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PUBLISHABLESUMMARYREPORT–Section4.1

GrantAgreementnumber:613977

Projectacronym:ODIN

Projecttitle:Food-basedsolutionsforOptimalvitaminDNutritionandhealththroughthelifecycle

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A. Executive summary PreventionofvitaminDdeficiencyisapublichealthpriority,asnutritionalricketsandosteomalaciahavesevereandlastingconsequencesforbonegrowthandskeletalintegritythroughoutlife.Non-skeletaleffectsoflowvitaminDstatus,includingrespiratoryinfection,perinatalhealthoutcomesandcardiovasculardisease,forexample,arethesubjectofaglobalresearcheffort.TheEuropeanCommissionfundedODINproject(Food-basedsolutionsforoptimalvitaminDnutritionandhealththroughoutlife:www.odin-vitd.eu)isamultidisciplinaryconsortiumof30partnersfrom18countries.ODINcompleteda4-yearprogrammeofresearchinDecember2017.LedbyProfMaireadKielyandProfKevinCashman,atUniversityCollegeCork,theODINprojectwasbuiltaroundaprioritisedagenda,outliningcurrentknowledgegapsinvitaminDnutrition.

Asmuchof Europe experiences 4-6wintermonths duringwhichUVB availability is too low topermitskinsynthesisofvitaminD,thedietiscriticaltomeetingpopulationrequirements.VitaminDispresentinthefoodsupply,infewfoodsandinlowconcentrationsandintakesaretypically<5µg(<200 IU)/day, which is insufficient to offset the seasonal sunshine UVB deficit. NutritionalsupplementscontributeahighproportionofvitaminDintakeamongusers,butsupplementuptakeisnotuniversalandgenerallylowamongadolescentsandyoungadults,whoareatriskofvitaminDdeficiency. TheODINmission is todevelopeffective, safeandsustainable solutions topreventvitaminDdeficiencyandimprovevitaminD-relatedhealthoutcomesusingafood-firstapproach.Withabudgetof€6M,ODINadoptedatriageapproachtoprioritiseitsobjectives,whichweredeliveredbytheconsortiumacrossanambitiousprogrammeencompassingbothdose-responseandfood-basedrandomisedcontrolledtrials,researchinprimaryfoodproductionandfoodtechnology,dataminingofepidemiologicalcohortstudiesanddietaryandUVBmodellingexperiments.

Todate,ODINhaspublished75peer-reviewedscientificarticlesinqualityjournals,manyofwhicharethefirstintheirfield,withmoreunderreview/inpreparationforpublicationin2018.Significantachievements:

ODINgeneratedreliableprevalencedataforvitaminDdeficiencyacrossEuropeforthefirsttime.Among55,844individualsin18representativestudiesofchildren,teens,adultsandelderlypersonsacrossalatitudegradientof35oNto69oN,13%(or1in8)hadvitaminDdeficiency,onthebasisofaserum25-hydroxyvitaminD(25(OH)D)concentration<30nmol/Land40%hadlowvitaminDstatus,with25(OH)D<50nmol/L.Personsofethnicminoritywereatmuchhigherriskthantheirwhitecounterparts,http://www.odin-vitd.eu/public/7-european-vitamin-d-deficiency-map/.

Among6000womeninearlypregnancyintheUK,SwedenandIreland,therewasaslightlyhigherprevalenceofvitaminDdeficiencyandlowvitaminDstatus.InthislargeststudyofvitaminDinpregnancytodate,15%(or1in7)had25(OH)D<30nmol/Land44%were<50nmol/L.AlmosthalfofinfantshadvitaminDdeficiencyatdelivery,particularlyiftheirmothershadlowvitaminDstatus.

ODINconductedanindividualparticipantdataanalysisamong26,916olderadultsofmortalityinstudieswithmortalityandcardiovascularoutcomes.Thelowestriskwasata25(OH)Dconcentrationof78nmol/Landtheriskofmortalityincreasedas25(OH)Ddecreasedfrom<50to<30nmol/L.

In dose-response vitamin D intervention studies, ODIN researchers provided vitamin D intakerequirementestimatesinyoungchildren,teens,pregnantwomenandindividualsofethnicminority.

Using a farm to fork approach, ODIN demonstrated that natural enhancement of animal feedcoulddelivermeasurableincreasesinvitaminDinmeatsandhenseggs,whichincreasedvitaminDstatusinhumanvolunteers.Similarly,ODINsuccessfullyincreasedthevitaminDcontentoflow-fatcheeseanddemonstratedbenefitsfordeficiencypreventioninolderwomen.

Over-reliance on a single food source (e.g. dairy) will not ensure population coverage andweneedtoaccommodatedietarydiversityforeffectivedeliveryofadditionvitaminDtothepopulation.ODIN developed a specialized food composition dataset for vitamin D and conducted dietarymodelling experiments in 10 dietary surveys from 4 countries to demonstrate the feasibility ofachievingdietaryrecommendationsforvitaminD,withoutincreasingtheriskofexcessiveintakes.

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TheODINhypothesis,thatcarefulapplicationoffortificationandbio-fortificationstrategiescouldsafely increase intakes of vitamin D across the distribution and prevent deficiency, is technicallyfeasible.Societalandeconomicbenefitsrequirefurtherinvestigation.B. Summary description of the ODIN project context and objectives

ODIN(Food-basedsolutionsforoptimalvitaminDnutritionandhealththroughthelifecyclewww.odin-vitd.eu) was a 4-year integrated project, which commenced in November 2013and finished in October 2017. The Cork Centre for Vitamin D and Nutrition Research atUniversityCollegeCork,IrelandledtheODINconsortiumof30partnersfrom19countries.

Projectcontextandmotivation

Vitamin D is a nutrient that has captured the attention of the public, the scientific andmedical communities, regulatory agencies and the food industry. While there are manycontroversies in relation to vitamin D requirements and its impact on human health, it isgenerallyagreedthatpreventionofvitaminDdeficiency,forpreventionofnutritionalricketsand osteomalacia, is a public health priority, as these disorders have severe and lastingconsequences for bone growth and skeletal integrity throughout life. While data showingassociationsbetweenvitaminDandnon-skeletaldisordersareabundant,theevidencebasetosupportaroleforvitaminDinpreventionofnon-bonerelateddisordersiscurrentlylessrobust. Nonetheless, public health authorities are now aware of the importance ofpreventing vitamin D deficiency, which was until recently an unacknowledged healthproblem.

ThemajorsourceofvitaminDinhumansissunshine;ultravioletB(UVB)radiationstimulatesskinsynthesisofcholecalciferol(vitaminD3),whichisstoredinadiposetissueormetabolisedintheliverto25-hydroxyvitaminD[25(OH)D],thebiomarkerofvitaminDstatus,andfurthermetabolised in the kidney to calcitriol, the biologically active metabolite. The mostextensivelydocumentedfunctionofvitaminDisregulationofserumcalciumandphosphatehomeostasis,acriticalcomponentofnormalskeletalmineralisationthroughoutthegrowingyearsandduringtheageingprocess.

Severalenvironmentalfactors,suchaslatitudeandprevailingweatherconditions,determinethe availability of sunshine of sufficient strength to stimulate skin synthesis of vitamin D.Personalattributes,suchasskinpigmentation,age,attire,sunscreen,workingenvironment,physicalactivityandsunexposurebehaviourcanalsopreventorimpedevitaminDsynthesis.SubstantialportionsoftheEuropeanpopulation,includingallwhoresideatlatitudesgreaterthanaround40oNrelyonbodystoresandvitaminDinthediettomaintainhealthyvitaminDstatusallyearround.AsmuchofEuropeexperiences4-6wintermonthsduringwhichUVBavailabilityistoolowtopermitcutaneoussynthesisofvitaminD3,dietarysupplyiscriticaltomeeting population requirements. Thus, a sizeable proportion of the school-aged andworkingpopulation,aswellasthemorewidelyacknowledgedolderadultdemographicisatriskoflowvitaminDstatus.

VitaminDdoesoccur in thediet,bothnaturally andasanaddednutrient for fortification,and in nutritional supplements. However, vitamin D intakes are typically low, as it occursnaturallyinfewfoodsandinlowconcentrations,andthedietarysupplyiscurrentlyunabletooffsettheseasonalsunshinedeficit.NutritionalsupplementscontributeahighproportionofvitaminD intakeamongusers,howeversupplementuptake istoo lowtomake itviablefordeficiencypreventionacross thepopulation.Despitemuch scientific research invitaminD,

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there are stillmany fundamental gaps in the field from the public health perspective andthese impede the development of strategies for prevention of vitamin D deficiency. ODINaimed to address some of these gaps and in so doing facilitate a food-first approach totackingvitaminDdeficiencyinEurope.

OverallobjectiveofODIN

To develop effective, safe and sustainable solutions to prevent vitamin D deficiency andimprovevitaminDrelatedhealthoutcomesusingafood-firstapproach.Weadoptedatriageapproachtoselectingthemostcriticalissuesforattention:

PrioritisedQuestions

VitaminDstatusandexposure

• WhatistheactualprevalenceofvitaminDdeficiencyinEuropeandhowdocountriescomparewitheachotherandtherestoftheworld?

• WhatisthedistributionofvitaminDintakeinEurope?• HowwillincreasingvitaminDinthefoodsupplyaffectthisdistributionandreducethe

prevalenceofinadequateintakes?• What is the potential contribution from UVB to circulating 25(OH)D across the

Europeanlatitudegradient(~35-70oN).• Whatisthedose-responseof25(OH)DtoUVBathabitualskinexposurelevels?

Food-basedstrategiestomeetdietaryrequirementsfordeficiencyprevention

• What changes in the food supply will increase population intakes of vitamin Dsufficientlytomodifythedistributionof25(OH)Dandpreventdeficiency?

• HowcanweharnesstechnologicaladvancesinfoodproductionandanimalnutritiontoincreasevitaminDinthefoodsupplywithconsiderationfordietarydiversityandlocalpreferences?

NutritionalrequirementsforvitaminD?

• What are the dietary requirements during pregnancy, childhood and adolescence topreventvitaminDdeficiency?

• WhatistheimpactofethnicityondietaryrequirementsforvitaminDinadults?

Healthandsafety

• Are associations between 25(OH)D and non-skeletal health in adults independent ofpre-existingrisk,bodycomposition,co-morbiditiesandcompromisednutritionalstatusandpossiblemodulationbygeneticvariation?

• Are associations between vitaminD and perinatal outcomes robust inwell-powered,prospective,clinicallyvalidated,disease-specificpregnancyandbirthcohorts?

• DoesvitaminDstatusmodulatephysicalgrowthanddevelopmentinearlylife?• ArehighvitaminDintakesandserum25(OH)Dconcentrationssafeinthelong-term?

Projectorganisationandarchitecturetoaddresstheseprioritizedquestions

ODIN assembled a world-leading, multidisciplinary partnership of scientific and medicalresearchersfromacademiaandresearchorganizationswithcomplementaryexpertiseinthearea of vitamin D nutrition and health to work closely with significant food and nutrition

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industriesandSMEsactiveinfoodandingredientdevelopment.TheODINconsortiumof20Europeanacademicandresearchinstitutionalpartners,10industryandSMEpartnersacross19countries,aswellastheOfficeofDietarySupplementsoftheNationalInstitutesofHealth(NIH) intheUSasanon-fundedcollaborator(seePart2ofthereportforpartner list),wasconfigured to have the expertise and excellence, necessary ethos of cooperation andcollaboration as well as overall skill sets required to address the prioritised researchquestions and to define food-based strategies and solutionswhichwould be feasible, safeandeffectiveforpreventionofvitaminDdeficiencyinEurope.

ODINimplementedanintegratedprogramofresearchacrossnineRTDwork-packages(WPs)dealingwithvitaminDstatusandexposure(dietandsun),dietaryrequirements,food-basedsolutions, human health and safety, as per the priority questions posed, as well as adedicatedWPforprojectcoordinationandaWPprovidinganinnovativetechnologytransferandstakeholderengagementstrategytogenerateandtranslatetheknowledgerequiredtoprevent vitamin D deficiency through food and confirm European leadership of vitamin Dpublichealthnutritionglobally.TheseWPswere:

WP1: VitaminDstatus:distributionofstandardizedserum25-hydroxyvitaminDconcentrationsinEuropeanpopulations[VDSPEurope]

WP2: DietaryexposuretovitaminDinEuropeanpopulationsWP3: Sunlightexposure:risk-benefitanalysis,implicationsforvitaminDrequirementsandstatusWP4: Dietary requirements for vitamin D during pregnancy, childhood and adolescence using

dose-responseRCTsWP5: Food-andfood-technology-basedsolutionsforpreventionofvitaminDdeficiency:Natural

sources,fortificationandbiofortificationwithvitaminD2/D3and25-hydroxyvitaminDWP6: Proofofeffectivenessof food-basedsolutions topreventvitaminDdeficiencyusing food-

basedRCTWP7: VitaminDandhealthoutcomesinpregnancyandearly-lifeWP8: VitaminDandhealthoutcomesinadults:mortalityandCVDWP9: SafetyconsiderationsinrelationtoincreasingvitaminDintakeandserum25OHDlevelsWP10: Technologytransfer,stakeholderengagement&disseminationWP11: Managementandcoordination

Thework-flowandinterdependenciesofODIN’s11WPsareshownintheFigurebelow.

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!!

WP11!

Management!&!Coordination!

!

WP7,!WP8!

Health!!

WP4!

Vitamin!D!Requirements!

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WP5,!WP6!

Food!Solutions!!

WP1!

25OHD!!

WP2!

Intake!!

WP3!

Sun!

WP10!

Technology!Transfer,!Stakeholder!Engagement!&!Dissemination!

WP9!

Safety!

