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.26",
"unstructured": "Lawlor DA et al. Triangulation in aetiological epidemiology. - PubMed - NCBI. International Journal of Epidemiology Published Online First: 1 December 2016. https://www.ncbi.nlm.nih.gov/pubmed/28108528 (accessed 18 Apr 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.27",
"unstructured": "Website NHS. Pregnancy supplements ‘don’t help, just take vit D and folic acid’, nhs.uk. https://www.nhs.uk/news/pregnancy-and-child/pregnancy-supplements-dont-help-just-take-vit-d-and-folic-acid/ (accessed 1 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.28",
"unstructured": "Mckensie R L , Liley J B , Björn L O . UV Radiation: Balancing Risks and Benefits. Wiley Online Library. 2009. https://onlinelibrary.wiley.eom/doi/full/10.1111/j.1751-1097.2008.00400.x (accessed 29 Mar 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.29",
"unstructured": "WHO | UV Index. Published Online First: 16 October 2017. http://www.who.int/uv/intersunprogramme/activities/uv_index/en/ (accessed 29 Mar 2020)."
},
{
"DOI": "10.1136/bmj.m810",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.30"
},
{
"DOI": "10.1017/s0007114599000264",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.31"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.32",
"unstructured": "pubmeddev, Hoge A et al. Vitamin D deficiency is common among adults in Wallonia (Belgium, 51°30’ North): findings from the Nutrition, Environment and Cardio-Vascular Healt… - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/26149190 (accessed 9 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.33",
"unstructured": "Government of Canada, Statistics Canada. Vitamin D levels of Canadians, 2012 to 2013. 2014. https://www150.statcan.gc.ca/n1/pub/82-625-x/2014001/article/14125-eng.htm (accessed 26 Apr 2020)."
},
{
"DOI": "10.1097/MD.0000000000011032",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.34"
},
{
"DOI": "10.1186/1471-2458-15-1",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.35"
},
{
"DOI": "10.1016/j.jsbmb.2013.11.003",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.36"
},
{
"DOI": "10.1186/s12889-018-5769-y",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.37"
},
{
"DOI": "10.1007/s00774-005-0637-0",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.38"
},
{
"article-title": "High Prevalence of Vitamin D Deficiency among Iranian Population: A Systematic Review and Meta-Analysis",
"first-page": "125",
"journal-title": "Iran J Med Sci",
"key": "2021010407251895000_2020.05.01.20087965v2.39",
"volume": "43",
"year": "2018"
},
{
"DOI": "10.1007/s00198-011-1597-y",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.40"
},
{
"DOI": "10.4178/epih.e2018050",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.41"
},
{
"DOI": "10.2139/ssrn.3571484",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.42"
},
{
"DOI": "10.2139/ssrn.3585561",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.43"
},
{
"DOI": "10.1186/1472-6823-13-14",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.44"
},
{
"DOI": "10.2307/j.ctv17260qm.6",
"doi-asserted-by": "crossref",
"key": "2021010407251895000_2020.05.01.20087965v2.45",
"unstructured": "CIA. Ethnic groups. CIA World Factbook. 2010. https://www.cia.gov/library/publications/the-world-factbook/fields/400.html (accessed 26 Apr 2020)."
},
{
"article-title": "The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. 1922. The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925.7",
"first-page": "E8",
"journal-title": "Biol Chem",
"key": "2021010407251895000_2020.05.01.20087965v2.46",
"volume": "277",
"year": "2002"
},
{
"DOI": "10.3201/eid1201.051254",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.47"
},
{
"DOI": "10.1038/nm1141",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.48"
},
{
"DOI": "10.1136/adc.2003.036780",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.49"
},
{
"DOI": "10.1002/path.1570",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.50"
},
{
"DOI": "10.1101/2020.01.31.929042",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.51"
},
{
"DOI": "10.1155/2012/256294",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.52"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.53",
"unstructured": "Oudit GY et al. The role of ACE2 in cardiovascular physiology. - PubMed - NCBI. 2003. https://www.ncbi.nlm.nih.gov/pubmed/12691672 (accessed 29 Mar 2020)."
