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

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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

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.

Methods

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.

Results

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).

Conclusions

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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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].

Abbreviations

25(OH)D:

25-Hydroxyvitamin D

AI:

Adequate intake

DRI:

Dietary reference intake

DRV:

Dietary reference values

EAR:

Estimated average requirement

EFSA:

The European Food Safety Authority

FFQ:

Food frequency questionnaire

IOM:

Institute of Medicine

IPD:

Individual participant data

NNR:

The Nordic Council of Ministers’ Nordic Nutrition Recommendations

RCT:

Randomized controlled trial

RDA:

Recommended dietary allowance

RI:

Recommended intake

RNI:

Reference nutrient intake

SACN:

The Scientific Advisory Committee on Nutrition

UVB:

Ultraviolet B

WHO-FAO:

World Health Organisation–Food and Agriculture Organization

SR-MA:

Systematic reviews and meta-analyses

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Author information

Authors and Affiliations

  1. Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland

    Kevin D. Cashman & Mairead E. Kiely

  2. Research Group for Risk-Benefit, Division for Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark

    Rikke Andersen, Ida M. Grønborg, Katja H. Madsen, Janna Nissen & Inge Tetens

  3. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg C, Copenhagen, Denmark

    Inge Tetens & Christian Ritz

  4. Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK

    Laura Tripkovic & Susan A. Lanham-New

  5. Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Madrid, Spain

    Laura Toxqui & M. Pilar Vaquero

  6. Institute of Nutrition, Friedrich Schiller University of Jena, Dornburger Str, 24, 07743, Jena, Germany

    Ulrike Trautvetter & Gerhard Jahreis

  7. Dairy Science Department, South Dakota State University, Brookings, 57007, USA

    Vikram V. Mistry

  8. Ethel Austin Martin Endowed Program in Human Nutrition, South Dakota State University, Brookings, 57007, USA

    Bonny L. Specker

  9. Überörtliche Gemeinschaftspraxis für Kinder- und Jugendmedizin Standort Dümpten, Mellinghofer Straße 256, 45475, Mülheim an der Ruhr, Germany

    Jürgen Hower

  10. Freelance Statistician, Kreppe 2, 85276, Pfaffenhofen/Ilm, Germany

    Anette Knoll

  11. Department of Nutritional Sciences, University of Toronto, Toronto, M563E2, Canada

    Dennis Wagner & Reinhold Vieth

  12. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, M5G1X5, Canada

    Reinhold Vieth

  13. Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden

    Inger Öhlund

  14. Department of Clinical Sciences, Pediatrics, Lund University, Lund, Sweden

    Pia Karlsland Åkeson

  15. School of Human Nutrition, McGill University, Sainte Anne de Bellevue, QC, Canada

    Neil R. Brett & Hope A. Weiler

  16. Department of Medicine, University College Cork, Cork, Ireland

    Kevin D. Cashman

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  1. Kevin D. Cashman
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Contributions

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). https://doi.org/10.1007/s00394-020-02298-x

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  • DOI: https://doi.org/10.1007/s00394-020-02298-x

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