Status&and&Exposure&

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C. Description of the main S&T results/foregrounds

TheODIN projectwas built around the research recommendations from a comprehensivereviewofpersistentknowledgegapsinvitaminDnutritionandpublichealth,providedbytheprojectcoordinators(Cashman&Kiely;https://www.ncbi.nlm.nih.gov/pubmed/22017772)in2011.ODINadoptedapragmaticapproachtoaddressingitsprioritieswithinthiswidersuiteofknowledgegaps,asmentionedinSectionBaboveandmorecomprehensivelydetailedbyKiely&Cashman (http://onlinelibrary.wiley.com/doi/10.1111/nbu.12159/epdf) on behalf ofthe project consortium. The ODIN mission is to develop effective, safe and sustainablesolutions to prevent vitamin D deficiency and improve vitamin D-related health outcomesusingafood-firstapproach.Underpinningdatatoachievetheseoutcomesweredeliveredbytheconsortiumacrossitsambitiousprogrammeencompassingbothdose-responseandfood-based randomised controlled trials (RCTs) with vitamin D, research in primary foodproductionandfoodtechnology,dataminingofepidemiologicalcohortstudiesanddietarymodelling experiments. The quality and reliability of ODIN analytical data, both serum25(OH)D and relatedmetabolites, aswell as food composition data,was a cornerstone ofexcellence in the project and its findings, assuring validity of experimental outcomes andprovidingreferencedataforpreviouslyunder-researchedpopulationgroups.Manyof thekeyS&T resultsand foreground informationgatheredwithinODINhavebeenpresented in the 75 papers arising from the project (see Section 4.2A below). A moredetailed overview of the work undertaken in each of ODIN’s 9 RTD work packages (WP),includingtheirkeyachievements,isprovidedbelow.Work package 1: Vitamin D status: distribution of standardized serum 25(OH)DconcentrationsinEuropeanpopulations

The main objective of WP1 was to estimate the prevalence of vitamin D deficiency inEuropeanpopulations andquantify themagnitudeof thepublic healthproblemaswell ashighlight at-risk population subgroups. The distributions of standardized serum 25(OH)Dconcentrations in national surveys and epidemiological cohorts/samples of Europeanchildren,adolescents,adultsandelderly(includingethnicsubgroups)weretobeestablishedviaamajorunderpinninginfrastructuraldevelopment intheformoftheinternational,NIH-ledVitaminDStandardizationProgram(VDSP)anditsprotocols.

WP1wascompletedonschedule(month18)andsuccessfullyappliedtheVDSPprotocolstoexisting serum 25(OH)D data from 14 representative childhood/teenage (eight) andadult/olderadult (six)Europeanpopulations, representingasizeablegeographical footprintand a total sample size of 55,844, to quantify the prevalence of vitamin D deficiency inEurope.ThisfirstinternationallycomparabledatasetofvitaminDstatuswaspublishedintheAmerican Journal of Clinical Nutrition in 2016 (under open access athttp://www.ncbi.nlm.nih.gov/pubmed/26864360)anddescribed“Anoverallpooledestimate,irrespective of age group, ethnic mix, and latitude of study populations, of 13.0% of the55,844Europeanindividualshadserum25(OH)Dconcentrations<30nmol/Lonaverageintheyear,with17.7%and8.3%inthosesampledduringtheextendedwinter(October-March)andsummer (April-November) periods, respectively. According to an alternate suggesteddefinition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinnedethnicsubgroupshadmuchhigher (3- to71-fold)prevalenceofserum25(OH)D<30nmol/L

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thandidwhitepopulations”.Theconcerningmagnitudeofthedeficiencyestimates, fromapublic health perspective, attracted an accompanying editorial in theAmerican Journal ofClinical Nutrition (open access at https://www.ncbi.nlm.nih.gov/pubmed/26984486) whichhighlighted the importance of the data. In addition, and of key relevance to ODIN, theauthorsoftheeditorialsuggestedthat‘becausefoodfortificationisdeeplylackingwithintheEU,we suggest that futurework, whichmay lead to realistic and actionable public healthpolicies, should focus on determining the most effective fortification strategies to meetrequirements for vitamin D among community-dwelling Europeans’. This is the overallobjectiveoftheODINproject,namelytodevelopeffective,safeandsustainablesolutionstopreventvitaminDdeficiencyand improvevitaminDrelatedhealthoutcomesusinga food-firstapproach.

Ofnote,thepaperhasbeencited>190timesalreadysinceitspublicationinMarch2016andwas included in the ‘The Top 18 Vitamin D Papers in 2015-2016’ (source: OrthomolecularMedicineNewsService,February13,2017).Toenhancetranslationandaccessibilityofthedata, as well as engagement with ODIN, we developed an online European Vitamin DDeficiency Map. This map, generated by the Cork Centre for Vitamin D and NutritionResearchpresentsdataonstandardizedserum25(OH)DfromODINaswellasanumberofassociated projects,where theODIN leaders at University College Cork, togetherwith theNIHOffice ofDietary Supplements and collaborating Europeanpartners have standardized25(OH)D data in a number of important European population studies. These data arepresented in summary and user-friendly format in this new interactive map (see below)available at: http://www.odin-vitd.eu/public/7-european-vitamin-d-deficiency-map/, whichhasbeendisseminatedwidelythroughtheODINnewsletter,conferences,VDSPwebinars.

Someof theprevalencedata in thismaphasalsobeencross-connectedtoUVBavailabilitydatainanODINonline‘VitaminDwinter’map(seeunderWP3).

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OtherWP1S&Tresultswere:FindingsinrelationtovitaminDstatusinCentralandEasternEuropeanCountries(CEEC)

• Basedon a systematic literature reviewof vitaminD status in theCEEC, nonationallyrepresentative datasets were identified that could be used to conduct analysis ofappropriately phenotyped and curatedbiobanks using theODIN analytical platformasusedintheabovementionedrepresentativepopulationsfromelsewhereinEurope.

• Fromtheliterature,itcouldbeconcludedthat25(OH)Dlevelsare,onaverage,below75nmol/LinmoststudiesinCEEC.

• In winter season, 25(OH)D levels in adults are, on average, below 50 nmol/L inmoststudies included in this review (basedonBulgaria,Estonia,Hungary, Lithuania,Poland,Serbia,Ukraine).

• No studies on vitamin D status were found for Albania, Bosnia and Herzegovina, andMacedonia.

• Nationalstudiesarelimitedforchildren,adolescents,pregnantwomenandtheelderlyinCEEC.Thisworkiscurrentlyinpreparationforpeerreviewandthefulldataandfindingswillbemadepublicallyavailableafterpublication.

FindingsinrelationtovitaminDstatusinSouthernEuropeancountries

• The results from a systematic literature review of studies from Southern Europeancountries, published in the European Journal of Nutrition in 2017 (open access athttps://www.ncbi.nlm.nih.gov/pubmed/29090332), were indicative of a relatively highheterogeneity of published evidence regarding serum 25(OH)D concentrations andvitaminDstatusamongSouthernEuropeancountries.

• Data were extracted from 107 studies, stratified by sex and age group, representing630,093individuals.Morethanone-thirdofthestudiesreportedmeanserum25(OH)Dconcentrations below 50 nmol/L and ~ 10% reported mean serum 25(OH)Dconcentrations below 25 nmol/L. Overall, females, neonates/ infants and adolescentshadthehigherprevalenceofpoorvitaminDstatus.Asexpected,therewasconsiderablevariabilitybetweenstudies.Specifically,meanserum25(OH)Drangedfrom6.0(inItaliancentenarians) to 158 nmol/L (in elderly Turkish men); the prevalence of serum25(OH)D < 50nmol/Lrangedfrom6.8to97.9%(inItalianneonates).

• An audit of available quality bio-banks in southern European countries identified thatserum and/or plasma samples existed for a total number of 22,346 subjects aged 10yearsandolderfromfourcountriesinsouthernEurope(France,Greece,ItalyandSpain)aswell as from Israel and Turkey. Thequality of bio-banks identified could representcandidate bio-banks, the serum or plasma samples of which could be used forconductingfuturebiochemicalanalyses(i.e.withLC-MS/MS)tomeasure25(OH)DlevelsaspertheVDSPprotocols,intherespectivepopulations.

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Workpackage2:Dietaryexposureandmodellingforfoodfortification

ThemainobjectivesofWP2weretodescribevitaminD intakesfromfoodandsupplementsources, using standardized food composition data and a consistent approach to foodindexingandgrouping,innationallyrepresentativefoodconsumptionandnutritionEuropeansurveys. Data on ethnic and traditional foods to inform food-based strategies to ensureadequate vitamin D in the food supply of all European citizens were to be compiled. Anintegrated approach to data compilation in the nutrition surveys in Central and EasternEuropean Countries (CEEC) was to be used for vitamin D intake assessment. Dietarymodeling incasedatasetswouldbeused topredict the impacton thevitaminDsupply infoods and the distribution of intakes using fortification and bio-fortification strategies inODIN. This would ensure appropriate levels of addition to ensure efficacy in terms ofinadequateintakesandminimizetheriskofexceedingtolerableupperintakelevels(ULs).

WP2 was successfully completed during the 2nd reporting period (month 30). The ODIN-EUROFIRvitaminDfoodcompositiondatabasewasconstructedinthefirstreportingperiodandhassincebeenpublishedinFoodChemistry(openaccess)athttps://www.sciencedirect.com/science/article/pii/S030881461731289X?via%3Dihub andwidely disseminated. In the 1st period we also described the first harmonised, validatedvitamin D intake data in 10 nationally representative surveys from 4 EU countries andreportedintakesof3-5μg/dintheUK,Denmark,theNetherlandsandIrelandwith77-100%ofpeopleatriskofinadequatevitaminDintakes.SometraditionalsourcesofvitaminD,suchaseggs,werestillimportant,whileotherssuchasoilyfish,madealimitedcontributiondueto low consumption levels in most countries, particularly among children. These data areunderreviewinanextendedjointpublicationwiththeintakemodellingexperiments.

InWP2,wedevelopedandvalidatedanovelsystemforODINtoprogressstep-wisedietarymodelling of incremental food fortification scenarios, based on data from WP5, andcompleted these analyses in the 2nd period (month 19-30). Data from incremental andcombined dietary modelling experiments in 10 nationally representative surveys in 4 EUcountries showed thatproposedcombinedODIN fortificationandenhancement strategies,includingmilk,eggs,cheeseandmeatachievedesiredpopulationintakesanddistributionsofvitaminD,relativetotheEARof10μg/day/d,withoutincreasingtheriskofexcessiveintakes.Supplementaldosesexceeding25μg/dayinchildrenand50μg/dayinadultswereassociatedwithriskofexceedingtheage-specificULs.

Ingeneral,weconfirmedthatcurrentlevelsofvitaminDfortificationarelowandtodate,noEUcountryotherthanFinlandhastakenastrategicapproachtofortification,whichlimitsitsbenefit, discussed in our open access Journal of Nutrition articlehttps://academic.oup.com/jn/article-lookup/doi/10.3945/jn.114.209106. There is currentlynoevidenceofexcessiveintakesofvitaminDacrossthe10surveysinthefourcountrieswestudied.

VariableestimatesofvitaminD intakes fromasystematic reviewofCEECshowedvery lowintakesofvitaminD,whichisprobablyafunctionofthedietaryassessmentmethodandfoodcompositiondataavailable,butnosurveywasidentifiedtocontributetotheODINdatabank.There is an urgent need for quality dietary survey data in CEEC countries. These data arebeingpreparedforpeer-review,inconjunctionwiththedatafromWP1.

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Theanalysisofethnicandtraditional foods inODINconfirmedthattargetedapproachestodesigningfoodfortificationstrategieswererequiredforethnicsubgroups.Potentiallyusefulfoodsarebakedgoodsandvegetableoils.However,contemporaryintakedataareurgentlyrequired among ethnic subgroups to perform dietarymodelling experiments as these arecurrentlynotavailableorinsufficientlysmalldatasets.

Workpackage3:Sunlightexposure:risk-benefitanalysis

ThemainobjectivesofWP3weretomodelsolar-derived,vitaminD-effectiveUVBavailabilityacross several European member states, based on local climatology, to corroborate theprevalenceofvitaminDdeficiency/inadequacy,defined inWP1.EstimatesofpotentialUVBexposureaswellasnationallyrepresentativevitaminDintakeestimateswerealsotobeusedin the development of mathematical models for predicting population serum 25(OH)DdistributionsarisingfromchangesinvitaminDintakewhileaccountingforsolarUVB-derivedsources. WP3alsoaimed toprovidenewUVrisk-benefitdata in termsof the responseofserum25(OH)D toUVBexposure in a controlledhuman studywith artificialUV light. Thestudy aimed at testing whether simulated summer UVB exposure level of public healthrelevance (~12% body surface to 15-25 min of summer noon equivalent sun) enablesadequatesubcutaneousvitaminDsynthesiswhileavoidingriskofDNAdamageinskin.

WP3 was completed on schedule (month 36) and using a validated UV irradiance modelsuccessfully modelled vitamin D-effective UVB availability across the European memberstates(nine)forwhichvitaminDstatusdatawasgeneratedinWP1.Theresults,publishedinNutrients in 2016 (open access at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037520/), showed that UVB availabilitydecreased with increasing latitude (from 35◦N to 69◦N), while all locations exhibitedsignificantseasonalvariationinUVB(seeFigurebelow).

Figure.MeanmonthlymodeledUVBdoseseffectiveforpre-vitaminD3synthesis(Jm

-2)acrossEuropeforJune(lefthandpanel)andDecember(righthandpanel),basedonaverageofdatafromyears2003–2012.

TheUVBdatasuggestedthatthedurationofvitaminDwintersrangedfromnone(at35◦N)toeightmonths(at69◦N).ThisdatawasalsotranslatedintoanonlineVitaminDWinterMap(see below; and available at: http://www.odin-vitd.eu/files/vit%20D%20winter%20map%20landscape%20new.pdf.

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WP3 has successfully developed and validated the two planned European case-studyintegrated models of sun-diet-25(OH)D, and has demonstrated their utility in predictingpopulationserum25(OH)DdistributionsarisingfromchangesinvitaminDintake,accountingfor solar UVB-derived sources. These models enable food-based strategies for theprevention of vitamin D deficiency to be evidence-based. In the first model, which wasdeveloped for Ireland and published in the Journal of Nutrition (open access athttps://www.ncbi.nlm.nih.gov/pubmed/26290010), the UVB- and vitamin D intake-serum25(OH)D components of the integrated model were both validated with the use ofindependent data, including standardized serum 25(OH)D data from the nationallyrepresentativeNational Adult Nutrition Survey in Ireland (generated inWP1). Themodelpredicted that the percentage of vitaminD deficiency [serum25(OH)D <30nmol/L] in theadultpopulationduringanextendedwinterperiodwas18.1% (vs.18.6%measured). Theperformanceoftheintegratedmodelwastestedwiththeuseof3hypotheticalfortificationscenariosasexemplars.ThisshowedthattheprevalenceofvitaminDdeficiencyintheadultIrish population could be reduced in a stepwise manner with the incorporation of anincreasednumberofvitaminD-fortifiedfoods,downto6.6%withtheinclusionofenhancedfortifieddairy-relatedproducts,fatspreads,fruitjuiceanddrinks,andcerealproducts.