},
{
"DOI": "10.1007/s11897-013-0178-0",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.54"
},
{
"DOI": "10.1099/vir.0.043919-0",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.55"
},
{
"DOI": "10.1038/nature03712",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.56"
},
{
"DOI": "10.1002/path.2987",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.57"
},
{
"DOI": "10.1155/2014/689360",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.58"
},
{
"DOI": "10.1038/srep41926",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.59"
},
{
"DOI": "10.1136/thoraxjnl-2014-206680",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.60"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.61",
"unstructured": "Ednan K . Bajwa, Ishir Bhan , Sadeq Quraishi , Michael Matthay , B. T. Thompson . Low Vitamin D Status Occurs in 90% of Patients with ARDS and Is Associated with Longer Duration of Mechanical Ventilation. 2016. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A1846 (accessed 24 Mar 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.62",
"unstructured": "Yuan W et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/17690094 (accessed 24 Mar 2020)."
},
{
"DOI": "10.1210/me.2013-1146",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.63"
},
{
"DOI": "10.3892/mmr.2017.7546",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.64"
},
{
"DOI": "10.3390/nu5072502",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.65"
},
{
"DOI": "10.3389/fimmu.2018.00458",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.66"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.67",
"unstructured": "Glicio EJ . Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report. Published Online First: 5 May 2020. https://papers.ssrn.com/abstract=3593258 (accessed 24 May 2020)."
},
{
"DOI": "10.1101/2020.04.24.20075838",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.68"
},
{
"DOI": "10.1007/S40520-020-01570-8",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.69"
},
{
"DOI": "10.1016/j.dsx.2020.04.050",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.70"
},
{
"DOI": "10.1007/s10067-015-2970-6",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.71"
},
{
"DOI": "10.1016/S0140-6736(20)31129-6",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.72"
},
{
"DOI": "10.1016/j.socscimed.2017.12.005",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.73"
},
{
"DOI": "10.1016/j.socscimed.2018.04.010",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.74"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.75",
"unstructured": "Establishing the risk related to hormone replacement therapy and cardiovascular disease in women. Pharmaceutical Journal. https://www.pharmaceutical-journal.com/research/review-article/establishing-the-risk-related-to-hormone-replacement-therapy-and-cardiovascular-disease-in-women/20202066.article (accessed 24 May 2020)."
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.76",
"unstructured": "[No title]. https://www.tandfonline.eom/doi/full/10.1080/07853890.2018.1453233 (accessed 22 May 2020)."
},
{
"DOI": "10.1210/jc.2018-01414",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.77"
},
{
"DOI": "10.1023/A:1020315127304",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.78"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.79",
"unstructured": "Pearl J . Causality. Cambridge University Press 2009. https://play.google.com/store/books/details?id=LLkhAwAAQBAJ"
},
{
"DOI": "10.1001/jamainternmed.2018.3931",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.80"
},
{
"key": "2021010407251895000_2020.05.01.20087965v2.81",
"unstructured": "[No title]. https://publications.parliament.uk/pa/cm201314/cmselect/cmpubacc/295/295.pdf (accessed 24 May 2020)."
},
{
"DOI": "10.1371/journal.pone.0114023",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.82"
},
{
"DOI": "10.1016/j.jclinepi.2017.12.018",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.83"
},
{
"DOI": "10.1016/j.aam.2006.12.003",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.84"
},
{
"DOI": "10.1186/s13063-015-1023-4",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.85"
},
{
"DOI": "10.1056/NEJMra1614394",
"doi-asserted-by": "publisher",
"key": "2021010407251895000_2020.05.01.20087965v2.86"
}
],
"reference-count": 86,
"references-count": 86,
"relation": {},
"resource": {
"primary": {
"URL": "http://medrxiv.org/lookup/doi/10.1101/2020.05.01.20087965"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"subtype": "preprint",
"title": "Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes",
"type": "posted-content"
}
