Integrating Meeting 5 Budapest, 22 nd June 2011

1. Research Activities to produce processes and guidance for deriving European nutrient recommendations (RA4)Highlights Integrating Meeting 5 Budapest, 22nd June 2011

2. Overall objective To develop the processes started in RA1 to RA3, with valuable insight from the Integrating Activities (1-4), in order to produce resources that can be used in the process of setting micronutrient recommendations.

3. RA4 Overview RA4.1 RA4.1: Planning and alignment of RA4 and further exploration of priority micronutrients (led by UEA) RA4.2: Individual and “health space” approach (led by TNO) RA4.3: Science/policy interface (led by UNIS) RA4.4: Overall RA4 scheme (led by WU & ILSI) The RA4 concept centres around the development of a generic ‘scheme’ or ‘framework’ that summarises the work of EURRECA and process of deriving micronutrient requirements RA4.2, RA4.3, RA4.4

4. RA4.1: Planning and alignment of RA4 and further exploration of priority micronutrients • In addition to managing RA4, the RA4.1 work-package will: • Collate EURRECA information on the priority micronutrients • Address two new micronutrients: riboflavin & vitamin D • Encourage collaborative work with external experts • A ‘kick-off’ meeting was held at IM4 in Copenhagen for all interested EURRECA partners • Discussion of RA4 scheme/framework • Proposal for 2011 work plans

5. RA4 Scheme/Framework Step 4 Step 1 • Data • intake-status-health • factorialestimates • bioavailability • interactions • inter-individualvariability • biomarkers of ‘optimum health’ Step 3 Step 2 • Public health issues • Criteria for selection of • micronutrient • population group • healthoutcome • Methodology • intake • status • new approachese.g. metabolomics • Committee • Purpose • composition • goal Step 5 Step 6 Step 7 • Reference values • averagerequirement • variations in requirement/intake • population groups/scaling • global approach • Requirements • criteriaused for determiningrequirement • dose response/factorialapproach • genotype/individualvariability • multiple micronutrients • Guidance for policy options • Criteria for policy instruments e.g. • food fortification • foodbaseddietary guidelines • behaviourchange Step 8 Implementation and impact evaluation

6. The presentation, content and application of the scheme/framework will be refined during the RA4 process. RA4 work-packages will give feedback on the development of the generic scheme, and it will also be tailored to individual micronutrients. External micronutrient experts have been invited to give input during the process. World Public Health Nutrition Conference, Porto, 2010. Matthys C. et al. EURRECA’s approach for estimating micronutrient requirements. Int J VitNutr Res (submitted)

7. RA4.1: Expert workshop (15-16 Feb 2011, Leiden) Experts invited for each of the priority micronutrients: • Richard Hurrell (iron) • Michael Zimmermann (iodine) • John Hesketh (selenium) • Michael Hambidge (zinc) • John Scott (B12) • Anne Molloy (folate)

8. Workshop aims • To consider the proposed generic scheme for deriving DRVs, which can be refined for individual micronutrients • To reach a consensus on approaches needed to derive reference values for iron, zinc, selenium, iodine, folate and vitamin B12 (priority micronutrients) • To identify gaps in knowledge and consider future research requirements and priorities

9. Workshop activities • Introductory talks on population groups (Ambroise Martin), steps 3-6 of the RA4 scheme (Sue F-T) and steps 1, 2 & 7 (Monique Raats) • Working groups discussed steps 3-6 of the scheme in relation to each priority micronutrient, led by the invited expert and a rapporteur • Feedback presentations given by experts and reports written by the rapporteurs • Established basis for future collaborations with external experts (in some cases continuation of RA1& RA3 activities) • Feedback on the scheme for RA4.4 and ‘executive summary’ reports for priority micronutrients

10. Micronutrient summaries • Highlights of 1.5 days discussion on each micronutrient in separate working groups (WGs) • Not an exhaustive summary: full reports are available on the EURRECA intranet • Invited expert in each working group, but some EURRECA partners present are also international micronutrient experts