Thesecondmodel,whichwasfortheUKandpublishedintheJournalofSteroidBiochemistryand Molecular Biology (open access at https://www.ncbi.nlm.nih.gov/pubmed/27637325),was a more complex model as it had to take account of the fact that unlike the Irishpopulation,theUKpopulationisanethnicallymixedone(consistingof~90%whiteand~10%black andAsianminority ethnic individuals, based on recent census data). ThisUKmodelused key data from UVB observational and interventional studies in Manchester, UK toinform the design of the dark-skinned model component, which was then successfullyintegrated with that for the white population to generate an overall model. This wasvalidatedagainststandardizedserum25(OH)DinthenationallyrepresentativeNationalDietand Nutrition Survey – 4 year rolling programme in the UK (generated in WP1). Theintegrated UK model successfully predicted measured average wintertime 25(OH)Dconcentrations in addition to the prevalenceof serum25(OH)D<30nmol/L in adultwhiteandblackandAsianethnicminoritygroups[BAME](18-70y) intheUK-basedNationalDiet

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andNutrition Survey both separately (21.7%and49.3%predicted versus20.2%and50.5%measured,forwhiteandBAME,respectively)andwhencombinedatUKpopulation-relevantproportionsof97%whiteand7%BAME(23.2%predictedversus23.1%measured).

Thus, the Irish and UK integrated models, as case-studies, highlight how mathematicalmodelspresentaviableapproachtoestimatingchangesinthepopulationconcentrationsof25(OH)D and prevalence of vitamin D deficiency that may arise from various dietaryfortification approaches. Data from WP2 (above) which showed that a combined foodfortificationapproach,whichincludedmilkandcheeseaswellasbiofortifiedeggs,beefandpork,wasmosteffectiveatincreasingthepopulationintakes,wereusedinthetwomodelsintermsofpredictingpopulationserum25(OH)DdistributionsarisingfromchangesinvitaminDintake arising from food-based solutions for prevention of vitamin D deficiency, whileaccountingforsolarUVB-derivedsources.Thecombinedfoodfortificationapproachbroughtabout39-46%modelled reductionson theprevalenceofvitaminDdeficiency in these twopopulations. Suchmodels can be of great utility to public health bodies in devising food-basedstrategiesandpolicies.Equivalentmodelscouldbeconsideredforotherage-groups,once the underpinning data are available. This work is currently in preparation for peerreviewandthefulldataandfindingswillbemadepublicallyavailableafterpublication.

The sun exposure trial (at 12-14% skin area exposure) within WP3, which explored theresponseofserum25(OH)DtoUVBexposureinacontrolledhumanstudywithartificialUVlighttoprovidedatatotestwhethersimulatedsummerUVBexposurelevelofpublichealthrelevance,wasalsosuccessfullycompletedin55volunteers.Theresultsshowthatexposureof hands, forearms and face only to simulated Manchester summer sunlight in whiteCaucasianadultsproducesasmallbutsignificantincreaseincirculatingserum25(OH)D.Thisresulted inoverthree-quarterswithserum25(OH)Dconcentrationsaboveadeficiencycut-off (30nmol/L)butonlyaboutonequarterof thevolunteersachievingcirculating25(OH)D≥50 nmol/L, reflective of vitamin D adequacy. These findings are important in terms ofinformingthe impactofsummersunlightexposureonvitaminDstatus. Theurinary-basedbiomarkerofDNAdamageinskinwasnotfoundtobesensitiveenoughtoexplorewhethersuch beneficial exposures froma vitaminD perspective, had any adverse consequences intermsofDNAdamageinskin.Thisworkiscurrentlyinpreparationforpeerreviewandthefulldataandfindingswillbemadepublicallyavailableafterpublication.Workpackage4(andpartofWP6):DietaryrequirementsforvitaminDinunder-researchedpopulationsubgroupsusingdose-responseRCTs

Pregnancy and infancy are life-stages for which evidence of low vitamin D status iswidespreadbuttheevidencebasisforsettingdietaryrequirementsforvitaminDisweakest.Currently,dietaryrecommendationsforpregnantand lactatingwomenarethesameasfornon-pregnant individuals,due to theabsenceofdose-response trialdataonwhich tobasepregnancy-specific recommendations.Ataminimum,maternal vitaminDdeficiency shouldbe prevented to safeguard fetal skeletal development. However, due to the gap betweenmaternaland fetalcirculating25-hydroxyvitaminD,maternaldeficiencypreventionwillnotensure fetal protection.We proposed thatmaternal vitamin D recommendationsmust beestablishedfromtheperspectiveofthefetalrequirement,whichisunknown.Thissignifiesaparadigm shift in determining nutritional requirements during pregnancy. DietaryrequirementsforvitaminDduringbothchildhoodandadolescencehavebeenpredominantlybasedontwostudiesin8and11yolds,leavingunder-8’sandover-12’sunanswered.Finally,

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it is not knownwhether ethnic differences in the response to vitamin D supplementationaffects dietary requirements for vitamin D, which has implications for policy makers,consumers,themedicalprofessionandthefoodindustry. Accordingly,themainobjectivesofWP4weretoconduct3dose-responseRCTsinNorthernEuropeancountries(UK,Denmarkand Ireland) to establish the distribution of vitamin D dietary requirements for themaintenanceofwinterserum25(OH)Dconcentrationsatthresholdlevelsrangingfrom30to50 nmol/L in children and adolescents and to estimate the dietary intake of vitamin Drequired to maintain maternal 25(OH)D in late gestation at concentrations sufficient toprevent neonatal deficiency at the 25-30 nmol/L threshold. Likewise, one of the keyobjectivesinWP6wastoconductadose-responseRCTtoestablishvitaminDrequirementsofadultsofnon-Europeanrace/ethnicityresidentinHelsinki,Finlandduringwintertime.

All four of these vitaminD requirement RCTswere successfully completed safely and to ahigh standard. The twoWP4dose-responseRCTs toestablish thedietary requirement forvitaminDinchildrenandadolescentswerebothpublishedinthesameissueoftheAmericanJournal of Clinical Nutrition in 2017 (available under open access at:https://www.ncbi.nlm.nih.gov/pubmed/27733403 andhttps://www.ncbi.nlm.nih.gov/pubmed/27655438, respectively). The new vitamin Drequirement estimates from these two papers attracted an accompanying editorial in theAmerican Journal of Clinical Nutrition (open access athttps://www.ncbi.nlm.nih.gov/pubmed/27733393),whichhighlightedtheimportanceofthedata. The data from these two RCTs have also been combined with data from 5 othervitamin D RCTs and used in the ODIN-based individual participant data (IPD)-level meta-regressionanalysesofvitaminDrequirements,thefirstof itskindandpublishedin2017inNutrients (open access at https://www.ncbi.nlm.nih.gov/pubmed/28481259). Thisimportant IPD analyses of vitaminD dietary requirementswithinODIN clearly showed thebenefitofusingpooleddatafromindividualparticipantsinvitaminDRCTscomparedtotheaggregate-basedapproachusedbyseveraloftheauthoritativeagenciesintheirre-evaluationof vitaminD requirements. The former captures the between-individual variability,wherethelatterdoesnot(seebelow),andsuchvariabilityisofintrinsicimportancetoestablishingRDAestimates.

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The3rdWP4vitaminDRCTinpregnantwomenisinpressattheAmericanJournalofClinicalNutrition(DOI:nqy064).Briefly,thestudyshowedthat30μg/dvitaminDsafelymaintainedserum 25(OH)D concentrations � 50 nmol/L in almost all white-skinned women duringpregnancyatnorthernlatitude,whichkept25(OH)D>25nmol/Lin99%and�30nmol/Lin95%ofumbilicalcordsera.

ThemaingroupfindingsoftheWP6VitaminDRCTinFinnishCaucasianwomenandwomenof East African descent resident inHelsinkiwill soonbe published in theBritish Journal ofNutrition (in press), and the associated vitamin D requirement data from this trial will besubmittedforpublicationduringQ12018.

ThemajorvitaminDdietaryrequirementoutcomesoftheseWP4andWP6RCTsinchildren,adolescents,andtheIPDanalysesaswellasthatinpregnancyandinwomenofEastAfricandescentversusthoseofwhitedescentareshowninsummaryformintheTablebelow:

Table.ODIN-deriveddietaryrequirementsforvitaminDforunder-researchedpopulationsubgroupsaswellasitsIPD-derivedestimates

Serum25(OH)Dcut-off1 ≥30nmol/L ≥50nmol/L

Requirement… RDA(µg/d)2 EAR(µg/d)3 RDA(µg/d)2

Children(4-8y) 8.3(6.9,10.2) 8.0(6.8,9.2) 19.5(17.2,23.0)Teenagers(14-18y) 13.1(10.5,16.6) 11.6(9.2,13.9) >30IPDestimate(4-90y) 12.7(10.0,15.5) 10.4(8.6,12.3) 25.7(21.2,30.2)Pregnancy4 13.8(8.8,18.1) - 28.9(20.6,41.1)

125(OH)D,25-hydroxyvitaminD;IPD,individualparticipant-leveldata.2ThevitaminDintakethatwillmaintainserum25(OH)Dconcentrationsin97.5%ofindividualsabovetheindicatedcut-offconcentrationduringwinter,representingaRecommendedDietaryAllowance(RDA).3ThevitaminDintakethatwillmaintainserum25(OH)Dconcentrationsin50%ofindividualsabovetheindicatedcut-offconcentrationduringwinter,representinganEstimatedAverageRequirement(EAR).4Basedonyear-roundestimates.

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• TheindividualRCTsshowthatintakesintherangeof8to13µg/dayareneededtoensurethatnearlyall(i.e.,97.5%)whitechildrenandteenagersavoidvitaminDdeficiency(serum25(OH)D<30nmol/L)duringwinteratNorthernlatitudes.ThisagreeswellwiththeestimatefromtheIPDanalysisbasedon7RCT(n=882),namely12.7µg/day.

• ThetwoindividualRCTsalsoshowthatinrelationtoadequacy(serum25(OH)D≥50nmol/L)duringwinteratNorthernlatitudes,intakesintherangeof8to12µg/dayareneededtoensurethathalf,and20to~30µg/dayareneededtoensurenearlyall(i.e.,97.5%),reachthiscut-off.

• TheRCTinpregnancyshowsthatintakesof14and30µg/dayareneededtoensurethat25(OH)Dconcentrationsinpregnantwomenare>30nmol/Land>50nmol/L,respectively.Maintenanceofmaternal25(OH)D>50nmol/Lpreventsumbilicalcordconcentrations<30nmol/Lin95%ofinfants,onayear-roundbasis.

• DietaryrequirementsforvitaminDaresignificantlyhigherinwomenofEastAfricandescentthaninwomenofFinnishdescent.Thisworkiscurrentlyinpreparationforpeerreviewandthefulldataandfindingswillbemadepublicallyavailableafterpublication.

Workpackage5:Food-andfood-technology-basedsolutionsforpreventionofvitaminDdeficiency:Naturalsources,fortificationandbiofortificationwithvitaminD2/D3and25-hydroxyvitaminD.

ThemainobjectivesofWP5weretoexploretechnologicalsolutionsinthefoodsectorwhichmayunderpinsustainablefood-basedstrategies,beyondfluidmilkandfatspreads,tobridgethegapbetweencurrent intakesof vitaminD inEuropeanpopulationsanddietary targetsand in sodoinghelppreventvitaminDdeficiency.Theadvantagesand limitationsof suchtechnologicalsolutionswereevaluatedusingacombinationofanimalandhumanstudies.Much of the new data from theseWP5 studies on UVB-exposedmushrooms and bakers’yeast,vitaminD-biofortifiedeggs,beef,porkandculturedfish,aswellasvitaminD-fortified,low-fat, cheese have been, or are in preparation, for publication (see Table below). TheinvestigationofthepotentialadvantagesandlimitationsofuseofUVB-exposedmushroomsand bakers’ yeast food-based solutions for prevention of vitamin D deficiency has clearlyshownthatfromatechnologicalperspectivedramaticincreasesinthecontentofvitaminD2in the food produce is feasible, but evidence of their efficacy in terms of raising serum25(OH)D inRCTs ismoremixed. ThevitaminD2 in theUVB-exposedyeastsurvivedbakingandwas confirmed analytically in the resulting bread, but it did not induce an increase inserum total 25(OH)D (i.e., 25(OH)D2 plus 25(OH)D3) in subjects who consumed the breadover8weeksofwinterinFinlandaspartofoneofourODINWP5RCTs(paperpublishedinBritish Journal of Nutrition; https://www.ncbi.nlm.nih.gov/pubmed/26864127). The papersuggestedthatthesefindingsarelikelystemmingfromthefactthatthevitaminD2wasnotbioavailable to transit the intestine into thecirculation,which interestinglyhas sincebeingshowninaninvitrodigestionmodelalso.Likewise,despitedramaticincreasesinvitaminD2contentofUVexposedmushrooms,theireffectonserumtotal25(OH)DinavailableRCTsisvery variable. Themeta-analysis performed inWP5 suggested that individualswith lowervitaminDstatusmaygetthebenefit,butpotentiallynotthosewithhighervitaminDstatus(paperpublished in JournalofNutrition;https://www.ncbi.nlm.nih.gov/pubmed/26865648),althoughthisshouldbeconfirmedexperimentally.

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The feeding studies in pigs, cattle, and farmed fish withinWP5 exploring the potential ofbiofortification(enhancementviainclusionofadditionalvitaminDand/or25-hydroxyvitaminD[inthecaseoffishandpigs]infeedstuffs)demonstratedthatsmalltomoderateincreasesinthetotalvitaminDactivityoftheresultingmeats/fishfleshareachievable.Incontrastthehenfeedingstudyshowedthateggscontainingabout5µgtotalvitaminDactivity/eggcouldbegeneratedbythisbioforticationmeans,andthishadameasurableimpactonwinter-timeprevalenceofvitaminDdeficiencyinaRCTofolderadults(publishedintheAmericanJournalofClinicalNutrition; https://www.ncbi.nlm.nih.gov/pubmed/27488236). Adedicated food-based RCT inWP5, which aimed to provide proof of effectiveness of a novel, vitamin D-fortifiedfood,showedthatconsumptionof60gofvitaminD3enriched,reduced-fatGoudatype cheese (providing a daily dose of 5.7 μg of additional vitamin D3) was effective inincreasingmeanserum25(OH)DconcentrationandincounteractingofvitaminDdeficiencyduringwintermonthsinpostmenopausalwomeninGreece.ThisworkwaspublishedintheEuropean Journal of Nutrition (open access at:https://www.ncbi.nlm.nih.gov/pubmed/27449925).

