Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D


Context and purpose

Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D.


IPD analysis using data from 1429 participants (ages 2–89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models.


Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI).


IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.

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Fig. 1
Fig. 2

Code availability

The R code for fitting linear and nonlinear models is presented in Cashman KD, Ritz C (2019). Individual participant data (IPD)-level meta-analysis of randomised controlled trials among dark-skinned populations to estimate the dietary requirement for vitamin D [34].



25-Hydroxyvitamin D


Adequate intake


Dietary reference intake


Dietary reference values


Estimated average requirement


The European Food Safety Authority


Food frequency questionnaire


Institute of Medicine


Individual participant data


The Nordic Council of Ministers’ Nordic Nutrition Recommendations


Randomized controlled trial


Recommended dietary allowance


Recommended intake


Reference nutrient intake


The Scientific Advisory Committee on Nutrition


Ultraviolet B


World Health Organisation–Food and Agriculture Organization


Systematic reviews and meta-analyses


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Author information




KDC, MEK and CR designed the research; KDC and MEK defined the eligibility criteria for the food-based vitamin D randomized controlled trials (RCTs) for inclusion in the individual participant data (IPD)-level meta-regression analysis; KDC conducted the electronic searches; Study selection and decision on which met the eligibility criteria and we included was conducted by KDC and MEK; KDC, LT and MEK performed the quality assessment of eligible studies; KDC, RA, IMG, KHM, JN, IT, LT, SAL-N, LT, MPV, UT, GJ, VVM, BLS, JH, AK, DW, RV, IO, PKA, NRB, HAW accessed, formatted and supplied the IPD from their 11 included RCTs which formed the core pooled dataset upon which this work was based; An assessment of the risk of bias in the included RCTs was performed by KDC and LT; CR performed the statistical analyses and derivation of vitamin D dietary reference value estimates; KDC and CR wrote the first draft of the paper, with all authors providing input and comment on subsequent versions; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kevin D. Cashman.

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Conflicts of interest

The following authors had no conflicts of interest: Kevin D. Cashman, Mairead E. Kiely, Rikke Andersen, Ida M. Grønborg, Katja H. Madsen, Janna Nissen, Inge Tetens, Laura Tripkovic, Laura Toxqui, M. Pilar Vaquero, Ulrike Trautvetter, Gerhard Jahreis, Vikram V. Mistry, Bonny L. Specker, Jürgen Hower, Anette Knoll, Dennis Wagner, Reinhold Vieth, Inger Öhlund, Pia Karlsland Åkeson, Neil R. Brett, Christian Ritz. Hope A. Weiler at the time of the trial received a small speaker’s honoraria for presenting at the annual conferences organized by Dairy Farmers of Canada [Weiler H. Role of dairy in body composition and health. Dairy Research Symposium, Dairy Farmers of Canada and Agriculture Canada, Ottawa, Feb 5, 2016]. Susan A. Lanham-New is Research Director of D3Tex Ltd which holds the UK and Gulf Corporation Council (GCC) Patents for the use of UVB material in preventing vitamin D deficiency in women who dress for cultural style. SLN also received a small speaker’s honoraria for presentations at two conferences on Vitamin D organised by Solaris.

Ethics standards

Approval by a research ethics committee to conduct this meta-analysis was not required because the aim of this secondary analysis was consistent with the ethical approval received for the individual studies. The current analysis was conducted on anonymized data.

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Cashman, K.D., Kiely, M.E., Andersen, R. et al. Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D. Eur J Nutr 60, 939–959 (2021).

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  • Vitamin D recommendations
  • Dietary reference values
  • Recommended dietary allowance
  • Individual participant data-level meta-regression analyses
  • Vitamin D-fortified foods