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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data
Open accessAbstract
Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.
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TL;DR
This individual participant data meta-analysis of 25 randomised controlled trials found that vitamin D supplementation reduced the risk of acute respiratory tract infection overall (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96). Benefit was strongest in participants receiving daily or weekly vitamin D without bolus doses and in those with baseline 25-hydroxyvitamin D <25 nmol/L.
Key findings
- Overall, vitamin D supplementation reduced the proportion of participants experiencing at least one acute respiratory tract infection: adjusted odds ratio 0.88 (0.81 to 0.96), P=0.003, NNT=33 (20 to 101); P for heterogeneity <0.001.
- Daily or weekly vitamin D without additional bolus doses was protective (adjusted odds ratio 0.81, 0.72 to 0.91; NNT=20), whereas regimens including at least one bolus dose were not (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05).
- Among those receiving daily or weekly vitamin D, protection was greater with baseline 25-hydroxyvitamin D <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53; NNT=4) than with baseline ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006).
- Vitamin D did not increase serious adverse events of any cause (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83); hypercalcaemia occurred in 21/3850 (0.5%) and renal stones in 6/3841 (0.2%), evenly represented between arms.
Methods
- Systematic review and individual participant data meta-analysis of randomised, double-blind, placebo-controlled trials of vitamin D3 or vitamin D2; searches of Medline, Embase, CENTRAL, Web of Science, ClinicalTrials.gov, and ISRCTN to December 2015 identified 25 eligible trials with 11,321 randomised participants aged 0 to 95 years.
- Primary outcome was incidence of acute respiratory tract infection; one-step and two-step random-effects IPD meta-analyses were adjusted for age, sex, and study duration, with prespecified subgroup analyses by baseline 25-hydroxyvitamin D, dosing regimen, dose size, age, body mass index, asthma, COPD, and influenza vaccination.
- IPD were obtained for 10,933 (96.6%) participants for the primary analysis; risk of bias was assessed with the Cochrane tool, and GRADE was used to assess quality of evidence.
Limitations
- Stated: funnel plot asymmetry raised the possibility that small trials showing adverse effects of vitamin D were missed; power was limited for some subgroups and secondary outcomes, so null or borderline results may reflect type 2 error; adherence data were not available for all participants; acute respiratory tract infection definitions were diverse and few events had virological, microbiological, or radiological confirmation.
- Stated: residual confounding by other effect modifiers cannot be excluded, especially in stratified analyses with few trials represented, so the authors advise caution interpreting the dosing-frequency-stratified subgroup results.
- Evident from the text: race or ethnicity was not investigated as an effect modifier because data were missing for 3680/10,933 (34%) participants and power was limited; two trials were at unclear risk of bias due to high loss to follow-up (Dubnov-Raz: 52% did not complete all symptom questionnaires; Laaksi: 37% lost to follow-up).
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91)”
- Also stated in: § Incidence of acute respiratory tract infection · plain
“Meta-analysis of data from trials in which vitamin D was administered using a daily or weekly regimen without additional bolus doses revealed a protective effect against acute respiratory tract infection (adjusted odds ratio 0.81, 0.72 to 0.91, NNT=20, 13 to 43; 5133 participants in 15 studies; within subgroup P<0.001; see Cates plot, supplementary figure S1).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Incidence of acute respiratory tract infection · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05).”
- Also stated in: § Incidence of acute respiratory tract infection · plain
“No such protective effect was seen among participants in trials where at least one bolus dose of vitamin D was administered (adjusted odds ratio 0.97, 0.86 to 1.10; 5800 participants in 10 studies; within subgroup P=0.67; P for interaction 0.05).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Incidence of acute respiratory tract infection · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001).”
- Also stated in: § Incidence of acute respiratory tract infection · plain
“Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96, P=0.003; P for heterogeneity <0.001; NNT=33, 95% confidence interval 20 to 101; 10 933 participants in 25 studies; see Cates plot, supplementary figure S1).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Incidence of acute respiratory tract infection · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IPD were obtained for 10 933 (96.6%) participants.”
- Also stated in: § Study selection and IPD obtained · plain
“Outcome data for the primary analysis of proportion of participants experiencing at least one acute respiratory tract infection were obtained for 10 933 (96.6%) of the randomised participants.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Study selection and IPD obtained · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53)”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified.”