11. Iron Expert: Richard Hurrell Derive requirements using factorial approach (including bioavailability data) Bioavailability data required for different population groups (subject and food effects) Data required on obligatory losses in different population groups (menstruation, lactation, elderly) Genetic pre-determinants of iron absorption: further investigations required as variations in iron status largely unexplained Obesity and overweight result in inflammation and possible different requirements: status biomarkers required for inflammatory states

12. Selenium Expert: John Hesketh • Dose response data most appropriate for deriving requirements (factorial estimates not appropriate) • Current selenium biomarkers up to ~100µg/day, require new biomarkers to cover a range of health outcomes (e.g. in particular 100-200 µg/day) • Risk:benefit analysis for intake vs health (narrow range) • Inter-individual variability: more data required for I-S-H SNPs • Consider effect of different selenium species/forms • Multiple micronutrient interaction (iodine, vitamin E, ascorbic acid)

13. Vitamin B12Experts: John Scott & Anne Malloy • Dietary requirements should be based on intake-status relationship (dose response) : insufficient data to use factorial approach • The lack of a functional B12 biomarker limited data on which to base dose-response relationships • Few (and conflicting) data on inter-individual variability (possible polymorphisms for transcobalamin-2 binding proteins?) • Bioavailability: problems with gastric atrophy in elderly • Interactions: folate supplementation may mask B12 deficiency • Unclear whether scaling between population groups is valid, but currently the only option

14. FolateExperts: John Scott & Anne Malloy • Factorial estimates not appropriate for deriving requirements: need to use dose response • Assessment of dietary intakes affected by different bioavailability of folate and folic acid: need to apply dietary folate equivalents (DFEs). DFE ratio of 1.7 is not universally accepted • Strong evidence base for the relationship between folate intake and neural tube defects • Possible dietary interactions between folate and choline/betaine or zinc • MTHFR polymorphisms do not need to be considered when deriving requirements as overridden by the impact of ethnic variability and intake

15. IodineExpert: Michael Zimmermann • Factorial estimates for pregnancy and lactation are generally considered valid; those for infants are not (dose response data limited to studies using iodized oil ) • Needs to be greater emphasis on infants and the elderly: requirements, health effects in these groups need to be defined • Intake assessment in all populations requires most attention: (1) use of iodized salt & other vehicles by food industry, (2) decreased salt intake, (3) lack of accurate food composition data • FFQ to assess intake in multiple settings should be evaluated • Effects of micronutrient interactions: iron and selenium on requirements and status

16. Zinc Expert: Michael Hambidge • The factorialapproachwith a bioavailability factor is the preferredapproach for determiningdietary zinc requirements: need to includeeffects of phytate (and otherdietaryfactorse.g. Ca & Fe) • Inter-individualvariability: more data required, no evidence of ethnicityeffect • Most currentknowledge of zinc homeostasisisbased on research in healthyadult males: efforts shouldbe made to obtain data on bothgendersat all ages, includingduringpregnancy and lactation (to avoidscaling) • If scalingisonly option, thenneed consensus regardingwhichgrowth/weight data to use • Definition of population groups required, especially ‘elderly’: cut off points needed to define (un)healthy

17. Overall workshop outcomes • General consensus on the usefulness of the EURRECA scheme for deriving DRVs • Not a case of ‘one size fits all’ for DRVs: scheme reflects the need to assess different options based on availability of data for different micronutrients • Scheme highlighted the paucity of data for some of the EURRECA priority micronutrients • Highlighted the general need to develop approaches for evaluating data for multiple health outcomes and/or micronutrients (integration of outcomes) • Consideration should be given to definitions of population groups and ‘healthy’, particularly in the context of normal ageing • Agreement from invited experts to continue collaboration and offer input to EURRECA

18. Best Practice Guidelines Experts • A set of Best Practice Guidelines for biomarkers of micronutrient status is being finalised • Summarizes results of systematic reviews and quality-rated biomarkers (where SRs not performed) + + Systematic Reviews

19. RA4: Expert Collaboration RA4.1, RA1.2 & RA3.3 workshop experts providing final edit and suggestions for EURRECA Best Practice Guidelines Best Practice Guidelines: status • Sustainability • EURRECA website (3 years) • Biomarkers of Nutrition for Development (BOND)