Overall,theseWP5datainformedthemodellingexperimentsinWP2and3.WP5alsotestedthepossibilityofnoveltreatmentofhensandpigswithUVlighttomimicsummersunshine,onvitaminDactivityofeggsandpork.Forhens,theUVdose/treatmentwhichdidnotleadtoerythemawasnot sufficient to increase the vitaminD contentof eggs,while forpigs itcouldincreasethetotalvitaminDactivityofpork.FurtherresearchonthepotentialofuseofartificialUVlightasameansofincreasingvitaminDinanimalfoodsisnecessary.

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Table.TechnologicaladvancesforimprovingthevitaminDcontentinselectedpriorityfoodgroups/products,theirassociatedknowledgegaps,andhowODINresearchtackled.

Foodgrouping

Pre-ODINvitDnutritionalvalue

TechnologicaladvancesforimprovingthevitaminDcontent

Associatedknowledgegapsrelatedtotheseadvances

WhathasODINaddedtoourknowledgeinthisarea?

Mushrooms

<0.1μg/100gcultivatedmushrooms

• IrradiationofmushroomswithUVBlightcandramaticallyincreasethecontentofvitaminD2

• ThesevitaminD2-enrichedmushroomscanbeconsumerasisorcanbepowdered(viafreeze-dryingandgrinding)andincludedinappropriatefoodproductse.g.,breadsamongstothers.

• ThestabilityofvitaminD2infoodsmadefromthepowderedUVB-exposedmushroomsisunclear

• WillincreasedconsumptionofD2-

enhancedmushrooms,andassociatedfoodproducts,reduceserum25(OH)D3concentration?

AnartificialUV-Bdoseof0.53J/cm2raisedthemushroomvitaminD2contenttomuchhigherlevelsof67.1±9.9μg/gdryweight(DW)thansunexposure(3.9±0.8μg/gDW),andbothmuchhigherthannormalmushroomlevels(seeopposite).

https://www.ncbi.nlm.nih.gov/pubmed/26314311https://www.ncbi.nlm.nih.gov/pubmed/27323764

Asystematicreviewandmeta-analysisofresponsesofserum25(OH)D2and25(OH)D3toconsumptionofUV-exposedmushroomsbyhealthyparticipantsshowsthat,whilevariable,theirconsumptionmayincreaseserumtotal25(OH)DwhenbaselinevitaminDstatusislowviaanincreasein25(OH)D2anddespiteaconcomitantbutrelativelysmallerreductionin25(OH)D3.WhenbaselinevitaminDstatusishigh,theincreasein25(OH)D2andarelativelysimilarreductionin25(OH)D3mayexplainthelackofeffectoverall. Thisneedstobeconfirmedexperimentally.https://www.ncbi.nlm.nih.gov/pubmed/26865648

Bread

<5%oftheMeanDailyIntakeofvitaminD[MDI]

• VitaminDbaker´syeast(usingUVBlighttoenhanceitsvitaminD2)hasbeenapprovedbytheUSFDA.Thus,byitsinclusioninbreadsandotherappropriatebakedproducts,thiscouldbeanimportantproductinimprovingvitaminDstatus.

• ThebioavailabilityofthevitaminD2fromtheyeastinbakeryproductsisunclear.

• WillincreasedconsumptionofD2-

enhancedbreadsreduceserum25(OH)D3concentration?

TheefficacyofbiofortifiedyeastasasourceofvitaminD2wasevaluatedusingasingle-blind,randomised,placebo-controlledRCTconductedoverwintertimeinadultwomeninFinland.

VitaminD2fromUV-irradiatedyeastinbread(confirmedbyHPLCafterbaking)wasnotbioavailableinhumans.https://www.ncbi.nlm.nih.gov/pubmed/26864127.BreadwithvitD2added,whileincreasingserum25(OH)D2,itreduced25(OH)D3.

Fish

Fish[combined]14%MDI:

Wildsalmon25μg/100gv. Farmedsalmon6μg/100g

• Article9t(b)ofCouncilDirective70/524/EECallowsamax.contentof3000IUvitD3/kgfeedforfish.

• Microandmacro-algeahasbeensuggestedasanaturalformforuseinvitaminDbio-fortificationoffish.

• HyD®iscommerciallyavailable.

• LevelsofvitaminD3and25-hydroxyvitaminDachievedinfarmedfishwiththesevariousfeedingapproachesarenotclear.

• Thefeasibilityofuseofmicro-andmacro-algeaforvitaminDbiofortificationpurposesinfishhasnotbeassessed,andhasnotcomparedwithmoretraditionalapproachesofadditionofsyntheticvitaminD3tofishfeeds.

Adose-relatedvitaminDfeedingtrialinculturedsalmonshowedthatatahighdietarylevel(57,600IU/kgdiet),thesalmonfilletcontained10.2µgtotalvitaminDactivity/100g.Lowerlevelsofdietaryinclusionwerelesseffective.

UVtreatmentofmicro-algaedramaticallyincreasedtheirvitaminD2content,butthisisnotwellutilisedbyfish.Micro-algaeusedtomicroencapsulatevitaminD3wastestedinfeedingtrialswithculturedseabreamandtrout,andwasfoundtobenomoreeffectivethantraditionalfortificationoffeedswithvitD3orHyD

®(allat3000IU/kg);andnoneshowedmajorbenefitovertheusualadditionlevel(1200IU/kg).

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Eggs

9%MDI

• Article9t(b)ofCouncilDirective70/524/EECallowsamaximumcontentof3000IUvitaminD3/kgfeedforpoultry.

• 25-hydroxyvitaminD(HyD®)iscommerciallyavailableforpoultryfeeds.

• IrradiationofchickenswithUVBlighthasbeenshowntoreplacetheneedforvitaminDinfeed.

• LevelsofvitaminD3and25-hydroxyvitaminDachievedineggswiththesefeed-basedapproachesarenotclear.

• ThebioavailabilityofvitaminD3and25-hydroxyvitaminDfromeggsinhumansisunclear.

• IrradiationofhenswithUVBlightmay

beabletodramaticallyincreasethecontentofeggbutthishasnotbeentested.

AhenfeedingtrialwithvitaminD3orHyD®showedthatHyD®

(3000IU/kgequiv)hadthehighesttotalvitaminDeggyolkcontent(5.1μg/egg)comparedto3000IU/kgvitD3.https://www.sciencedirect.com/science/article/pii/S1466856416305604

ARCTinvestigatingtheeffectoftheconsumptionofvitaminD-enhancedeggs(producedbyfeedinghensatthemaximumconcentrationofvitaminD3orHyD

®lawfullyallowedinfeed)onwinterserum25(OH)Dinhealthyadultsshowedthatweeklyconsumptionof7vitaminD-enhancedeggshasanimportantimpactonwintervitaminDstatusinadults.https://www.ncbi.nlm.nih.gov/pubmed/27488236

WhileitistechnicallyfeasibletoincreasetheeggvitaminDcontentbyexposinghenstoUVBlight,theUVBdosage/exposureatwhichthereisnoaccompanyingadverseeffectonhensneedstobefurtherinvestigated.

Meat:Beef

Pork

26%MDI[ascombinedfoodgroup]

• Article9t(b)ofCouncilDirective70/524/EECallowsamaximumcontentofvitaminD/kgoffeed:-4000IUvitD2orD3/kgforcattle.-2000IUvitD2orD3/kgforpigs.

• HyD®iscommerciallyavailableforuseinanimalfeeds.

• TheUVB-exposedmushroompowder(above)isalsosuitableforuseinanimalfeedstuffs.

• IrradiationofpigswithUVBlighthasbeensuggestedasapossiblemechanismforenhancingthevitaminDcontentofpigmeat.

• DatatosuggestthatvitaminD2andD3infeedsforpigsandcattleareequivalentislacking.

• TheimpactofHyD®(plus/minusvitaminD)inanimalfeedstuffsonvitaminD3and25-hydroxyvitaminDinbeef,pigmeatisnotclear.

• ImpactofUVlighttreatmentofpigs

andresultingpigmeatvitaminDcontentisnotclear.

AfeedingtrialshowedthatsupplementationofbeefheiferdietswithvitD₃yieldedhigher(P<0.001)beeftotalvitaminDactivity(by30-49%;P<0.05)[1.4µg/100g]andserumtotal25(OH)D(by26-36%;P<0.05),comparedtothatfromVitD₂andMushroomD2(all4000IU/kg)supplementedanimals;nosignificantdifferences(P>0.05)inthelatter2groups.https://www.sciencedirect.com/science/article/pii/S0308814618303364

AfeedingtrialshowedthatsupplementationofpigdietswithvitD₃yieldedhigher(by~40%;P<0.05)porktotalvitaminDactivity[0.8µg/100g]comparedtothatfromVitD₂andMushroomD2(all2000IU/kg)supplementedanimals;nosignificantdifferences(P>0.05)inthelatter2groups.(inpressinMeatScience)

HyD®isnotasyetpermittedforuseincattleinEurope,butisallowedforpigsandinafeedingtrialwasshowntohavegreatesteffectonraisingserum25(OH)DandporktotalvitaminDactivity[1.3µg/100g]comparedtoD3and/orD2.

UVtreatmentofpigsusingUVemittingLEDs,atadosewhichdidnotinduceerythema,ledtoatotalvitaminDactivitylevelinporkcomparabletothatachievedwiththeHyD®-supplementeddiet.

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Workpackage6:Proofofeffectivenessoffood-basedsolutionstopreventvitaminDdeficiency

A systematic review and meta-analysis from the Cork Centre for Vitamin D and NutritionResearchofRCTsusingvitaminD-fortifiedfoodsconcludedthatwhilefortifiedfoodsincrease

serum25(OH)D,theevidencefromthelimitednumberoftrialstodateistoofragmentedto

confirmproof of efficacy of food-based solutions to prevent deficiency. Thus, building on

datafromWPs2and5,themainobjectivesofWP6weretodeliverthisproofofefficacyand

safetybyfocussingtheresearcheffortonEU-residentadultswhoaremostatriskofvitamin

Ddeficiencyeitherduetoskincolour,sunexposurepracticesordietaryhabits,intwoways:

firstly,bycarryingoutafood-basedRCTinwhiteandSouthAsianwomeninCopenhagenand

secondly,bycompletinganewtrial-andindividualparticipantdata(IPD)-levelmeta-analysis

andmeta-regressionoffood-basedRCTsconductedbyWP6participantswithinandoutside

ofODIN.AsmentionedaboveunderWP4forease,WP6alsohadthevitaminDrequirement

RCTinethnicversuswhiteadultwomen.

WP6wascompletedonschedule(month44)andthedatafrombothtasksareinpreparation

for publication. The aimof theWP6 food-based RCTwas to investigate the efficiency and

safety of relatively low-dose vitamin D fortification of four different foods (designed to

collectively deliver an extra 10-20 μg vitaminD/d) to prevent vitaminD deficiency (serum

25(OH)D<30nmol/L)inwhiteandSouthAsianwomenathighriskofvitaminDdeficiencyin

Copenhagenduring3monthsofwinter. Themeanbaseline serum25(OH)D in theDanish

and the Pakistani groups was ~50 nmol/L. Inclusion of the four vitamin D-fortified foods

contributed toamedian vitaminD intakeof30μg/day, andwhengivenover12weeksof

winterwaseffectiveinincreasingthemeanserum25(OH)Dinbothgroupsofwomenlivingin

Denmark.TheDanishwomenhadagreater response to thevitaminD-fortified foods than

did thePakistaniwomen.Noneof theDanishwomenandonly3%of thePakistaniwomen

consuming the vitamin D-fortified foods had serum 25(OH)D <30 nmol/L at endpoint,

whereas 13 and 20% of Danish and Pakistani women receiving the placebo, non-fortified

foods, respectively, had serum 25(OH)D <30 nmol/L at endpoint of the 3-month, winter-

based RCT. This work is currently in preparation for peer review and the full data and

findingswillbemadepublicallyavailableafterpublication.

The aims of the newWP6 trial- and IPD-levelmeta-analysis andmeta-regression of food-

based RCTs conducted by WP6 participants were firstly, to evaluate the impact of food

fortification interventionsonreducingtheprevalenceofvitaminDdeficiencyandsecondly,

usingtheapproachdevelopedunderWP4(above)toconductthefirst-ever IPD-levelmeta-

regressionanalysesoftheresponseofwinterserum25(OH)DtoincreasedvitaminDintake,

again inaEuropean-basedRCTsettingbut inthisWP,theincreasedvitaminDintakearose

fromconsumptionofvitaminD-fortified/enhancedfoods.Atotaloffivewinter-basedRCTs

with vitamin D-fortified/enhanced foods conducted in Europe were identified – two RCTs

were fromODIN, onewasODINassociated (but fundedby the Irish government) and two

otherRCTswere fromODINpartnersbut fundednationally (UKandDenmark). Anaprioricriteriawas that the RCTswere limited to those of onlywhite adults andwith foodswith

enhancedvitaminD3content.Withcombineddatafromthefivefood-basedvitaminDRCTs

(784participants;390treatedand394controls),a randomeffectsmeta-analysisshoweda

highlysignificant(P<0.00001)treatmenteffectonserumtotal25(OH)Dconcentration.While

therewasahighdegreeofheterogeneityacrossthefiveRCTs(I2=99%;P<0.00001),andthus

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warranting somecaution in the interpretationof the treatmenteffect, thepointestimates

for all RCTs showed a statistically significant effect of vitamin D-fortified/enhanced food

consumptiononserumtotal25(OH)D. Meta-analysisofthefiveRCTsalsoshowedthatthe

odds of vitamin D deficiency in winter was dramatically lower (P<0.00001) for thoseparticipants consuming vitamin D-fortified/enhanced foods compared to those not

consumingsuchfoods.ThisworkiswillbepresentedforpeerreviewoncetheaboveWP6

food-based RCT paper is published, and the full data and findings will bemade publically

availableafterpublication.

Basedona2-stepnon-linearIPDmeta-regressionmodelofthesefood-basedvitaminDRCTs

(asperWP4 IPDmeta-regressionanalysisof supplementalvitaminD), thevitaminD intake

estimatesrequiredtomaintainserum25(OH)Dconcentrationsabovethevariousthresholds

usedbythevariousregulatoryagencieswereverysimilartothosederivedfromourearlier

IPDanalysis.

Overall, the newWP6 food-based RCT aswell as the IPDmeta-regression analyses of five

food-based vitaminD RCTs, the first of its kind, shows how an increased vitaminD intake

would keep most people above the proposed thresholds below which the risk of clinical

vitaminDdeficiencyincreases. TheconstituentRCTsusedinourIPDanalyseshighlightthe

feasibilitybywhichinclusionofthevitaminD-fortified/enhancedfoodsinthedietcanallow

forsuch intakestobeachievedaswellasalsodemonstratingthe lackof technologicaland

consumeracceptabilitybarrierstotheproductionofvitaminD-fortified/enhancedfoods.