- Also stated in: § Study selection and IPD obtained · plain
“of these, 25 studies with a total of 11 321 randomised participants fulfilled the eligibility criteria (fig 1).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Study selection and IPD obtained · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05).”
- Also stated in: § Incidence of acute respiratory tract infection · plain
“No such protective effect was seen among participants in trials where at least one bolus dose of vitamin D was administered (adjusted odds ratio 0.97, 0.86 to 1.10; 5800 participants in 10 studies; within subgroup P=0.67; P for interaction 0.05).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Incidence of acute respiratory tract infection · plain
- Probably not a substantial claim. 25
- It may state two separate claims as one. 17
- The quote only partly states this claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our search identified 532 unique studies that were assessed for eligibility”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Study selection and IPD obtained
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Baseline serum 25-hydroxyvitamin D concentrations were determined in 19/25 trials: mean baseline concentration ranged from 18.9 to 88.9 nmol/L.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Study and participant characteristics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For both of these subgroup analyses, broadly consistent effects were observed for event rate analysis (see supplementary table S5) and survival analysis (see supplementary table S6).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Incidence of acute respiratory tract infection
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Incidence of acute respiratory tract infection was the primary or co-primary outcome for 14 studies and a secondary outcome for 11 studies.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Study and participant characteristics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Trials were conducted in 14 countries on four continents and enrolled participants of both sexes from birth to 95 years of age.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Study and participant characteristics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among those receiving daily or weekly vitamin D, protective effects were strongest in those with profound vitamin D deficiency at baseline, although those with higher baseline 25-hydroxyvitamin D concentrations also experienced benefit.”
- Also stated in: § Conclusions and policy implications · plain
“the protective effects against acute respiratory tract infection in this group were strongest in those with profound vitamin D deficiency at baseline (NNT=4)”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
- The authors state this as an assumption: Use of bolus doses of vitamin D was ineffective.
- Also stated in: § Conclusions and policy implications · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The process of checking IPD identified three typographical errors in published reports.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Study and participant characteristics
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Survival analysis revealed consistent trends that did not attain statistical significance, possibly owing to lack of power (fewer studies contributed data to survival analyses than to analyses of proportions and event rates).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Strengths and limitations of this study
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The body of evidence contributing to these analyses was assessed as being of high quality.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Vitamin D metabolites have also been reported to induce other innate antimicrobial effector mechanisms, including induction of autophagy and synthesis of reactive nitrogen intermediates and reactive oxygen intermediates.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Introduction
What the sources say
- Not checked yetcites [8] Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol 2011; 7: 337- 45. 10.1038/nrendo.2010.226 pmid:21263449. 21263449
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In the paper
“For the primary analysis we investigated the likelihood of publication bias through the construction of a contour enhanced funnel plot.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Quality assessment across studies
What the sources say
- Not checked yetcites [33] Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 2008; 61: 991- 6. 10.1016/j.jclinepi.2007.11.010 pmid:18538991. 18538991
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In the paper
“Two investigators (ARM and DAJ) independently assessed study quality, except for the three trials by Martineau and colleagues, which were assessed by CAC. Discrepancies were resolved by consensus.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Risk of bias assessment for individual studies
What the sources say
- Not checked yetcites [28] Higgins JP, Altman DG, Gøtzsche PC, et al. Cochrane Bias Methods Group Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928 10.1136/bmj.d5928 pmid:22008217. 22008217 PMC3196245
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“local ethical permission to contribute deidentified IPD from primary trials was required and obtained for studies by Camargo et al21”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Protocol and registration
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In the paper
“participant characteristics such as age and body mass index have been reported to modify the 25-hydroxyvitamin D response to vitamin D supplementation”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Introduction
What the sources say
- Not checked yetcites 17 18
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: Use of bolus doses of vitamin D was ineffective.
