Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials

  1. David A Jolliffe
  2. Carlos A Camargo
  3. John D Sluyter
  4. Mary Aglipay
  5. John F Aloia
  6. Davaasambuu Ganmaa
  7. Peter Bergman
  8. Heike A Bischoff-Ferrari
  9. Arturo Borzutzky
  10. Camilla T Damsgaard
  11. Gal Dubnov-Raz
  12. Susanna Esposito
  13. Clare Gilham
  14. Adit A Ginde
  15. Inbal Golan-Tripto
  16. Emma C Goodall
  17. Cameron C Grant
  18. Christopher J Griffiths
  19. Anna Maria Hibbs
  20. Wim Janssens
  21. Anuradha Vaman Khadilkar
  22. Ilkka Laaksi
  23. Margaret T Lee
  24. Mark Loeb
  25. Jonathon L Maguire
  26. Paweł Majak
  27. David T Mauger
  28. Semira Manaseki-Holland
  29. David R Murdoch
  30. Akio Nakashima
  31. Rachel E Neale
  32. Hai Pham
  33. Christine Rake
  34. Judy R Rees
  35. Jenni Rosendahl
  36. Robert Scragg
  37. Dheeraj Shah
  38. Yoshiki Shimizu
  39. Steve Simpson-Yap
  40. Geeta Trilok-Kumar
  41. Mitsuyoshi Urashima
  42. Adrian R Martineau

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Abstract

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  1. Version published to 10.1016/s2213-8587(21)00051-6
  2. ScreenIT

    SciScore for 10.1101/2020.07.14.20152728: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Research Ethics Committee approval to conduct this meta-analysis was not required in the UK; local ethical permission to contribute data from primary trials was required and obtained for studies by Camargo et al13 (The Ethics Review Committee of the Mongolian Ministry of Health), Murdoch et al14 (Southern Health and Disability Ethics Committee, ref. URB/09/10/050/AM02), Rees et al17 (Committee for the Protection of Human Subjects, Dartmouth College, USA; Protocol # 24381), Tachimoto et al28 (Ethics committee of the Jikei University School of Medicine, ref 26-333: 7839), Tran et al18 (QIMR Berghofer Medical Research Institute Human Research Ethics Committee, P1570) and Urashima et al6,20 (Ethics committee of the Jikei University School of Medicine, ref 26-333: 7839).
    Randomizationnot detected.
    BlindingRisk of Bias Assessment for Individual Studies: We used the Cochrane Collaboration Risk of Bias tool51 to assess the following variables: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Study Identification and Selection: Two investigators (ARM and DAJ) searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry using the electronic search strategies described in the Methods Section of Supplementary Material.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Cochrane Central Register of Controlled Trials
    suggested: (Cochrane Central Register of Controlled Trials, RRID:SCR_006576)
    Once queries had been resolved, clean summary data were uploaded to the study database, which was held in STATA IC v14.2 (StataCorp, College Station, TX).
    STATA
    suggested: (Stata, RRID:SCR_012763)
    StataCorp
    suggested: (Stata, RRID:SCR_012763)
    Risk of Bias Assessment for Individual Studies: We used the Cochrane Collaboration Risk of Bias tool51 to assess the following variables: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.
    Cochrane Collaboration Risk of Bias
    suggested: None
    These were meta-analysed in a random effects model using the Metan package53 within STATA IC v14.2 to obtain a pooled odds ratio with a 95% confidence interval and a measure of heterogeneity summarized by the I2 statistic and its corresponding P value.
    Metan
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our work also has limitations. Given the need to generate a rapid update of our previous work in the context of the COVID-19 pandemic, we meta-analysed aggregate (trial-level) data, rather than individual participant data; this allowed us to proceed rapidly, without the delays introduced by the need to establish multiple data sharing agreements. However, we did contact authors to get unpublished estimates of effect that were stratified by pre-defined baseline 25(OH)D levels, harmonised across studies: thus, we were able to provide accurate data for the major participant-level effect-modifier of interest. Despite the large number of trials overall, relatively few compared effects of lower-vs. higher-dose vitamin D: our power for this secondary comparison was therefore limited. We lacked the individual participant data to investigate race/ethnicity and obesity as potential effect-modifiers. We also could not account for other factors that might influence the efficacy of vitamin D supplements for ARI prevention (e.g., taking the supplement with or without food) or secular trends that would influence trials, such as the increased societal use of vitamin D supplements;59 concurrent use of standard dose vitamin D supplements or multivitamins in the “placebo” group would effectively render these as high-vs. low-dose trials and potentially drive results toward the null. A final limitation relates to the funnel plot, which suggests that the overall effect size may have been over-estim...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. ScreenIT

