人工食用色素对儿童注意力障碍或多动症影响的研究模型（英文） 12页

AResearchModelforInvestigatingtheEffectsofArtificialFoodColoringsonChildrenWithADHDRonaldE.Kleinman,RonaldT.Brown,GaryR.Cutter,GeorgeJ.DuPaulandFergusM.ClydesdalePediatrics;originallypublishedonlineMay16,2011;DOI:10.1542/peds.2009-2206Theonlineversionofthisarticle,alongwithupdatedinformationandservices,islocatedontheWorldWideWebat:http://pediatrics.aappublications.org/content/early/2011/05/11/peds.2009-2206PEDIATRICSistheofficialjournaloftheAmericanAcademyofPediatrics.Amonthlypublication,ithasbeenpublishedcontinuouslysince1948.PEDIATRICSisowned,published,andtrademarkedbytheAmericanAcademyofPediatrics,141NorthwestPointBoulevard,ElkGroveVillage,Illinois,60007.Copyright©2011bytheAmericanAcademyofPediatrics.Allrightsreserved.PrintISSN:0031-4005.OnlineISSN:1098-4275.Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download SPECIALARTICLESAResearchModelforInvestigatingtheEffectsofArtificialFoodColoringsonChildrenWithADHDAUTHORS:RonaldE.Kleinman,MD,aRonaldT.Brown,PhD,bGaryR.Cutter,PhD,cGeorgeJ.DuPaul,PhD,dandabstractFergusM.Clydesdale,PhDeTheUnitedKingdomandEuropeanUnionrecentlyrestrictedtheuseofaDepartmentofPediatrics,MassachusettsGeneralHospitalandartificialfoodcolorings(AFCs)toimprovethehealthofchildren.TheseHarvardMedicalSchool,Boston,Massachusetts;bDepartmentofPsychology,WayneStateUniversity,Detroit,Michigan;decisionsprovideaninterestingcasestudyoftheroleofscientificcDepartmentofBiostatistics,UniversityofAlabama,evidenceintheassessmentoffoodadditivesandrisktochildren’sBirmingham,Alabama;dDepartmentofEducationandHumanhealthandformulationoffoodpolicy.AlthoughtherecontinuestobeServices,LehighUniversity,Bethlehem,Pennsylvania;andeDepartmentofFoodScience,UniversityofMassachusettsuncertaintyconcerningthelinkbetweenAFCsandattention-deficit/Amherst,Amherst,Massachusettshyperactivitydisorder(ADHD),policydecisionshavebeenmadethatKEYWORDShavefar-reachingimplications.Inaddition,publicitysurroundingthechildren,attention-deficit/hyperactivitydisorder,artificialfoodpolicychangesmayshapepublicperceptionsconcerningeffectivecolorings,eliminationdiet,foodsafetymanagementofADHD.WebelievethatthebalanceofexistingevidenceABBREVIATIONSneitherrefutesnorsupportsthelinkbetweenAFCsandADHD,whichAFC—artificialfoodcoloringADHD—attention-deficit/hyperactivitydisorderhighlightstheneedforcarefullydesignedstudiestofurtherinvestigateDSM—DiagnosticandStatisticalManualthelinkbetweenAFCsandADHD.InthisarticlewedescribeamodelforMTA—MultimodalTreatmentStudyofChildrenWithADHDsuchstudies.Indevelopingourmodel,wedrewfromcurrentinvesti-TheUMassAmherstFoodScienceStrategicPolicyAlliancehasagativestandardsinADHDresearch,suchasthoseusedinthelandmarkstrictpolicystatingthatanyandallPolicyAlliance–sponsoredMultimodalTreatmentStudyofChildrenWithADHD.Thesestandardsworkandpublicationsrelatedtothatworkmustbefreeofinfluencebycorporatesponsors.Inaddition,theUMassencompassmethodologicconsiderationsincludingsampleselection,AmherstFoodScienceStrategicPolicyAlliancecomplieswithalloutcomeassessment,anddataanalyses.Itisourhopethatthismodelconflict-of-interestguidelinespublishedintheAmericanJournalresearchmethodologymayprovevaluableinaddressingdesigncon-ofClinicalNutritionandpreparedbyaworkingcommitteeoftheInternationalLifeSciencesInstituteofNorthAmerica.TofurthersiderationsinfuturestudiesofAFCsandADHDwiththegoalofproduc-ensurethehigheststandardsofobjectivity,allparticipatingingreliabledatathatwillenablepolicy-makerstobetterformulateresearchersandauthorsarerequiredtostateexplicitlythateffective,evidence-basedfood-policydecisions.Pediatrics2011;127:industryfundinghashadnoinfluenceontheformulationofe1575–e1584theirworkandtomakefulldisclosureofrelevanttiestoindustrysothatreadersmayjudgeanyunintentionalbias.www.pediatrics.org/cgi/doi/10.1542/peds.2009-2206Inrecentyears,debatesconcerningthesafetytohumanhealthofdoi:10.1542/peds.2009-2206ingredientsandtechnologiesusedbythefoodindustryhavebecomeAcceptedforpublicationFeb25,2011increasinglycommon.ExamplesincludecontroversiessurroundingAddresscorrespondencetoRonaldE.Kleinman,MD,Departmentoftheroleofirradiationinfood-processing,1–3healthrisksassociatedPediatrics,MassachusettsGeneralHospital,CPZS578,175withplasticsindrinkandfoodcontainers,4–6useofantibioticsandCambridgeSt,Boston,MA02114.E-mail:rkleinman@partners.orghormonesbythemeatindustry,3,7–9anddevelopmentofgeneticallyPEDIATRICS(ISSNNumbers:Print,0031-4005;Online,1098-4275).modifiedfoods.10–12PolicydiscussionsrelatedtotheseissuesoftenCopyright©2011bytheAmericanAcademyofPediatricscenterondefiningacceptableriskanditsdeterminants,aprocessinFINANCIALDISCLOSURE:Withreferencetothisarticle,onlyDrwhichscienceplaysacrucialrole.13,14TheplaceofobjectivescientificClydesdalehasaworkingrelationshipwithacompanyinvolvedinthemanufactureoffoodcolorings.TheUMassAmherstFoodevidenceisespeciallyimportantwhenoneconsidersthetendencyforScienceStrategicPolicyAlliancereceivesfundingfromCargill,stigmasaboutproductsortechnologiestoarisefrompopularpercep-Inc,Coca-ColaCompany,ConAgraFoods,Inc,Kraft,Mars,Inc,NestleR&DCenter,Inc,PepsiCola,Inc,TateandLyleNorthtionsofrisk,whichareoftendrivenbyfearsormisinformation.15,16America,UnileverNA,MassachusettsDepartmentofAgriculturalResources(grant),andUniversityofTheongoingdebateconcerningthelinkbetweenartificialfoodcoloringMassachusettsAmherst.DrKleinmanhasservedonthescientificadvisoryboardsofGeneralMills,Beechnut,Hero(AFC)andattention-deficit/hyperactivitydisorder(ADHD)providesaFoods,theGrainFoodsFoundation,andBurgerKingandusefulcasestudyoftheroleofscientificevidenceintheassessmentof(Continuedonlastpage)foodadditivesandrisktochildren’shealthandformulationoffoodpolicy.Thereisdisagreementonthequestionofwhetheranassocia-tionexistsand,ifitdoes,howstrongsuchanassociationmaybe.17–26APEDIATRICSVolume127,Number6,June2011e1575Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download recentmeta-analysisofexistingstud-implicationsforthequestionofOVERVIEWOFEXISTINGRESEARCHiesconcludedthatthelinkbetweenwhetherAFCsplayacausativeroleinONFOODADDITIVESANDADHDADHDandAFCswassupportedbyADHD.ResultsfromnumerousstudiesToestablishacontextforourrecom-better-designedstudies.Furthermore,haveindicatedthatADHDislargelymendations,weconductedareviewoffindingsfromarecentlargeandcare-heritable.37Onthebasisofthesefind-theexistingliteratureonfoodaddi-fullydesignedstudyconductedintheings,itispossiblethatAFCsmayinter-tivesandADHDthrough2009byusingUnitedKingdombyresearchersattheactwithunderlyinggeneticfactorsseveralbiomedicalandpsychologicalUniversityofSouthamptonhavere-andacttotriggerthedisorder.databases(OvidMedline,PsycINFO,vealedalinkbetweenconsumptionofWhetherthishypotheticalphenome-GoogleScholar,andPubMed).Inaddi-AFCsand/orpreservativesandin-noninvolvesnocases,onlyasmalltion,wesearchedthebibliographiesofcreasedsymptomsofADHDamongfractionofcases,oralargerper-keyarticles.childreninthegeneralpopulation.27centageofcasesremainstobede-Ourliteraturesearchidentified25Theseresultsandfindingsfromanterminedandshouldbethesubjectearlierstudybythesamegroup28blinded,controlledhumanstudiesoffurtherinvestigation.IfAFCsdoin-promptedchangesinfoodregulationspublishedfrom1970throughAprilcreasetheriskofdevelopingADHDinintheUnitedKingdomandEuropean200938–62and2meta-analysesofhu-asubgroupofchildren,itisimpor-Unionandproposedfederalandstatemanstudies.22,24AllstudiesreviewedtanttoidentifytheriskgroupthatlegislationintheUnitedStates.29–34Thewerecontrolled,double-blindtrials,maybenefitfromamodifieddiet,asUKFoodStandardsAgencyhascalledmanyofwhichinvolvedacrossoverde-isdoneforphenylketonuriaandforvoluntarybanson6AFCs.31Inaddi-sign.Severalimportantconclusionsotherdiseases.Thus,thereisaneedtion,theEuropeanParliamenthascanbedrawnonthebasisofourre-formorestudiesthatfocusonpossi-calledforwarningsonproductsthatviewoftheexistingliteratureonAFCsbleassociationsbetweenAFCsandcontainAFCs.35However,findingsfromandADHD.First,thereisarelativelyADHDtobuildonresultsfromexist-theSouthamptonstudy,whichfocusedsmallbodyofcontrolledhumanre-ingstudies.onageneralpopulationsample,stillsearchinthisarea,andmoststudiesdonotshedlightonthequestionofCurrentfood-policydevelopmentsinwererelativelysmall.WiththemajoritywhetherAFCsmaycontributetoADHDtheUnitedKingdom,EuropeanUnion,ofstudiesconductedbefore1990,di-asaclinicalsyndrome.Inaddition,theandUnitedStates,withrespecttotheagnosticcriteriausedforsampleselec-studywasnotdesignedtoseparatelylinkbetweenAFCsandADHD,supporttionwerelargelyoutdated,whichraisesassessthepotentialeffectsofindivid-theneedforamodelresearchmethod-concernsaboutthegeneralizabilityofre-ualcompoundsinthetestmixture,ologytoinformfood-policydecisions.sultstoanADHDpopulation.38–55,57–59,61,62whichcontainedbothAFCsandsodiumInthisarticlewepresentsuchamodel.Theoutcomeassessmentmethodol-benzoate,apointthatillustratesjustOurresultsrepresenttheconsensusogyusedinthemajorityofstudiesoneoftheintricaciesinvolvedininves-opinionofagroupofexpertscon-lacksconsistencywithcurrentstan-tigationsinthisarea.NewregulationsvenedbytheUniversityofMassachu-dardsforADHDassessment,whichintheUnitedKingdomandtheEuro-setts(UMass)AmherstFoodSciencerequiremeasuringchangeinbothpeanUnionreflectthejudgmentthatStrategicPolicyAlliance,apublic-symptomsofthedisorderandfunc-theriskofdevelopingsymptomsofandindustry-sponsoredpolicyinsti-tionalimpairmentsassociatedwithADHDasaresultofAFCexposureout-tutelocatedatUMassAmherst.Thethedisorderandensuringthatmea-weighstheconsiderableproblemsas-opinionsandpositionstakeninthissurementsaremadeinmultipleset-sociatedwithreplacingAFCswithnat-consensusreportarescientificallytingswithmultipleinformantsanduralsubstitutes,aswellasthebenefitsbasedandnotinfluencedbythedifferentmethodologies.63Thesedis-ofexistingcolorings(eg,culturalUMassAmherstFoodScienceStrate-crepanciesraisequestionsconcern-perceptionsoffoodappearance,ef-gicPolicyAllianceoritsmembers.ingthereliabilityoftheconclusionsfectofcoloringsonperceptionofWetakenopositionontheeffectsofdrawninthesestudies.Becausethetaste36)ortheunexpectedconse-AFCsonADHDbutrecognizethatmajorityofstudiesinvolvedsmallquencesofsuchrule-making,betheythereisaneedformorewell-samples,insufficientpowermaypositiveornegative.designedresearchtoexaminethehaveaffectedresultsfromstudiesRecentadvancesinourunderstandinglinkbetweenAFCsandtheclinicalthatfailedtodetectdifferencesbe-oftheetiologyofADHDhaveimportantsyndromeofADHD.tweengroups.e1576KLEINMANetalDownloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download