In the paper
“and in some cases an increased risk of adverse outcomes”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Introduction
What the sources say
- Not checked yetcites [19] Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010; 303: 1815- 22. 10.1001/jama.2010.594 pmid:20460620. 20460620
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“we performed prespecified subgroup analyses by extending the one step meta-analysis framework to include treatment-covariate interaction terms.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Exploration of variation in effects
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Initially we reanalysed all studies separately; the original authors were asked to confirm the accuracy of this reanalysis where it had been performed previously, and any discrepancies were resolved.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Synthesis methods
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure that reported subgroup effects were independent, we adjusted interaction analyses for potential confounders (age, sex, and study duration).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Exploration of variation in effects
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This evidence was assessed as being of high quality (see supplementary table S3).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Incidence of acute respiratory tract infection
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias)34 to assess the quality of the body of evidence contributing to analyses of the primary efficacy outcome and major safety outcome of our meta-analysis”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Quality assessment across studies
What the sources say
- Not checked yetcites [34] Guyatt GH, Oxman AD, Vist GE, et al. GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924- 6. 10.1136/bmj.39489.470347.AD pmid:18436948. 18436948 PMC2335261
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“On receipt, three investigators (DAJ, RLH, and LG) assessed data integrity by performing internal consistency checks and by attempting to replicate results of the analysis for incidence of acute respiratory tract infection where this was published in the trial report.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Data collection processes
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Race or ethnicity was not investigated as a potential effect modifier, as data for this variable were missing for 3680/10 933 (34%) participants and power for subgroup analyses was limited by small numbers in many racial or ethnic subgroups that could not be meaningfully combined.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Results > Incidence of acute respiratory tract infection
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“People with chronic obstructive pulmonary disease who have lower baseline vitamin D status have been reported to derive greater clinical benefit from supplementation than those with higher baseline status”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Introduction
What the sources say
- Not checked yetcites 15 16
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To minimise the chance of type 1 error arising from multiple analyses, we inferred statistical significance for subgroup analyses only where P values for treatment-covariate interaction terms were <0.05.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Exploration of variation in effects
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not adjust for other covariates because missing values for some participants would have led to their exclusion from statistical analyses.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Synthesis methods
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The methods were prespecified in a protocol that was registered with the PROSPERO International Prospective Register of Systematic Reviews”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Protocol and registration
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Our IPD meta-analysis approach followed published guidelines.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Methods > Synthesis methods
What the sources say
- Not checked yetcites [20] Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 2010; 340: c221 10.1136/bmj.c221 pmid:20139215. 20139215
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results add to the body of evidence supporting the introduction of public health measures such as food fortification to improve vitamin D status, particularly in settings where profound vitamin D deficiency is common.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Conclusions and policy implications
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
- The authors state this as an assumption: Use of bolus doses of vitamin D was ineffective.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings therefore have a high degree of internal and external validity.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Strengths and limitations of this study
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“our power to detect effects of vitamin D supplementation was limited for some subgroups (eg, individuals with baseline 25-hydroxyvitamin D concentrations <25 nmol/L receiving bolus dosing regimens) and for some secondary outcomes (eg, incidence of lower respiratory tract infection).”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Strengths and limitations of this study
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Use of vitamin D was safe: potential adverse reactions were rare, and the risk of such events was the same between participants randomised to intervention and control arms.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“study definitions of acute respiratory tract infection were diverse, and virological, microbiological, or radiological confirmation was obtained for the minority of events.”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Strengths and limitations of this study
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the relevant effect modifiers were specified a priori and measured at baseline”
§ Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data > Discussion > Strengths and limitations of this study
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
The acute respiratory tract infection case definitions used across the included trials are sufficiently comparable to be pooled in the meta-analysis.
“Data relating to study characteristics were extracted for the following variables: setting, eligibility criteria, details of intervention and control regimens, study duration, and case definitions for acute respiratory tract infection.”
The paper relies on this without support.
The 25-hydroxyvitamin D measurements from different assays and laboratories are comparable enough to classify participants by baseline vitamin D status.
“Baseline serum 25-hydroxyvitamin D concentrations were determined in 19/25 trials: mean baseline concentration ranged from 18.9 to 88.9 nmol/L.”
The paper relies on this without support.
Outcome data missing for 3.4% of participants are missing at random.
“Outcome data for the primary analysis of proportion of participants experiencing at least one acute respiratory tract infection were obtained for 10 933 (96.6%) of the randomised participants.”
The authors state this as an assumption.
Use of bolus doses of vitamin D was ineffective.
“under the assumption that use of bolus doses was ineffective”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Benefits are particularly apparent in those who are very vitamin D deficient [115].”
From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [115]
In the citing paper
“Supplementation with vitamin D can protect against respiratory tract infections and reduce the risk of acute respiratory illness and influenza, especially with once-daily dosing [112,113,114,115].”