    SciScore for 10.1101/2020.07.14.20152728: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementEligibility Criteria for Selecting Studies: Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and prespecified as an efficacy outcome.Randomizationnot detected.BlindingRisk of Bias Assessment for Individual Studies We used the Cochrane Collaboration Risk of Bias tool46 to assess the following variables: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.Power Analysisnot detected.Sex as a biological variableData Sharing: the study dataset is available from d.a.jolliffe@qmul.ac.uk. ble 1: Characteristics of the 39 eligible trials and their participants g Participants Mean age, Male: years Female (s.d.) 25(OH)D assay, Mean Baseline EQA scheme baseline 25(OH)D <25 25(OH)D, nmol/L (%) nmol/L (s.d.) Mean attained Intervention: Oral dose of Contr 25(OH)D, intervention Control vitamin D3, arm, nmo/L (s.d.) Offspring: 10 µg vs. 20 µg daily g alia Participants Mean age, Male: years Female (s.d.) 25(OH)D assay, Mean Baseline EQA scheme baseline 25(OH)D <25 25(OH)D, nmol/L (%) nmol/L (s.d.) Mean attained Intervention: Oral dose of Contr 25(OH)D, intervention Control vitamin D3, arm, nmo/L (s.d.) children Healthy children 8.1 (1.2) Healthy older adults 158:127 72.2 (4.9) 408:379 25(OH)D assay, Mean Baseline EQA scheme baseline 25(OH)D <25 25(OH)D, nmol/L (%) nmol/L (s.d.) (Biomerieux)

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data Sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled
    EMBASE
    suggested: (EMBASE, SCR_001650)
    Study Identification and Selection Two investigators (ARM and DAJ) searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomized Controlled Trials Number (ISRCTN) registry using the electronic search strategies described in the Methods Section of Supplementary Material.
    MEDLINE
    suggested: (MEDLINE, SCR_002185)
          <div style="margin-bottom:8px">
        <div><b>Cochrane Central Register of Controlled Trials</b></div>
        <div>suggested: (Cochrane Central Register of Controlled Trials, <a href="https://scicrunch.org/resources/Any/search?q=SCR_006576">SCR_006576</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Once queries had been resolved, clean summary data were uploaded to the study database, which was held in STATA IC v14.2 (StataCorp, College Station, TX).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>STATA</b></div>
        <div>suggested: (Stata, <a href="https://scicrunch.org/resources/Any/search?q=SCR_012763">SCR_012763</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>StataCorp</b></div>
        <div>suggested: (Stata, <a href="https://scicrunch.org/resources/Any/search?q=SCR_012763">SCR_012763</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Risk of Bias Assessment for Individual Studies We used the Cochrane Collaboration Risk of Bias tool46 to assess the following variables: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>Cochrane Collaboration Risk of Bias</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">These were meta-analysed in a random effects model using the Metan package48 within STATA IC v14.2 to obtain a pooled odds ratio with a 95% confidence interval and a measure of heterogeneity summarized by the I2 statistic and its corresponding P value.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>Metan</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr></table>

    Data from additional tools added to each annotation on a weekly basis.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2020.07.14.20152728 on medRxiv