PONE-D-25-03098Effects of Vitamin D on COVID-19 Risk and Hospitalisation in the UK BiobankPLOS ONE

Dear Dr. Monroy Iglesias,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Additional Editor Comments:

In the analyses, please consider potential changes in Vitamin D levels over time (using a subsample of participants with repeat measurements available) as well as seasonal variations. 

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a large study of vitamin D status and COVID-19 risk in the UK Biobank – it is not the first such study but it adds in data on a substantial subset with cancer and is well analysed and well written so adds helpfully to the literature. It has the well documented drawback that vitamin D levels are historical rather than current but this is well discussed – hopefully the authors might be able to provide more data on the utility of this analysis by correlating results over time in the patients who had more than one vitamin D level – see point 4 below.

A few other points need addressing.

1. The Abstract / Methods section should state when vitamin D levels were taken eg 2006-2013.

2. The Abstract / Results section is confusingly written – OR of less than 1.0 (0.97; 0.95) and OR of more than 1.0 (1.19 ; 1.36) are all presented as “positive associations” and OR of more than 1.0(1.50 etc) as “strong negative associations”.

I would suggest:

(a) Change second sentence eg to “Although unadjusted analyses showed a small increase in infection rates in association with vitamin D insufficiency (OR 1.07; 95%CI 1.04-1.10) and deficiency (OR 1.20; 95%CI 1.16-1.27), multivariate analysis conversely showed a borderline negative association between risk of COVID-19 infection in the whole cohort and vitD insufficiency (OR 0.97, 95%CI 0.94-1.00) or deficiency (OR 0.95; 95%CI 0.90-0.99).

(b) Change last sentence to: “Strong associations were found between vitamin D deficiency and increased risk of COVID-19 infection in Asian (OR 1.50; 95%CI 1.08-2.07), and Black (1.57; 95%CI 1.14-2.16) populations and also for increased risk of COVID-19 hospitalisation in the White (OR 1.44; 95% CI 1.25-1.66) population”.

(c) Move to the last sentence the reference to the cancer data eg “In the cancer population, no significant association was found between vitamin D status and either COVID-19 infection or hospitalisation”.

3. Introduction para 1 – it seems an odd omission not to mention obesity or ethnicity as risk factors for COVID-19 severity – moreover both of these factors are associated with vitamin D status.

4. Methods – vitamin D assessment – it is stated that a subset of the cohort (n=17,036) had a second vitamin D measurement some years after the first. It would be very helpful to know how well the two samplings correlated – perhaps people with previous low levels might have taken supplements – any data on this? And has any attempt been made to adjust vitamin D level for month/season of sampling?

5. Methods – COVID-19 assessment – should state when PCR status was checked – was there a fixed/same time point for all the cases and if so when? (eg “prior to …… date”.

6. Results line 2 “hospitalized with to COVID-19.”

7. Legends to Tables 3 to 6 repeat “smoking status”

8. Discussion – when citing other studies that have reported associations between COVID-19 risks and vitamin D status it would be helpful in each case to state what definition has been used for deficiency (eg 25(OH)D <25, <50, <75 nmol/l).

9. Discussion para 7 - the statement “The results from our current study also suggest that VitD

supplementation may be beneficial in reducing hospitalisation of COVID-19 infection in the general population.” Implies that you have data on supplementation – better would be “…. might be beneficial….”.

10. Discussion cites 3 previous studies of vitamin D/COVID-19 in the UK Biobank but a couple of others came up on a quick pubmed search: An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank.

Li X, van Geffen J, van Weele M, Zhang X, He Y, Meng X, Timofeeva M, Campbell H, Dunlop M, Zgaga L, Theodoratou E.Sci Rep. 2021 Sep 14;11(1):18262. doi: 10.1038/s41598-021-97679-5.PMID: 34521884

Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank.

Raisi-Estabragh Z, McCracken C, Bethell MS, Cooper J, Cooper C, Caulfield MJ, Munroe PB, Harvey NC, Petersen SE.J Public Health (Oxf). 2020 Aug 18;42(3):451-460. doi: 10.1093/pubmed/fdaa095.PMID: 32556213

Reviewer #2: Despite the well-established links between VitD and COVID-19 (18-21)

19. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate

doses of solar ultraviolet-B radiation. Cancer. 2002;94(6):1867-75.

20. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D

Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med.

2019;380(1):33-44.

21. Vieth R. Critique of Public Health Guidance for Vitamin D and Sun Exposure in the

Context of Cancer and COVID-19. Anticancer Res. 2022;42(10):5027-34.

Comment: The statement in the text should separate the findings for COVID-19 from those for cancer.

Regarding Ref. 19, a better reference is

Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients. 2022 Mar 30;14(7):1448. doi: 10.3390/nu14071448.