Workpackage7:VitaminDandhealthoutcomesinpregnancyandearlylife

The potential role of vitamin D in supporting a healthy pregnancy and promoting optimal

growthanddevelopmentremainsunresolved.Conflictingresultsintheselifestagesaredue

to a number of factors, primarily the dearth of prospectively collected, clinically validated

data on health outcomes, inadequate subject phenotyping and analytical differences in

quantifying25(OH)D. Accordingly, themainobjectivesofWP7were toexamineproposed

associations between vitamin D status and perinatal and infant outcomes. Maternal

determinantsofcirculatingserum25(OH)Dinneonatesatdeliveryandfactorsthatinfluence

the vitamin D composition of humanmilkwere to be described.WP7would examine the

interactions between vitamin D status during pregnancy and infancy and skeletal

development and body composition in children. In addition, an analysis to elucidate the

vitaminDhypothesiswithrespecttoatopicdisorders, includingeczemaandasthma,would

beconducted.Theseobjectivesweretoberealizedusingthestrategyadoptedthroughout

ODIN,whichistopartnerwithongoingandexistingprojectstoachievecriticalmassbothin

the quality of the biobanks and datasets employed and to enlist the specialist expertise

requiredtoaddressthequestionofvitaminDandhealthinthesevulnerableandneglected

lifestages.

WP7wassuccessfullycompletedduringthecourseofODIN.Wepublishedthefirstreportof

CDC-accredited 25(OH)D data and pregnancy outcomes from a clinically validated

prospectivepregnancycohortstudyof1786primiparouswomenbased inCork.Thispaper

waspublished intheAmericanJournalofClinicalNutrition (availableunderopenaccessat:https://www.ncbi.nlm.nih.gov/pubmed/27357092)anddescribeda36%reduction in riskof

uteroplacental dysfunction, indicatedby a compositeoutcomeof small for gestational age

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birth andpre-eclampsia, amongwomenwhohad circulating 25(OH)D concentrationsof at

least75nmol/L.WealsoexploredtheconceptoffunctionalvitaminDdeficiencyandcalcium

metabolicstressintheSCOPEpregnancycohort,byanalysingintactparathyroidhormonein

1800womenat15weeksofgestation,andconductingastratifiedanalysis toexamine the

differential effects of low vitamin D status concomitant with high PTH, on perinatal

outcomes.Thedata,currentlyunderreview,showedthattheriskofelevatedmeanarterial

pressureandSGAbirthwereelevatedwith functionalvitaminDdeficiency,suggestingthat

trialstodeterminetheeffectsofvitaminDonperinatalhealthshouldconsidertheeffectsof

calciumnutritioninthestudydesign.

Wewent on to apply the validated protocols developed in the Vitamin D Standardization

ProgrammetotwoadditionalcommensurateprospectivepregnancycohortstudiesintheUK

(SouthamptonWomen’sStudy,SWS)andSweden(GraviD),givingatotalsamplesizeof5928,

and described the distribution of 25(OH)D across the cohorts and the prevalence of low

vitamin D status, using a number of internationally recognized thresholds. Our analysis

showed that the standardised prevalence of 25(OH)D concentrations below the IOM

thresholdindicatingincreasedriskofvitaminDdeficiencyrangedfrom5%intheSWScohort,

inlatepregnancyto17%inSCOPEIrelandcohortinCork.TheoverallprevalenceofvitaminD

deficiencyamongthissampleofalmost6000womeninearlypregnancyintheUK,Sweden

and Ireland was 14.7%, or 1 in 7 women. In early pregnancy, 38-49% had 25(OH)D <50

nmol/L,withanaverageprevalenceof43.6%acrossthethreecohortsand75-88%ofwomen

had25(OH)D<75nmol/Linearlypregnancy.Thisstudy,whichisthefirsttoextendtheVDSP

protocolstoperinatalcohorts,describetheonlycommensuratepregnancycohortsthathave

standardised25(OH)Ddata,andthusrepresentthelargestsourceofreliableinformationon

vitamin D status in early pregnancy to date. Extension of the VDSP to additional

contemporary cohortswithwell-curatedandbiobanked species isof crucial importance to

understandtheextentofthevitaminDdeficiencyproblemanditsimplicationsforperinatal

health.Thestudyisbeingpreparedforpeerreviewduring2018.

In our analysis of infant health outcomes,WP7 startedby completing an IPD analysis of 3

existing studies of maternal-infant pairs in Denmark and Ireland to describe the early life

predictors of neonatal and infant vitamin D status. The data showed that at birth, a high

proportionofinfantshad25(OH)D<50nmol/Lwhenmotherswereunsupplementedduring

pregnancy, particularly infants born during wintertime. In early life, a daily vitamin D

supplement of 10 µg seemed to assure replete vitamin D status without causing risk of

excessive 25(OH)D concentrations among partially breastfed or weaned infants who also

received vitamin D from infant formula. In a large prospective birth cohort in Cork, we

publishedthefirstCDC-accrediteddataon25(OH)D,aswellasthe3-epimerof25(OH)D3,in

1050umbilicalcords(openaccesstheJournalofSteroidBiochemistryandMolecularBiologyathttps://www.sciencedirect.com/science/article/pii/S0960076016303454?via%3Dihub).Overall,35%ofcords (50%duringwinter)had25(OH)D<25nmol/L,46%were<30nmol/L

and80%were<50nmol/L. In thispredominantlywhite cohort, themainpredictorof cord

25(OH)D was summer delivery. Maternal smoking during pregnancy (9% prevalence) was

negatively associated with cord 25(OH)D and there were no associations between cord

25(OH)D and birth weight or any anthropometric measures at birth. Despite the high

prevalence of vitamin D deficiency at birth, there were no documented musculoskeletal

complications during infancy, which was likely due to widespread supplementation with

vitaminD.Theproportionof25(OH)Das3-epi-25(OH)D3was11.2%andcord3-epi-25(OH)D3

17

concentrationswerestronglyassociatedwithcord25(OH)D3.Forthefirsttime,wereported

anegativeassociationof3-epi-25(OH)D3withgestationalageandmaternalage.Thesedata

provided further evidence of very low vitamin D status among infants born to un-

supplementedmothers.

Analysis of the vitamin D content of 750 bio-banked humanmilk samples was conducted

using the Aarhus LC-MS/MS platform for humanmilk analysis in four separate studies of

lactationthatwerecarriedoutinIreland,Denmark(2studies)andtheGambia.ThevitaminD

contentofmilkrangedfrom1.3to3.7µgoftotalvitaminDactivity/L.

We estimated that an exclusively breastfed infantwhosemother had adequate vitamin D

statuswouldreceive~2µg/dayofvitaminD,assuminganaverageconsumptionofmilkof

~750ml/day(upto6monthsofage).Thisis20%oftheadequateintake(AI)of10µg.Factors

that were important influencers of the vitamin D content of human milk were maternal

vitaminDstatus,milk itsfatcontentandthenumberofdayspostpartumwhenthesample

wascollected.MaternalBMIhadanegativeassociationwithmilkvitaminDcontent in the

Corkstudy,asdidcirculatingparathyroidhormone.

As theevidence forarelationshipbetween inuterovitaminDexposureandatopicdisease

has been inconsistent, we sought to interrogate two extensively characterised, disease-

specificmaternal-infantcohortswithgoldstandardanalysisofantenatalandumbilicalcord

vitaminDstatusandclinicallyvalidatedatopicoutcomes,toinvestigatethepotentialroleof

intrauterine vitamin D exposure in the development of atopic disease. We undertook a

comprehensiveevaluationoftherelationshipbetweenintrauterinevitaminDexposureand

the development of eczema, food allergies, asthma and other atopic disorders using data

from the Cork BASELINE Birth Cohort (BASELINE) and theManchester Asthma and Allergy

Study(MAAS).Serum25(OH)DandvitaminDmetaboliteconcentrationsfor1035 infants in

BASELINEand458infants inMAASwereanalysedatUniversityCollegeCork.TheBASELINE

and MAAS cohorts differed in terms of the (self-reported) inherited risk of atopy. In

BASELINE, 49% ofmothers and 37% of fathers reported a previous history of atopy; both

parentsreportedatopichistoryin19%ofchildren.InMAAS,72%ofinfantswerecategorised

ashigh-risk,withatopyinbothparentsand18%ofinfantswerecategorisedaslowrisk,with

no parental history. Analysis of the BASELINE cohort did not show any significant

independent association between intrauterine vitamin D exposures and clinically validated

atopicdiseaseoutcomes.InMAAS,umbilicalcord25(OH)Dwasassociatedwithatopy.Aper

10nmol/L incrementwas positively associatedwith a 27% and 30% greater likelihood of a

positive skin prick test (SPT) response for pollen at 3 years and for grass at 8 years,

respectively.Each10nmol/Lincreaseincord25(OH)Dwasassociatedwitha36,40and45%

increaseinlikelihoodofserumIgE-definedsensitivitytograssat5and8yearsandforpeanut

at8years,respectively.CordvitaminDconcentrations(per10nmol/L)werealsosignificantly

associatedwithincreasedoddsofallergicrhinitisat11years[OR(95%CI):1.17(1.00,1.38)],

butnotwithasthmaat5years.Thesedataarecurrentlyunderreview.

Withregardtoinfantgrowthandbonemineraldensity,thequestionofwhetherincreasing

maternal vitaminD statusduring inpregnancymight improveoffspringbonedevelopment

remainsunresolved.Inparticular,thereisapaucityofdatarelatingtolong-termfollow-upof

children. Interpretation of this data is also limited by variability in 25-hydroxyvitamin D

(25(OH)D) analysis, sampling and population differences. InWP7, we conducted a meta-

analysis using data from two commensurate mother-offspring observational birth cohort

18

studies: The Southampton Women’s Survey (SWS) and the SCOPE-BASELINE Cork Birth

Cohort Study. Serum25(OH)Dat11and34weeks in SWSandat15and inumbilical cord

samples inBASELINEwereanalysed.At6yearsofage,children inSWSunderwentawhole

body and lumbar spine DXA scan. Whole body and lumbar spine DXA assessments were

carried out in BASELINE children at 5 years of age. Maternal 25(OH)D assessments were

groupedintoearlyandlatepregnancy/cordandassociationswithbonemineralisationwere

investigatedwith 25(OH)D as a continuous and binary predictor. Early pregnancy 25(OH)D

andchildhoodDXAdatawereavailable for879and440mother-offspringpairs inSWSand

SCOPE-BASELINE,respectively.1,004and321mother-offspringpairs fromSWSandSCOPE-

BASELINE, respectively,were included in the analysis of late pregnancy/cord 25(OH)D and

offspringbonemass. Therewereno significant associationswith early pregnancy 25(OH)D

andeitherwholebodylesshead(WBLH)or lumbarspine(LS)bonemineralcontent(BMC),

bone area, bone mineral density (BMD) or size adjusted BMD in univariate or adjusted

analyses.Childrenofmothersaboveathresholdof25nmol/Lforearlypregnancy25(OH)D

had significantly greater whole body BMD and trended towards higher BMC.While there

werenosignificantassociationsbetweenlatepregnancy/cord25(OH)DandoffspringWBLH

bonemineralisation,apositiveassociationwasidentifiedbetween25(OH)DandLSbonearea

and a trending association with LS BMC, which remained statistically significant in

multivariateanalyses.Latepregnancy/cordblood25(OH)D>25nmol/lwasassociatedwith

greaterWBLH BMC and BMD and LS BMC and bone area,which persisted inmultivariate

analysis. In summary, thismeta-analysis demonstrated that lowmaternal 25(OH)D in both

early and latepregnancyandatdelivery is associatedwith reducedbonemineralisation in

earlychildhood.

Workpackage8:VitaminDandhealthoutcomesinadults:mortalityandCVD

VitaminD deficiency is a significant predictor of all-causemortality, cardiovascular disease

(CVD) and metabolic risk factors including elevated blood pressure, impaired glucose

homeostasis,dyslipidemiaandsystemicinflammation.Challengesininterpretingcohortand

RCTdataarecomplicatedbyvariousclassificationsofserum25(OH)Dconcentrations,clinical

outcomedefinitionsandstatisticalapproaches.Thus,thekeyobjectivesofWP8were,using

astandardizedanalyticalmethodfor25(OH)D(asperWP1)andharmonizedclinicalendpoint

classification,toconductanIPDmeta-analysesofsevenlargecohortstudiesandaseparate

IPD analyses of 11 current or completed vitamin D RCTs to elucidate associations of

circulating25(OH)Dandmajorclinicalnon-skeletaloutcomes,namely,overallmortality,CVD

mortality,cardiovascularevents,stroke,cancer,andincidenceoftype2diabetes.Inaddition

to considering the effects of lifestyle, adiposity and diet, WP8 aimed to explore the

potentially significant role for genetics (single nucleotide polymorphisms [SNP] in genes

involved inthevitaminDsynthesisormetabolicpathways) indeterminingvitaminDstatus

anditsassociationwithclinicaloutcomesbyperformingMendelianRandomizationstudiesin

a subset of the 8 cohorts for which SNP data was available, and which elucidate the

independent effects of genotype on 25(OH)D concentration variability. These WP8

objectivesweretoberealizedusingthestrategyadoptedthroughoutODINmentionedabove

underWP7, namely to partnerwith ongoing and existing projects to achieve criticalmass

both in the quality of the biobanks and datasets employed and to enlist the specialist

expertise required to address the question of vitamin D and our prioritized adult health

outcomes.

19

WP8wassuccessfullycompletedin2017andthedatahavebeen,orareinpreparation,for

publication (see below). WP8 published the first IPD meta-analysis using standardized

25(OH)D data in PLoS One in 2017 (available under open access at:

https://www.ncbi.nlm.nih.gov/pubmed/28207791). In almost 27,000 participants (median

age 61·6 years, 58% females) with a median circulating 25(OH)D concentration of 53·8

nmol/L,we reportedadjustedhazard ratios (with95%confidence interval) formortality in

the25(OH)Dgroupswith40to49·99,30to39·99,and<30nmol/Lof1·15(1·00–1·29),1·33

(1·16–1·51), and 1·67 (1·44–1·89), respectively, compared to participants with circulating

25(OH)Dconcentrationsof75to99·99nmol/L,overamedianfollow-uptimeof10·5years

(seeFigurebelow).Weobservedsimilarresultsforcardiovascularmortality,buttherewasno

significant association between 25(OH)D and cancer mortality. On the basis of this

associationbetweenlowcirculating25(OH)Dandincreasedriskofall-causemortality,itisof

public health interest to evaluate whether treatment of vitamin D deficiency prevents

prematuredeaths.Ofnote,thepaperwasincludedinthe‘TheTop12VitaminDPapersfor

2017’(source:OrthomolecularMedicineNewsService,January12,2018).