From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [115]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The higher-baseline-vitamin-D subgroup has six or 11 trials
MinorThe text says 1603 participants with higher baseline vitamin D concentrations came from six daily-or-weekly-dosing studies, but the corresponding Table 3 row lists 11 trials. The row's denominators, 729 and 874, sum to the stated 1603 participants.
“1603 participants in six studies; within subgroup P=0.02”
“| ≥25 | 8 | 550/910 (60.4) | 663/1121 (59.1) | 1.02 (0.83 to 1.24) | 0.87 | 0.42 | | 11 | 477/729 (65.4) | 516/874 (59.0) | 0.75 (0.60 to 0.95) | 0.02 | 0.006 |”
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Metadata
- Authors
- Martineau, A. R., Jolliffe, D. A., Hooper, R. L., Greenberg, L., Aloia, J. F., Bergman, P., Dubnov-Raz, G., Esposito, S., Ganmaa, D., Ginde, A. A., Goodall, E. C., Grant, C. C., Griffiths, C. J., Janssens, W., Laaksi, I., Manaseki-Holland, S., Mauger, D., Murdoch, D. R., Neale, R., Rees, J. R., Simpson, S., Stelmach, I., Kumar, G. T., Urashima, M., & Camargo, C. A.
- Affiliations
- Queen Mary University of London (GB)
- Winthrop-University Hospital (US)
- Karolinska Institutet (SE)
- University of Milan (IT)
- Harvard University (US)
- University of Colorado Anschutz (US)
- McMaster University (CA)
- University of Auckland (NZ)
- Universitair Ziekenhuis Leuven (BE)
- University of Tampere (FI)
- Pennsylvania State University (US)
- University of Otago (NZ)
- QIMR Berghofer Medical Research Institute (AU)
- Dartmouth College (US)
- University of Tasmania (AU)
- Medical University of Lodz (PL)
- University of Delhi (IN)
- Jikei University School of Medicine (JP)
- Corresponding author
- Martineau, Adrian R
- ORCID
- Martineau, Adrian R
- Jolliffe, David A
- Hooper, Richard L
- Greenberg, Lauren
- Aloia, John F
- Bergman, Peter
- Esposito, Susanna
- Ganmaa, Davaasambuu
- Ginde, Adit A
- Goodall, Emma C
- Grant, Cameron C
- Janssens, Wim
- Laaksi, Ilkka
- Mauger, David
- Murdoch, David R
- Neale, Rachel
- Rees, Judy R
- Simpson, Steve
- Stelmach, Iwona
- Kumar, Geeta Trilok
- Urashima, Mitsuyoshi
- Camargo, Carlos A
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2017-02-15
- Volume
- 356
- Pages
- i6583
- ISSN
- 1756-1833 (ISSN-L)
- 0959-8138
- PMC
- PMC5310969
- OpenAlex
- W2588906490
- Semantic Scholar
- 2d2b56615f204e2bf868d391328109bebbac8c94
- Cited by
- 2,040
- References
- 60
- Citations by year
- 2026: 76 · 2025: 96 · 2024: 126 · 2023: 241 · 2022: 305 · 2021: 459 · 2020: 454 · 2019: 113 · 2018: 107 · 2017: 61
- FWCI
- 32.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BMJ (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
- Tampere University Institutional Repository (Tampere University) (publishedVersion, other-oa)
- UTAS Research Repository (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- eCite Digital Repository (University of Tasmania) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- Greater South Information System
- Funders
- National Institute for Health and Care Research (RP-PG-0407-10398, 13/03/25, HTA/13/03/25)
- Health Technology Assessment Programme (13/03/25)
- National Heart, Lung, and Blood Institute (U10HL098115, U10HL064313)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutrition and Health Studies
- Keywords
- vitamin D supplementation, acute respiratory infections, vitamin D3, vitamin D2, 25-hydroxyvitamin D, bolus dosing, dose-response relationship, baseline vitamin D status, infection control, adverse events, children, adults, older adults, pregnant women, lactating women, postpartum women, preterm infants, preterm birth, preterm birth prevention, preterm birth risk
- MeSH terms
- Humans, Respiratory Tract Infections, Vitamin D, Randomized Controlled Trials as Topic, Dietary Supplements
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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