A major limitation of this study is that exposures and covariates were measured at baseline upon recruitment into the UK Biobank in 2006 to 2010, thus potential changes on VitD cannot be accounted for. A small subset of the cohort had a second VitD measurement taken during the first repeat assessment visit between 2012 and 2013 (n=17,036).

Comment: The measurements are likely to be too old and seriously undercut the value of the analysis.

Also, were they seasonally adjusted?

Long time gaps are associated with “regression dilution”

Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R.

Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.

Am J Epidemiol. 1999 Aug 15;150(4):341-53. doi: 10.1093/oxfordjournals.aje.a010013.

See, also, Figure 1 in

Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients. 2022 Mar 30;14(7):1448. doi: 10.3390/nu14071448.

Regarding season:

Hyppönen E, Power C.

Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors.

Am J Clin Nutr. 2007 Mar;85(3):860-8. doi: 10.1093/ajcn/85.3.860.

Both Hastie et al and Lin et al found no associations between VitD levels and risk of COVID-19 hospitalisation and mortality (28, 29).

Comment: The patients in the Hastie study were in the hospital about 11 days after first symptoms of COVID-19. Since two of the important mechanisms of vitamin D are increasing cathelicidin (LL-37) concentrations, which can reduce the viability of viruses and bacteria, and reduced production of pro-inflammatory cytokines, which can lead to the cytokine storm, are most beneficial early in the disease progression. Vitamin D can also reduce risk of death from ensuing pneumonia.

It should also be noted that acute inflammatory diseases reduce 25OHD concentrations. See

Smolders, J.; van den Ouweland, J.; Geven, C.; Pickkers, P.; Kox, M. Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence. Metabolism 2021, 115, 154434

And search Google Scholar for papers that cited this letter.

Significant digits. The general rule is that no more non-zero digits should be given than are justified by the uncertainty of the value.

See "Too many digits: the presentation of numerical data"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483789/

If the uncertainty (or difference when comparing numbers) is greater than about 7%, only two non-zero digits are justified.

P values should be given to two decimal places unless the first two are 00 or the number lies between 0.045 and 0.054. If the first two are 00, then only one non-zero digit can be given.

Thus, p values in the supplementary file should be adjusted

In Table 2

Mean (SD) 27.84 (4.82)

Should be

Mean (SD) 28 (5)

Please review all numbers in abstract, text, tables, and figures and adjust accordingly.

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Reviewer #1: No

Reviewer #2: Yes:  William B. Grant

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PONE-D-25-03098R1Effects of Vitamin D on COVID-19 Risk and Hospitalisation in the UK BiobankPLOS ONE

Dear Dr. Monroy Iglesias,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 12 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Sandar Tin Tin

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All comments satisfactorily addressed

Reviewer #2: .”However, we were unable to find the reference in Hastie et al. regarding patients being hospitalized about 10 days after symptom onset. If you happen to recall where that came from, we’d be happy to take another look, but for now we’ve left that detail out.

Re: Hastie. My mistake.

However, this article may be of interest.

Baseline clinical features of COVID-19 patients, delay of hospital admission and clinical outcome: A complex relationship.

Dananché C, Elias C, Hénaff L, Amour S, Kuczewski E, Gustin MP, Escuret V, Saadatian-Elahi M, Vanhems P. PLoS One. 2022 Jan 7;17(1):e0261428. doi: 10.1371/journal.pone.0261428.

Of possible interest

Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-control Study.

Jude EB, Ling SF, Allcock R, Yeap BXY, Pappachan JM. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4708-e4715. doi: 10.1210/clinem/dgab439.

7. Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute

respiratory infection: systematic review of clinical studies. J Steroid Biochem Mol Biol.

2013;136:321-9.

Comment: This reference is outdated. See

Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data.

Jolliffe DA, Camargo CA Jr, Sluyter JD, Aglipay M, Aloia JF, Bergman P, Bischoff-Ferrari HA, Borzutzky A, Bubes VY, Damsgaard CT, Ducharme FM, Dubnov-Raz G, Esposito S, Ganmaa D, Gilham C, Ginde AA, Golan-Tripto I, Goodall EC, Grant CC, Griffiths CJ, Hibbs AM, Janssens W, Khadilkar AV, Laaksi I, Lee MT, Loeb M, Maguire JL, Majak P, Manaseki-Holland S, Manson JE, Mauger DT, Murdoch DR, Nakashima A, Neale RE, Pham H, Rake C, Rees JR, Rosendahl J, Scragg R, Shah D, Shimizu Y, Simpson-Yap S, Kumar GT, Urashima M, Martineau AR. Lancet Diabetes Endocrinol. 2025 Apr;13(4):307-320. doi: 10.1016/S2213-8587(24)00348-6

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Reviewer #1: No

Reviewer #2: Yes:  William B. Grant

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Effects of Vitamin D on COVID-19 Risk and Hospitalisation in the UK Biobank

PONE-D-25-03098R2

Dear Dr. Monroy Iglesias,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Sandar Tin Tin

Academic Editor

PLOS ONE