Fig1.Dose-response trendofhazard ratiosofdeath fromall causesby standardized25

hydroxyvitaminD.[PLoS One. 2017 Feb 16;12(2):e0170791.]

OtherfindingsofWP8:

• TheresultsoftheMendelianRandomizationstudiesinthreeofthecohortsmayargue

infavourofacausalrelationshipbetweenvitaminDdeficiencyandall-causemortality,

butwithalargeuncertaintyintheeffectsize.ThesefindingsonvitaminDandmortality

deserve furtherstudyandconsideration in thepublichealthdiscussion regarding the

value of the vitamin D status of the general population. This work is currently

undergoing peer review and the data and findings will be made publically available

afterpublication.

20

• An IPDmeta-analysis of 12 vitaminDRCTs, to studywhether there are beneficial or

harmfuleffectsofvitaminD3supplementationaccordingtosubgroupsofre-measured

serum25(OH)Doncardiovascularandgluco-metabolicsurrogatemarkers,showedthat

besides its effect on parathyroid hormone, vitaminD supplementationmight have a

beneficial effect on low density lipoprotein cholesterol concentrations, particularly

when the achieved 25(OH)D concentrations remain <125 nmol/L. Other outcomes

(such as blood pressure, high density lipoprotein and total cholesterol, triglycerides,

glycatedhaemoglobin(HbA1c),fastingglucose,insulinandC-peptide,and2-hglucose)

wereunaffectedby vitaminD3 supplementation in this pooled analyses. Thiswork is

currentlyinpressatTheAmericanJournalofClinicalNutritionandthedataandfindingswillbemadepublicallyavailableafterpublication.

• WealsoperformedasystematicquantitativereviewoncharacteristicsofRCTsincluded

inmeta-analyses on non-skeletal effects of vitamin D supplementation, published in

PLoS One in 2017 (available under open access at:

https://www.ncbi.nlm.nih.gov/pubmed/28686645). We identified 54 SRs including

datafrom210RCTs(seebelow).

• Most meta-analyses as well as the individual RCTs reported null-findings on risk of

cardiovasculardiseases,type2diabetes,weight-loss,andmalignantdiseases.Beneficial

effects of vitamin D supplementation was reported in 1 of 4 meta-analyses on

depression, 2 of 9 meta-analyses on blood pressure, 3 of 7 meta-analyses on

respiratory tract infections, and8of 12meta-analysesonmortality.MostRCTshave

primarily been performed to determine skeletal outcomes, whereas non-skeletal

21

effectshavebeenassessedassecondaryoutcomes.Onlyone-thirdoftheRCTshadlow

levelof25(OH)Dasacriterionforinclusionandameanbaseline25(OH)Dlevelbelow

50 nmol/L was only present in less than half of the analyses. Published RCTs have

mostlybeenperformedinpopulationswithoutlowcirculating25(OH)Dlevels.Thefact

thatmostmeta-analysesonresultsfromRCTsdidnotshowabeneficialeffectdoesnot

disprove the hypothesis suggested by observational findings on adverse health

outcomesoflowcirculating25(OH)Dlevels.

Workpackage9:SafetyconsiderationsinrelationtoincreasingvitaminDintakeandserum25(OH)Dconcentrations

Themain objective ofWP9was to integrate data fromWPs 1-8 and compile a dossier to

document all safety issues across the project. The ODIN safety dossier was to include

informationarisingfromtheprojectonthefollowing:

• DietaryintakesofvitaminDabovetheEFSATolerableUpperLevel(50-100µg/d;age-dependent,2012)

• Prevalenceofhighserum25(OH)Dconcentrations(>125nmol/L)

• Informationonadversehealtheffectsofsustainedhighconcentrationsofserum

25(OH)D

• AnimalsafetyissuesrelatedtoincreasingthevitaminDcontentofanimal

produce/foodsviadietaryorUVBlightmeans(biofortification).

The risk of excessive intakes of vitamin D are close to zero following application of the

fortificationandbio-fortificationstrategiesproposedinODINto10nationallyrepresentative

dietarysurveysofadultsandchildreninfourEUcountries.Risksofexcessiveintakesamong

childrenandadultswereattributabletovitaminDsupplementationatdosesof25µgand50µg/dayinchildrenandadults,respectively,usingcurrentusageofsupplementationproducts.

High serum25(OH)D concentrationswere rare in cohort studies andnoadverseeffectsof

high 25(OH)D were detected. The prevalence of serum 25(OH)D >125 nmol/L increased

accordingtotreatmentdoseininterventionstudies,particularly>~70µg/day.Lowerdosesofsupplementsor food-based interventions for increasingvitaminD intakewereminimally

associatedwithhigh25(OH)Dconcentrations. Overall,outof3,419participantswhoeither

tookpartinODINRCTsorhadpreviouslyenrolledinRCTsre-analyzedbyODIN,atotalof322

(9.4%) individuals had serum 25(OH)D >125 nmol/L and 30 (<1%) had elevated serum

calcium. Therewere no documented adverse effects or serious adverse events associated

withanyoftheinterventions.AnalysisofdatafromtheODINinterventionstudiesaswellas

adult,pregnancyandbirthcohortsshowednoevidenceofadversehealtheffectsassociated

with vitamin D intake, supplementation (at modest doses) or high serum 25(OH)D

concentrations. Thiswork iscurrently inpreparationforpeerreviewandthefulldataand

findingswillbemadepublicallyavailableafterpublication.

This summaryof S&T results arising from the 9RTDWPsweremadepossible not only by

excellentcollaborationamongthepartnerswithintheODINconsortiumbutalsobyexcellent

management and coordination which was effected through a highly experienced ProjectExecutiveManagement Board, projectmanager and a dedicatedmanagementWP. These

findingshavebeenwidelycommunicatedanddisseminatedtoavarietyofstakeholders(see

Section4.2Abelow),atestamenttothecommitmentoftheprojectpartnerstopublication

anddisseminationactivities.

22

D. Impact section and dissemination/exploitation of results

The potential impact of the ODIN project’s key findings

ODINdriving excellence in vitaminD researchwhile ensuring value formoney to Europeantaxpayers

The researchundertakenwithinODINwhich led to theproject’s key results, asoutlined in

SectionCabove,providedtheEuropeantaxpayerwithadded-valuetotheworthofaround

€100M (see Figure below), as a conservative estimate. ODIN by utilizing its broad

collaborative network took advantage of existing randomized controlled trials, cohorts,

nationalhealthandnutritionsurveysandotherinfrastructuralcapacities,including:

Ø 17Nationalnutrition(orHealth)surveys/cohortsofchildrenandadults;

Ø 9Foodconsumptionandnutritionsurveys;

Ø 3previousRCTsdefiningdietaryvitaminDrequirements;

Ø 3previousorongoingfood-basedRCTswithvitaminDintermsimprovingstatus;

Ø 7 large cohort studiesof Europeanadults toelucidate associationsof serum25OHDand

majorclinicalnon-skeletaloutcomes;

Ø 11 eleven current or completed RCTs to test the effect of major clinical non-skeletal

outcomes;

Ø 4pregnancyandbirthcohortsand4lactationstudies;

Ø aswellasthesignificantcontributionoftheVitaminDStandardizationProgram(VDSP)led

bytheNIH,OfficeofDietarySupplements,onapro-bonobasis.

Throughitscreativeprogrammeofresearchthatincorporatedandbuiltupontheseexisting

resourceandinfrastructure,ODINwasabletostrategicallymobilisethe€6Mavailablefrom

theEC for theproject, todeliver itspriorityobjectives,asoutlinedabove inSectionB,and

alsotoavoidanypotentialduplication.Thus,ODINmaximizednationalandEUresourcesto

drive excellence in research and provide value for money to taxpayers in a challenging

economic environment. This was a powerful representation of the potential tomaximize

nationalandinternationalinvestmentforpublichealthandprivatesectorgain.

23

SocietalandassociatedfinancialimplicationsofODIN’sfindings

ODINhighlightsthemagnitudeofthepublichealthproblemofvitaminDdeficiencyinEurope

By utilizing data and biobanked blood samples from 14 of the above-mentioned National

nutrition (or Health) surveys/cohorts of children and adults, together with statistical

resourcesoftheVDSP,ODINproducedthefirstinternationallycomparabledatasetofvitamin

DstatusandprevalenceofvitaminDdeficiencyinEurope.Thisworkledtoanoverallpooled

estimate(irrespectiveofagegroup,ethnicmix,andlatitudeofstudypopulations)of13%of

thetotalsamplesizeof55,844Europeanindividualswithserum25(OH)Dconcentrations<30

nmol/L.Ofnote,dark-skinnedethnicsubgroupshadmuchhigher(3-to71-fold)prevalence

of serum 25(OH)D <30 nmol/L than did white populations. According to an alternate

suggested definition of vitamin D deficiency (serum 25(OH)D <50 nmol/L), the prevalence

was40%.ExtensionoftheVDSPprotocolsintoperinatalcohorts,establishedaprevalenceof

vitamin D deficiency of 15% (or 1 in 7) women in early pregnancy in the UK, Ireland and

Sweden,with 44%<50 nmol/L of 25(OH)D. Thus,ODINdefinitively showed that vitaminD

deficiency is evident throughout the European population at prevalence rates that are

concerningandthatrequiresactionfromapublichealthperspective.ThesevitaminDstatus

data formthebedrockonwhich tobasescientific judgments,andODINhasnowprovided

this high-quality, priority data for Europe. This new data, which has been widely

disseminatedandisbeinghighlycitedalready,hasalsoraisedawarenessamongthescientific

community,policymakers,foodindustryaswellasthegeneralpublic.

Implicationsofthesefindingsfordiseaseburden

ItisgenerallyagreedthatpreventionofvitaminDdeficiency(asdefinedbytheconservative

serum 25(OH)D threshold of <30 nmol/L) is a public health priority, for prevention of

nutritional ricketsandosteomalacia,whichhavesevereand lastingconsequences forbone

growthandskeletalintegritythroughoutlife.Thus,itisofgreatconcernthatevenacrude

estimation, based on the magnitude of European population coupled with the ODIN

prevalenceestimateforvitaminDdeficiency,suggestssomethingintheregionof96million

individualsdeficientinEurope.

While data showing associations between vitamin D status and non-skeletal disorders are

also abundant, the evidence-base is currently less robust than that for bone health.

Nevertheless, many investigators in the vitamin D field concur with a serum 25(OH)D

thresholdof<50nmol/LtodesignatevitaminDdeficiencyforprotectionofskeletalandnon-

skeletal health. ODIN again utilized its broad collaborative network and, by accessing 8

cohortstudiesinEuropeanadultsandolderadultsandutilizingtheVDSPprotocols,wasable

to undertake the first individual participant data (IPD) meta-analysis using standardized

serum25(OH)Ddata. Inalmost27,000participants (medianage61.6years,58% females)

withamedian25(OH)Dconcentrationof53.8nmol/L,ODINreportedadjustedhazardratios

(with95%confidence interval) formortality in the25(OH)Dgroupswith40to49.99,30to

39.99, and <30 nmol/L of 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89),

respectively,comparedtoparticipantswith25(OH)Dconcentrationsof75to99.99nmol/L,

overamedianfollow-uptimeof10.5years.ODINobservedsimilarresultsforcardiovascular

mortality, but therewasno significant associationbetween25(OH)Dand cancermortality.

Theseimportantobservationalfindingssuggesta67%higherriskofdeathfromallcausesin

24

thosewith serum25(OH)D<30nmol/L. Inour investigationofperinatal and infanthealth

outcomes inWP7, ODIN showed that having high vitamin D status during pregnancy was

associatedwithreducedriskofsmallforgestationalagebirthandpre-eclampsia.Ouranalysis

of neonatal vitamin D status indicated a very high prevalence of deficiency, particularly

amonginfantsborntomotherswhodidnotreceiveantenatalnutritionalsupplementation.In

childrenintheNorthofEnglandwithhighinheritedriskofatopy,ODINobservedapositive

association of cord 25(OH)D and skin prick test- and IgE-defined sensitivity to pollen and

grassthroughoutchildhood,aswellasIgE-mediatedsensitivitytopeanutandallergicrhinitis

inlaterchildhood.Ouranalysisalsoindicatedanassociationoflowmaternal25(OH)Dinboth

earlyandlatepregnancyandatdeliverywithreducedbonemineralisationinearlychildhood.

While these findings do not provide direct evidence of cause and effect for vitamin D

deficiency,ofnote,arecentIPDof25eligiblevitaminDsupplementationRCTs(total10 933

participants,aged0to95years)showedthatvitaminDsupplementationreducedtheriskof

acuterespiratorytractinfectionby12%amongallparticipants.Sub-groupanalysesshowed

that among those receiving daily or weekly vitamin D, protective effectswere stronger in

thosewithbaselineserum25(OH)Dlevels<25nmol/L(aOR0.30)thaninthosewith25(OH)D

levels≥25nmol/L(aOR0.75)(Matineauetal.2017).

At the outset of the project, the ODIN consortium chose to prioritize a low threshold for

serum25(OH)Dof30nmol/L,asareasonableandfeasiblepublichealthtargetfordeficiency

prevention. Thedata describedhere underpin our assertion that in the European context,

thistargetisavalidandmeaningfulfirstpriorityfromapublichealthperspective.

PotentialimpactinrelationtoreducingtheeconomicburdenofdiseaseinEurope

Thecostofnon-communicablediet-relateddiseaseissubjecttovariouscolossalestimates,in

therealmoftrillions,butaconsistentfindingisthatbudgetallocationstodiseaseprevention

are much lower than to treatment of chronic disorders, typically by pharmaceutical or

surgicalinterventions,thatarelifestyleordietaryinorigin.Asmentionedabove,theroleof

vitaminD inpreventionofmetabolicbonedisease isundisputed,andtheevidencebaseof

benefitsofvitaminDintermsofsomenon-skeletaldiseaseisstrengthening.

EstimatesfromaEurope-widestudyputthedirectandindirectcostsofinadequatevitaminD

status at €187 Billion for the region’s 363 million people in 2007 [now in excess of 500

million] (Grant et al. 2009). While these estimates are based on a serum 25(OH)D

concentrationof<100nmol/LdefininginadequatevitaminDstatus,itisclearthatvitaminD

deficiency using the more evidence-based lower serum 25(OH)D thresholds (as outlined

above)stillrepresentsasignificantburdentoEurope’shealth-carebudgets.Arecentstudy

of vitamin D and health care costs in the general population of North-Eastern Germany

showed that those with serum 25(OH)D of 25 nmol/L had a 13% higher relative risk of

hospitalizationcomparedtothosewithserum25(OH)Dof50nmol/L,whichwasassociated

with51%higherinpatientcosts(Hannemannetal.2017).