20. Biomarkers of Nutrition for Development (BOND) • Initiative coordinated by NIH (National Institutes of Health) • Aims to provide information to support nutrition research in terms of biomarker discovery, development and delivery/implementation • Intends to dovetail onto and support the goals of EURRECA through provision of information & service in support of global nutrition research and health enterprise • EURRECA outputs used : Biomarkers Table and Best Practice Guidelines • Several EURRECA partners involved with the initiative as micronutrient experts

21. RA4: the future... • Develop and refine the generic RA4 scheme/framework using input from the work on the priority & additional micronutrients: input from stakeholders, experts and EURRECA partners • Update the latest US AHRQ (Agency for Healthcare Research and Quality) review on vitamin D (Tufts review, 2009) by carrying out a systematic search of relevant vitamin D intake-status papers published since initial review • Systematically review the literature for riboflavin (vitamin B2) intake-status-health relationships and assess the interaction between B vitamins in relation to intake-status-health outcomes

22. RA4: the future (2) ... • Produce executive summaries for each of the priority micronutrients (iron, zinc, selenium, iodine, B12, folate) • Use the RA4 generic framework to collate and order the information, and tailor the scheme to each micronutrient, highlighting specific issues • Identify knowledge gaps and research priorities • Continue collaboration with external experts to disseminate work

23. Acknowledgements Invited RA4.1 Experts • Richard Hurrell, ETH Zurich • Michael Zimmermann, ETH Zurich & WUR • John Hesketh, University of Newcastle • Michael Hambidge, University of Colorado • John Scott, Trinity College, Dublin • Anne Molloy, Trinity College, Dublin

24. Final Leiden Highlight ?

25. Backup Slides

26. RA4.2: Individual and ‘health space’ approach (TNO) • Integration of IA3 deliverables into the EURRECA general framework (integration of the micronutrient phenotype database with the health space model database) • Construction of a web-based portal/database containing micronutrient-genetic variation literature

27. RA4.3: Science/policy interface (UNIS) • Draft supporting material/guidelines for science policy interface (steps 2 & 7 of RA4 scheme)  test the materials at a workshop • Further test the materials specifically for iodine, vitamin D and folate • Hold workshops to further refine and then finalise the materials (with external input) • Present the final outputs to relevant stakeholders & policy makers

28. RA4.4: Overall RA4 scheme (WU/ILSI) • Develop and refine the generic RA4 scheme/framework (using input from the work on the priority & additional micronutrients) • Discuss the proposed framework and its development with external experts and stakeholders • Produce a report containing the final generic framework and information on its development and application  the report will be key for disseminating RA4 work

29. RA4.1 Systematic search and review of the literature for 1. riboflavin and 2. B vitamin interactions • Develop a protocol that adapts the EURRECA approach to a more limited time frame  Adapt RA2/3 protocols, prioritising work where necessary to complete within the limited timeframe • Systematically review the available literature for riboflavin (vitamin B2) intake-status-health relationships • Assess the interaction between B vitamins in relation to intake-status-health outcomes  Prioritise health outcomes following the selection process • Summarise findings in papers/reports, highlighting knowledge gaps and future research requirements

30. Extend the work on vitamin D • Update the latest US AHRQ review on vitamin D (Tufts review, 2009) by carrying out a systematic search of relevant vitamin D intake-status papers published since • Use these new papers to refine the vitamin D intake-status relationships in European populations and population sub-groups for vitamin D. Compare estimates with current intake/status data in Europe. • Write a paper based on the findings of this task and associated tasks highlighting knowledge gaps and future research requirements in relation to vitamin D nutrition for Europe.

31. RA4.1: Planning and alignment of RA4 and further exploration of priority micronutrients (UEA) EXECUTIVE SUMMARIES For each of the priority micronutrients (iron, zinc, selenium, iodine, B12, folate): • Collate and summarise the evidence collected to date through EURRECA activities • Use the RA4 generic framework to collate and order the information, and tailor the scheme to each micronutrient, highlighting specific issues • Identify knowledge gaps and research priorities • Collaborate with external experts where possible to disseminate work