25

ODIN’sfindingshighlightthebenefitfromasocietalandeconomicperspectiveofafoodfirstapproachtowardstacklingvitaminDdeficiency

ODINwasabletomodeltheultravioletB(UVB)availabilityforsynthesisofvitaminDinskin

for the sameEuropean sites included in theestimationof vitaminDdeficiencyprevalence

exercise, and this highlighted that suchpotential for endogenous synthesis is limited for a

number ofmonths (i.e. the vitaminDwinter) in each of the included European countries.

IncreasedsummersunexposureasastrategyofincreasingvitaminDstatuscarriesthepublic

health risk of skin damage and cancer. Vitamin D intakes are typically low, as it occurs

naturallyinfewfoodsandinlowconcentrations,andthedietarysupplyiscurrentlyunableto

offsettheseasonalUVBsunshinedeficit.Thus,asperODIN’sapriorikeyobjective,focuswasplaced squarely on development of sustainable food-based strategies to bridge the gap

between current and recommended intakes of vitamin D to minimise the prevalence of

serum25(OH)Dconcentrations<30nmol/L.Developmentofsustainablefood-basedsolutions

aimedatincreasingserum25(OH)DinEuropeancitizen’srepresentsaneconomicallysound

approach to lowering the economic burden of disease in Europe, but in addition could

increase competitiveness of the European food industry through the development of new

food products (see below). A competitive food industry is critically important to the

economyofEurope,andinlinewithECpolicy.

In termsof a ‘food first’ approach towards tackling vitaminDdeficiency, a number of key

informationgapsexisted,andODINsuccessfullyaddressedseveralofthesegapswhichithad

prioritized. Nationally representativedataonhabitual vitaminD intakesand foodsources,

includingthecontributionsfromfortifiedfoodsandnutritionalsupplements,wererequired

forEuropesoastoclarifythedistributionofvitaminDintakeinEurope.Thisisthestarting

point in terms of devising evidence-based strategies which use food to tackle inadequate

intakeofvitaminDandthuslowertheprevalenceofvitaminDdeficiencyinEurope.

While representative data on vitamin D intakes in several EU countries exist, data from

European national nutrition and food consumption surveys were fragmented and used

various methods of food consumption data collection, analysis and reporting, making

meaningful comparison problematic. In addition, more comprehensive coverage of the

vitaminDcontent,including25(OH)D,ofstaplefoodswasrequiredwithinfoodcomposition

databases. Themost significantadvance in thestandardisationandharmonisationof food

composition data to date has been the EC-funded EUROpean Food Information Resource(EuroFIR) Network of Excellence, which included forty-nine partners from twenty-seven

countries, most of them national food composition database compilers, including the US

Department of Agriculture. ODIN, together with EuroFIR, constructed an ‘ODIN-EUROFIR

vitaminDfoodcompositiondatabase’usinganalyticaldatathathavebeenqualityassessed

using EuroFIR standards, including fortified foods and nutritional supplements. ODIN also

developedapproachestoanalysingintakedata,includingthecontributionsfromrecipesand

composite foods, which were standardised and estimates calculated using a single data

analysis platform todeliverharmonised vitaminD intakedata from thebasediet, fortified

products andnutritional supplements in four countries in 10methodologically comparable

nationalsurveysystems.

Following these enabling developments, ODIN described the first harmonised, validated

vitamin D intake data in 10 nationally representative surveys from 4 EU countries and

26

reportedintakesof3-5μg/dintheUK,Denmark,theNetherlandsandIreland,with77-100%

ofpeopleatriskofinadequatevitaminDintakes.SometraditionalsourcesofvitaminD,such

aseggs,werestillimportant,whileotherssuchasoilyfish,madealimitedcontributiondue

tolowconsumptionlevelsinmostcountries,particularlyamongchildren.

Afterestablishingthisbasepriority,ODINmovedtoaddressinganumberofotherkeyareas

of critical importance along the pathway towards a food first approach to addressing the

vitaminD deficiency problem. TheODIN concept is based on the premise that increasing

vitaminDintakemoderatelyacrossthepopulationintakedistribution,usingacombinationof

biofortification (through eggs, meat and fish, and mushrooms) and nutrient addition, will

generate increases inserum25(OH)Dconcentrationsacrossthestatusdistributionthatare

sufficient to ensure a minimal prevalence of vitamin D deficiency. This commodity-based

strategy, including both fresh and processed foods in several food groups, will ensure

widespreadcoverageof thepopulationandminimize the riskofexcessiveexposureat the

topendoftheintakedistribution.

The findings fromODIN’s threehuman intervention trials and animal/fish feeding trials (in

WP5 and WP6) highlighted how technological advances in food production and animal

nutritioncouldbeharnessedtoincreasevitaminDinthefoodsupplywithconsiderationfor

dietarydiversityandlocalpreferences.Ofnote,thethreeODINhumaninterventionstudies

with vitamin D-enhanced foods tested and illustrated the efficacy of these food-based

solutionsforpreventingvitaminDdeficiencyindiversepopulationgroups.Thefindingsfrom

these3 studieswere also combinedwithdata from3existingnon-ODIN, food-basedRCTs

(but from partners within the consortium) to provide the first IPD-level evidence of the

potential of vitamin D fortified/enhanced foods, some of which were products developed

duringtheproject,forprotectingwintervitaminDstatusoffree-livingpersons,bothpersons

ofEuropeanoriginresidentatNorthernandSouthernlatitudesanddark-skinnedSouthAsian

immigrants. This researchwas only feasible by partneringwith nationally funded projects

and harnessing prior expertise in implementing challenging food-based RCTs in the

community.Thesenewdataarekeyintermsofsupportingtheunderpinningevidencebase

forafoodfirstapproach.

Intermsofpopulation-levelevidence,ODINusedtheupdatedfoodanalyticalvitaminDdata

from ODIN’s human and animal food intervention trials in its novel and bespoke dietary

modellingtoanswerthequestionofhowwill increasingvitaminDinthefoodsupplyaffect

thisdistributionandreducetheprevalenceof inadequate intakes inEuropeanpopulations,

particularlyafterconfirmingtheirrelatively lowbase.ThenovelandvalidatedODINsystem

forprogressingstep-wisedietarymodellingofevidence-basedfoodfortificationscenariosin

the same 10 nationally representative surveys in 4 EU countries showed that proposed

combinationODINfortificationandenhancementstrategies,includingmilk,eggs,cheeseand

meatcouldachievedesiredpopulationintakesanddistributionsofvitaminD,relativetothe

Estimated Average Requirement of 10 μg/day, without increasing the risk of excessive

intakes. These findings highlighting not only the potential for addressing inadequacy of

vitaminDintake,butalsotheexcellentsafetyprofileofafoodfirstapproach.

Of key note, the research within ODIN in relation to food first approach towards tackling

vitamin D deficiency was only feasible on the back of a meaningful research partnership

betweenacademicscientistsandthefoodindustry,includingtheSMEsector.Itunderscores

27

theconclusionofaUSInstituteofMedicineworkshoponthetopicofBuildingPublic-Private

Partnerships in Food and Nutrition, which suggested that many of today’s public health

challenges would be well served by public–private partnership approaches, with all

stakeholdersengaged.Successful implementationof the research in relation to food-based

solutionsforvitaminDdeficiencyelementwithinODINwascontingentuponthestrengthof

thepublic-private collaboration. ODIN scientists in academia and researchpartneredwith

agri-food producers, industry and SMEs to devise new technologies and food products to

increasethevitaminDcontentoffoodthatare inclusiveandaffordableandmindfulofthe

requirementsoffoodpolicyandregulatorybodies.

ThefindingsinrelationtothevitaminDfood-basedsolutionshasbeenofmajorinterestto

theEuropeanfoodindustrysector,andisripetobetranslated intoNPD,withpotential for

increasedcompetitiveness.Asoneexample,duringthelaterstagesoftheODINproject,one

of our industry partners secured approval from their national food regulatory agency to

launchUVB-treatedmushrooms.ThiswasfacilitatedbyresearchundertakenwithinODINin

relationtotheirsafetyandefficacy.AnumberofEurope’smajorfoodindustryplayershave

interactedwithODINprincipleinvestigatorstodeveloptheirstrategyinrelationtovitaminD-

enhancedproducts. Theseinteractionsextendwellbeyonddairy,andincludecereals,agri-

foodproducersandingredientssuppliers.

ODINsfindingstounderpinEuropeanpublichealthnutritionpolicy

ODINconsidereditoneofitscoreobligationstoprovidereliableevidenceonwhichtheEC,

EFSAandothernationalregulatoryauthoritieswithinEuropecanbasedecisions,andwhich

willhavedirectbenefitsforEuropeancitizensandenabletheauthoritiesandtheindustryto

progresssafelywithimplementingstrategiesforvitaminDdeficiencyprevention.

A serious challenge that has existed for regulatory authorities charged with setting

recommendations for dietary intakes of vitamin D and issuing regulations for the safe

additionofvitamerstofoodsandfeeds,aswellastheagri-foodproducersandindustrywho

work within this framework to feed the population, is the persistence of fundamental

knowledge gaps throughout the vitamin D field, which have contributed to the risk of

unreliablerecommendationsandlackofclarityintheevidenceonwhichdecisionsaremade.

ODIN has contributed core data on prevalence of vitamin D deficiency as well as on

inadequacyofvitaminDintakeacrossEurope,whichwerethemostobviousknowledgegaps.

These highlight the need for action from a public health perspective. Global vitamin D

supplementationandbloodtestingarewidelyadvocated,athugecost,withallegedbenefits

to individuals and society that over-reach the currently available proof. The momentum

generatedbycallstoactionandimpassionedpleasforpoliticalinterventionhaveproduceda

chaotic range of recommendations for vitamin D from various agencies and institutes

representingclinicalspecialties.NotwithstandingthatvitaminDsupplementationisrequired

among certain high-risk groups, the uptake and dosing levels are highly variable.

Supplements only benefit those who use them, which nullifies the concept of global

supplementation among free-living individuals who exercise personal choice. The ODIN

consortium, having provided leadership and guidance on evidence-based practice in

implementing safe and sustainable strategies to prevent vitamin D deficiency with

concomitant public health benefits across the European population, urges regulatory

28

authoritiesandtheIndustrytoadoptastep-wiseapproachtomodifyingvitaminDintakesin

thepopulation.

Revised dietary recommendations for vitamin D for the EU population and regulations

governing the maximum allowable addition of vitamin D to foods and feeds have the

potential to directly impact nutritional status and health in >500 million EU citizens and

would indirectly influence global recommendations going forward. ODIN, through its four

dose-response RCTs, has provided experimental evidence on vitamin D requirements to

formulate intakerecommendations forpregnantwomen, infants,children,adolescentsand

ethnic immigrant people resident at Northern latitudes from specifically designed RCTs,

whichwerealmostcompletelyabsentpriortotheimplementationoftheproject.Thislackof

evidence had been widely acknowledged by expert authorities and agencies briefed with

establishednewrecommendationsforvitaminD.ODINhasalsopioneeredtheapplicationof

an IPDapproach toestimationof thedietary requirements for vitaminD,anareawhich is

receivingfocussedattentionbytheagenciesastheymoveforwardandlooktowardsfuture

iterationsoftheirDietaryReferenceValues(DRVs)forvitaminD.ODINagaincapitalizedon

existingextensiveresearchinfrastructureinEuropebyassemblingthelargestcriticalmassof

prospective adult, pregnancy and birth cohort studies to date and conducting a series of

collaborative trial and IPD-level meta-analyses which provided new insight into the

associations between vitamin D and perinatal outcomes, childhood [allergic disease, bone

growth and development and body composition] and ageing adults [prematuremortality,

cardiovasculardisease],alsowithaviewtothenextiterationtoDRVs.

Alsoof critical importance froma regulatoryperspective,ODINhasmaintainedawatching

safetybriefoverallitsactivitieswithrespecttoexposure,statusandhealthoutcomes.Over

its life-time, ODINmonitored the risk of exceeding tolerable upper intake levels (ULs) for

vitamin D, of generating serum 25(OH)D concentrations above thresholds (125 nmol/L)

consideredtobepotentiallyassociatedwithincreasedrisk,ofadversehealthconsequences

oflowandhighserum25(OH)Dconcentrationsandactivelymonitoredtheoccurrenceofany

adverseeffectsfromthesevenRCTsstipulatedwithinitswork-plan.Thismustunderpinany

implementation of recommendations in relation to food-based solutions and safeguard

humanhealthbyminimizingthedualriskofnutritionaldeficiencyandexcessinastep-wise,

controlledapproachgovernedbytheprinciplesofriskassessmentandriskmanagement.

ODINleadingthewaygloballyinrelationtocollaborativevitaminDresearchAs part of its work, a recent analysis of World-wide research architecture of vitamin D

researchexaminedcollaborativeefforts intheareaofvitaminD. Ofthe~26,000vitaminD

articlesincludedintheirexercise(spanning1900to2014),3,467articleswerearesultofan

international collaboration – of which 2,821 were of a bilateral nature (Brüggmann et al.2018).Only436weretrilateralcollaborations,while99publicationswereissuedbyauthors

fromfourcountriesworkingtogether.Thenumbersofpublicationswerequitelow(29,23,

14, and 18) when one looks at researchers working in collaborative efforts from five, six,

sevenandeightcountries,respectively.AnanalysisofODIN’spublicationsarisingfromdirect

project funding (see Section 4.2A below) shows that to date all of these papers were

collaborativeeffortsandbaronebilateralcollaboration,thereminderofthepaperswereata

29

minimum trilateral and up to inclusion of authors from 11 countries. ODIN’s two papers

includedin‘TheTopVitaminDPapers’for2015/16and2017hadresearchers,insomecases

more than one research group per country, from 11 and 8 countries, respectively. Using

IrelandastheODINcoordinatingcentreandasacase-studyfortheODINconsortiumoverall,

thestudybyBrüggmannetal. (2018)showedthattheratioofnumberofcollaborationsto

total vitaminD publications by that countrywas 0.48:1 as compared to theUS and Japan

(havingthegreatestand2ndgreatestnumberofvitaminDarticles, respectively)whichhad

ratiosof0.21:1and0.16:1,respectively.Thesemetricshighlightthecollaborativenatureof

ODIN’sresearch,andshow-casetheEuropeanmodelofcollaborativeprojects.

Detailedinformationinrelationtoothersocietalimplicationsarealsoprovidedinsection4.3

below.

30

DisseminationactivitiesandexploitationofODINproject’skeyfindings

The ODIN consortium was highly committed to and active in their dissemination of the

project results. ODIN’s full array of dissemination activities were in addition to its

communicationactionstopromotetheprojectbyprovidingtargetedinformationtomultiple

audiences beyond the scientific and medical communities, including the public and food

industrysector.

Disseminationwas through the followingmeans (additional details areprovided in Section

4.3below):

• TheODINwebsite (www.vitd-odin.eu) through itsNews feed sectionhasprovidedupdatesonODIN research findings thatwerepublishedandalsopresentedat various conferences

andworkshops;throughitsPublicationssectionprovidingalistofscientificpapersincludingsummaries for anumberof thesepublications, aswell as the threeODINnewsletters and

press releases. The website also includes a link to the user-friendly and interactive

EuropeanVitaminDdeficiencymap (http://www.odin-vitd.eu/public/7-european-vitamin-d-

deficiency-map/)andtheVitaminDwintermap,basedondataandpublicationsarisingfrom

WP1and3,respectively.TheODINwebsitehasbeenextensivelyupdatedoverthecourse

oftheprojectwithaviewtowardsitskeyroleasadisseminationchannel.

• Peerreviewedpublications:Todate,ODINpartnershavepublished75peer-reviewedvitamin

D-relatedpapersinhigh-impactinternationaljournals(SeeSection4.2Abelowwherepapers

presentedbyWP).Thesepublicationsarebasedeitherdirectlyonnewresearchfindingsin

ODIN (themajority ofwhich are available under open access) orwere enabled byODIN’s

researchactivities.ThepublicationofODINresearchwillalsocontinuepost-project,assome

of the research was conducted towards the end of the funding window. Two of ODIN’s

papershavebeenincludedintheTopVitaminDPapers,onepaperin‘TheTop18VitaminD

Papers in 2015-2016’ and another in ‘The Top 12 Vitamin D Papers for 2017’ (source:

OrthomolecularMedicineNewsService).

• ThreeODINnewslettersweredistributedelectronicallytothosewhosubscribedthroughtheODINwebsite.Whilethe1

stnewsletterfocusedontheODINprojectoverviewanditsoverall

aims, the 2nd and 3

rd newsletter focusedon key project findings and associated papers as

well as highlighting dissemination events at which ODIN results were shared. ODIN also

employedthevarioussocialmediachannels(42Facebookposts,117tweetsandre-tweets)

todisseminateinformationontheprojectfindingsandrelatednews.

• Presentation at key scientific conferences: ODIN partners attended a variety of scientificmeetings, such as symposia, congresses, conferences and workshops, where they

communicatedODINoutcomesandresults(SeeSection4.2below).Ofparticularnote,there

were 135 oral presentations by ODIN principle investigators or junior scientists on the

project’s findings,manyofwhichwerekeynote/invitedpresentations. Theconferencesat

which thesewere delivered represented a blend of European, North American as well as

thosefurtherafield,highlightingthereachofODIN’sdisseminationofitskeyresults.Ascan

beseeninSection4.2below,therewerealsomanyconferenceposterpresentations,print

newspaper articles, onlinenewspaper andmagazine articles aimed at health professionals

andmediapiecesononlinefoodindustrymagazines,TVinterviewsandradiointerviews.In

all,therehavebeen253disseminationactivities.

31

• TwotargetedstakeholderODINworkshops:ODINorganisedandhostedtwoverysuccessfulone-day dissemination events at the European Commission buildings in Brussels towhich

morethan60 invitedparticipants fromEuropeanCommissionregulatorybodies,European

food, health and consumer agencies and relevant food companies participated at each

event. Thefirstworkshop‘One-daysymposiumtooutlinethe implicationsofnewresearchdata on vitamin D from the ODIN project for public health policy and food innovation inEurope’ onMarch 3

rd, 2016 disseminated data fromODIN’s research on vitaminD status,

intakeandfood-basedsolutions.Thesecondworkshop‘DietaryRequirementsforVitaminDinChildren,Adolescents,Black-skinnedadultsandpregnantwomeninEurope’onMarch24

th,

2017 disseminated data on the project’s research on vitamin D dietary requirements in

various under-researched population subgroups. Both events received extremely positive

feedback from attendees and there was a very high level of audience engagement and

interaction.

• TheODINinternationalvitaminDconference:TheODINcoordinatorshostedanInternationalScientificConferenceVitaminD&HealthinEurope:CurrentandFuturePerspectivesonthe5th&6

thSeptember,2017atUniversityCollegeCork, Ireland. Theconferenceprogramme

focusedonpresentingtheexcitingfindingsthathaveemergedfromtheODINprojectaswellas learning from internationally-renownedscientists and their research into vitaminD and

health(http://www.vitamindconference.eu/page/6-programme/). Theconferencehadfour

plenary sessions and a special workshop which covered topics ranging from dietary

requirementsforvitaminD,foodstrategiesandnovelfoodsolutionsfortacklinginadequacy

of vitamin D intake and status, vitamin D in relation to adult health aswell as infant and

maternalhealthoutcomes.Inadditiontotheplenaryinvitedspeakers,therewereanumber

ofpromotedabstractoralpresentationsandanimpressivecollectionofposterpresentations

whichaddressedvariousvitaminD-relatedtopics. Theextremelypositive feedbackonthe

conference from participants and delegates (>150) suggested that the event provided a

supportive forum for the exchange of knowledge and ideas between researchers, policy

makersandthefoodsector.Thiswasahopefortheconference,asODINbelievedthiswas

necessary tosupportandstimulate innovativesolutions forpublichealth. Theconference

wasacknowledgedattheCorkConventionBureauawards.

• ODINwasinvitedtohostadedicatedsessionofthe3rdInternationalConference"VitaminD-minimum, maximum, optimum" in Warsaw, Poland September 22-23

rd, 2017. Research

findingsandhighlights fromODINwerepresentedbyfourofODIN’sprinciple investigators

(includingtheco-coordinators),followedbyaveryinteractivequestionandanswersession.

• ODIN and its findings featured in the European

Commission’sHorizon2020websiteasanexampleofsome

of the best research currently being carried out

https://ec.europa.eu/programmes/horizon2020/en/news/s

hining-light-vitamin-d-deficiency-europe). This was

followedbythreeECupdatednewsarticlesonODIN.

• ODIN was presented as an exemplar of the EC

modelofresearchandsustainablefoodfirstapproachesas

part of the highly subscribed Sustainable and HealthyNutritionsessionat theFOOD2030conference inBrussels,October2017,

32

• ODIN hosted a dedicated session as part of the International Union of Nutrition Sciences

congress,inBuenosAiresinOctober2016,calledVITAMINDSTATUSAROUNDTHEWORLD:

EPIDEMIOLOGICALDATAANDDIAGNOSIS.

• BeyonditscommitmenttodisseminationactivitiesinrelationtokeyresultsoftheODINproject,

theconsortiumwasalsohighlycommittedto their translationandexploitation. Exploitation is

importanttoconverttheknowledgegainedfromODINintosocio-economicbenefitsforEurope

and its citizens. As mentioned above, ODIN by fostering the existing, and forging new, links

between public research organisations and industry, have created an environment for

knowledge spill over. Commercialisation and transfer of knowledge are two mainstream

channelsforexploitationofpublicresearchresults.

ODIN has taken the following establishedmeasures aimed at ensuring ‘exploitation’ of its

results(andadditionaldetailsareprovidedinPartB2):

Usingthefindingsinfurtherresearchactivities(outsidetheaction):

Ø The standardized serum 25(OH)D, generated during the ODIN project, has been used in

researchactivitiesoutsidetheaction,whichhadbeenidentifiedasameansofexploitation

ofthesenewdata.

Ø Theknow-howgeneratedwithinODIN,particularly in relation to food-based solutionsandcertainhealthandmetabolismoutcomes,havebeenusedbyseveralpartnersinnewvitamin

Dresearchprojectproposalsinresponsetonationalfundingcalls.

Ø ThefindingsfromODINwillalsobeusedincollaborativeinitiativesgoingforward–thesewill

rangefromindividualparticipantdataanalyses,toinformingnutritionpoliciesandpractices

inrelationtovitaminDstatusinlowandmiddleincomecountries.

Ø Currently,theEC,theUNSustainableDevelopmentGoalsandmanygovernmentalagencies

and NGOs are deliberating the potential of using food-first strategies for micronutrient

deficiencyprevention. TheGAINalliance, theMicronutrient initiative, theBill andMelinda

Gates Foundationand the SUNMovement are actively seekingapproaches to address the

‘HiddenHunger’ ofmicronutrient deficiency. The validatedODINmodel of using agri-food

productionandfoodtechnologyapproachestoenrichfoodswithvitaminD,supportedbya

dietarymodellingframeworkthatdemonstratessafeandeffective levelsofadditiontothe

foodsupply, isatransferablemodelthatcouldbeappliedtoothermicronutrientsthatare

weaklysuppliedinthemoderndiet.

Developing,creatingormarketingaproductorprocess:

Ø TheoutcomesofODIN’sWP5RCTinrelationtopoorbioavailabilityofvitaminD2frombread

madewithUV-treatedyeastwasfollowedupwithanindustry-commissionresearchcontract

toundertakefurtherstudyoftheimpactoftheformofyeastonbioavailabilityofvitaminD2.

Ø The ODIN bioavailability trial with the vitamin D3-enriched low-fat cheese has generated

additional knowledge in relation to optimal enrichment of low-fat cheesewith vitamin D.

Thisprocessmayturnintodown-streammarketopportunities.

Ø The research undertaken in ODIN in relation to the safety and efficacy of UV-exposed

mushrooms facilitated one of our industry partners securing approval from their national

foodregulatoryagencytolaunchUVB-treatedmushrooms.

Ø The underpinning science behind the process of biofortification of eggs, red meats and

cultured fish, and of vitamin D enhanced pork achieved through a novel process of UV-

33

treatmentoftheanimals inthepenshavecontributedtothescopefor increasingmarkets

forsuchvitaminD-enrichedanimalfoodswithbenefitsforhumanvitaminDnutrition.

Ø Major food companies and regulatory authorities have requested and will facilitate

conversionofODINdatatoconcisedocumentsforuseinfoodlabellingandtoadvocatefor

updatestothefoodlabellingregulations(specificallytheoutdatedECRDA).

Ø Collectively, the view of a global science-based company active in health, nutrition and

materialswasthattheODINprojecthadsetanewbarforachievementwithinthecontextof

ECfundedresearch,inthecognateareasofSC1andSC2.

Creatingandprovidingaservice(s)–potentialforspin-offusingODINIP

The standardization of existing serum 25(OH)D data-sets from strategically important

population studies/surveys has been undertaken outside the ODIN action as a service to

interestedparties,includingindustry.Thisservicehasbeenundertakenasexternalresearch

contracts.TheonlineODINvitaminDdeficiencymaphasraisedawarenessoftheapproachand its application. There is also scope to offer associated service in which the UVB

availability of certain locations can be modelled using the approach used in ODIN and

illustrated in itsVitaminDwintermap. In linewiththis, the innovativeandvalidatedODINsystem for conducting dietary modelling of the vitamin D food supply, is of commercial

interest.Finally,there isscopetoofferaservicewhichtakesthedatafrommodelledUVB-

availabilityandthemodelledchangesinvitaminDintakearisingfromavitaminD-enhanced

food(s)andpredictstheimpactonthepopulationserum25(OH)Dandprevalenceofvitamin

Ddeficiency.

Transferofknowledgetorelevantagenciesbriefedwithprotectingpublichealth:

Beyond ODIN’s productive dissemination of its research findings, ODIN also sought to

maximiseitsdataandresultstothebenefitofsocietybyofferingrawdatafromourODIN’s

RCTsandIPDanalysesavailabletotheEuropeanFoodSafetyAuthority(EFSA)inrelationto

theirrecentDRVexerciseforvitaminD. ODIN,through its jointcoordinators,hasalsohad

directcommunicationswithandknowledgetransfertotheScientificAdvisoryCommitteeon

Nutrition(SACN)intheUKinrelationtotheirrecentexerciseonDRVforvitaminDaswellas

withtheHealthCounciloftheNetherlands(CommitteeonNutrition),whoarecurrentlyre-

evaluatingtheirvitaminDrecommendations.Thiscontinuesuponastrongtraditionofthe

ODINjointcoordinatorssharingdatawiththeInstituteofMedicinefortheir2011vitaminD

exercise.TheODINcoordinatorshaddialoguewiththeNutritionUnitatEFSAinrelationto

informationandknowledgeexchangeon theuseof IPDapproach toestimationofdietary

vitaminDrequirementestimatesandpossiblebetween-individualsurrogatesthatmightbe

appliedwithinmorestandardmeta-regressionapproaches.Thecoordinatorshavealsomet

withtheOfficeofDietarySupplementsatNIHinrelationtothepotentialandapplicationof

theIPDapproachtofuturedietaryreferenceintakeexercisesforvitaminD.Thereisscope

toofferaservicetorelevantgovernmentalstakeholderswhichutilisestheIPDapproachto

estimationofvitaminDrequirements.

ODINhasalso sharedasyetunpublished findingswith theEFSAWorkingGrouponAmino

Acids and Vitamins of the Panel on Additives and Products or Substances used in Animal

Feed (FEEDAPPanel) in response toan initiative to collectdataon vitaminD3 in fish flesh

and/or infishfeed(EFSA-Q-2014-00604,FAD-2014-0035). Thiswas insupportoftheEFSA

preparinganopiniononthesafetyofvitaminD3additiontofeedingstuffsforfish.

34

E. Project website and contact details

TheODINprojectwebsiteisavailableat:http://www.odin-vitd.eu

TheODINwebsitewillbemaintainedbeyondthelifetimeoftheprojectbytheCorkCentreforVitaminDandNutritionResearchatUniversityCollegeCork,eitherasanindependentwebsite,orasamicrosite,foraminimumofthreeyears.

ProjectCoordinatorscontactdetails:

ProfessorMaireadKiely,�

CorkCentreforVitaminDandNutritionResearch,SchoolofFoodandNutritionalSciences,

UniversityCollegeCork,

Cork,

Ireland.

Tel:+353214903394Fax:+353214270244E-mail:m.kiely@ucc.ie

ProfessorKevinCashman,�

CorkCentreforVitaminDandNutritionResearch,SchoolofFoodandNutritionalSciences,

UniversityCollegeCork,

Cork,

Ireland.

Tel:+353214901317Fax:+353214270244E-mail:k.cashman@ucc.ie