SPECIALARTICLESADVANCESINOURofthedisorderandchangesindiag-ingtheresearchquestion(s)inanun-UNDERSTANDINGOFADHDnosticrequirements.66Althoughtherebiasedmannermustbemade.havebeenadvancesinthemanage-BecausemostextantresearchonthementofADHDsincethe1960s,notreat-ExperimentalDesignlinkbetweenAFCsandADHDpredates1990,itisimportanttobeawareofkeymentstudyhashadmoreimpactthanAcarefullydesignedandsufficientlydevelopmentsthathavetakenplacethelandmarkMultimodalTreatmentpoweredrandomizedcontrolledtrialStudyofChildrenWithADHD(MTA).67–70regardingADHDsincethisresearch(RCT)wasconsideredthebestmeansappeared.SinceitsfirstappearanceinTheMTAhasevaluatedtherelativeef-ofinvestigatingthepotentialeffectsoftheDiagnosticandStatisticalManualficacyofthestimulantmedicationAFCsonADHD.OurmainphaseIIIRCTmethylphenidate,behavioraltreat-willbeprecededbyapreliminary,ofMentalDisorders(DSM),ADHDhasment,andcommunity-basedcareinsmallphaseIIstudy(Fig1)designedtobecomethemostcommoncognitive,thetreatmentofADHDinchildren,establishproofofconceptandexam-behavioral,andemotionaldisorderwhichledthewayinestablishingtreatedinchildren.63ADHDwasfirstin-ineissuesofdosingandtiming.Wede-methodologicstandardsinADHDre-terminedthatbeforeproceedingtoacludedintheDSMin1968as“hyperki-search.Manyoftheresearchstan-neticdisorderofchildhood.”Duringlarge,expensivephaseIIIRCTstudy,itdardsestablishedintheMTAarere-the1970s,thesymptomsofinatten-wouldbeprudenttohaveatleastsomeflectedinthemodelthatwedescribetion,impulsivity,andhyperactivitybe-evidenceofcausalityinthelinkbe-here.gantoberecognizedascoresymp-tweenconsumptionofAFCsandsymp-tomsandintegraltothedisorder.PROPOSEDMODELRESEARCHtomsofADHD.However,notuntil1980wastheMETHODOLOGYOurphaseIIstudywillbeconductedindisorderrecategorized(DSM-III)as2stages:stage1,inalaboratoryTheobjectiveofourmodelresearchattention-deficitdisorderwithorwith-(classroom)setting,whichwillallowmethodologyistoidentifyandaddressouthyperactivity.WiththeDSM-III-Rinforstructuredassessments;andstagekeyconsiderationsinthedesignofre-1987,criteriafordiagnosisofthedis-2,inthehomesetting(free-living).searchprojectsthatexamineassocia-orderrequiredthepresenceof8of14Eachphasewilllastfor1week.Provid-tionsbetweenAFCsandADHD.Itisoursymptomsrelatedtothe3coresymp-ingourphaseIIstudyestablishesathopethatresultsfromsuchprojectstomclusters(inattention,impulsivity,leastlimitedevidenceofcausality,itwillinformfood-policydecisionsthathyperactivity)andonsetbeforethewillbefollowedbyalarge-scale,short-affectchildrenwithADHD.ageof7years.64Currently,accordingterm(6-week),phaseIII,double-blind,toDSM-IV-TRcriteria,adiagnosisofSpecifyingtheResearchQuestionrandomized,controlled,parallel-groupADHDismadeonthebasisofdevel-Ourresearchmodelisintendedtoad-studydesignedtomeasuretheacuteopmentallyinappropriatesymptomsdressspecificquestionsthatconcerneffectsofAFCsonADHDsymptomsinofinattentionand/orhyperactivity-therelationshipbetweenAFCsandADHD.subjectswithADHD(Fig2).Thisstudyimpulsivity.ThreeADHDsubtypesareTheprimaryresearchquestionforourwillalsohaveanextensionphase(6recognized,includinginattentive,hy-modeliswhetherconsumptionofdi-months)forassessingmaintenance.peractive/impulsive,andacombinedetaryAFCsisassociatedwithchangesinDuringthisextension,studyinterven-subtype.ForavaliddiagnosisofADHD,ADHDsymptomsandfunctioninginchil-tionswillremainthesame,andperi-theremustbeevidenceofsymptomsdrenwithADHD.Animportantsecondaryodicassessmentswillbemade.Forearlyinlife(beforetheageof7years),questioniswhetherconsumptionofboththephaseIIandIIIstudies,wepro-symptomsmustbepervasiveacrossAFCsisassociatedwiththeoccurrenceposeusingacontrolgroupofchildrendifferentsettings,theymustbepersis-ofADHDsymptomsintypicallydevelop-withoutADHDtoassessthesecondarytentovertime,andtheymustleadtoingcontrolsubjects.questionofwhetherAFCsareassoci-clinicallysignificantimpairmentinso-atedwiththeoccurrenceofADHDcial,academic,oroccupationalfunc-StudyFundingsymptomsinthegeneralpopulation.tioning.65Althoughnotusedinisola-Inanyresearchproject,itisimportanttiontodiagnoseADHD,ratingscalestoensurefreedomfromrealorper-Treatment/Interventionhavebecomeusefulfordocumentingceivedbiases.71Therefore,allfundingAlthoughitmaybepossibletostruc-symptomsandmeasuringresponsessourcesmustbeclearlyidentified,andtureanaturalisticinterventionintotreatment.Thesescaleshaveassurancesthatthestudydesignandwhichsubjectsarerandomlyassignedevolvedalongwithourunderstandingmethodsareappropriateforaddress-toreceiveblinded,speciallypreparedPEDIATRICSVolume127,Number6,June2011e1577Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download FIGURE1PhaseII,proof-of-conceptstudytoestablishacausallinkbetweenAFCconsumptionandchangeinADHDscore(ADHDsubjects)orincreaseinADHDsymptoms(controlsubjectswithoutADHD)andtodeterminethedoseofAFCstobetestedinthephaseIIIstudy.Patientswillberandomlyassignedto1of5groups,eachreceivingAFC-freemealspluscapsulesthatcontain5differentconcentrationsofAFCs(0%,50%,100%,150%,200%),basedonconcentra-tionsofAFCsintypicalmeals.mealsthataresimilarinappearancelevelofAFCspermeal(breakfast,AFCs(Fig1).IfaneffectisseenwiththebutcontaineitherAFCsornaturalcol-lunch,dinner,drinks,andsnacks)willAFCmixtureat1ormoredosagelevels,oringsasameansofdeterminingthebedeterminedonthebasisofanalysisthenthestudywillberepeated,andeffectsofAFCsonADHDsymptoms,weofarepresentativesampleofmeals.individualcoloringswillbewithdrawnbelievethatconsiderationsoflogisticsinastagedmannertodetermineiftheThephaseIIstudyisdesignedtoprovideandcostmakethistypeofinterventioneffectresultsfrom1oracombinationproofofconceptandtoguidetreatmentunfeasible.Therefore,weproposeanofthecolorings.selectionandassessmenttimingfortheinterventioninwhichparticipantswilllargerphaseIIIstudy.ItisalsodesignedInthelargerphaseIIIstudy,subjectsberandomlyassignedtoarangeofdouble-blindtreatmentarmswithAFC-totestspecificAFCsaloneandincombi-withADHDandthosewithoutADHDfreemealsplusopaquecapsulesthatnationatdifferentconcentrationstode-willberandomlyassignedtothecontaindifferentconcentrationsoftermineifaneffectisassociatedwithansame5treatmentarmsasintheAFCsaboveandbelowtheamountsindividualAFCoracombinationofthem.phaseIIstudy(assumingthatall4foundintypicalmeals.WeproposeParticipantsinthephaseIIstudy,sub-activedosesproducearesult,andtestingAFCconcentrationsthatrangejectswithADHDandthosewithoutADHD,fewerwillbeusedifnoeffectsarefromAFC-free(0%)totwicethenormalwillberandomlyassignedto1of5seenatagivendoseordoses)totestortypicalAFCconcentration(200%)togroups;groupswillreceivecapsulestheAFCorAFCmixtureasdeter-obtainresultsthatrepresentawidethatcontain0%,50%,100%,150%,orminedinthephaseIIstudyatconcen-rangeofdietaryexposures.Anaverage200%concentrationsofamixtureoftrationsincluding0%,50%,100%,e1578KLEINMANetalDownloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download SPECIALARTICLESFIGURE2PhaseIIIrandomizedcontrolledtrialtoevaluatetheacuteeffectofconsumptionofdifferentconcentrationsofAFCsonADHDsymptomscoresinsubjectswithADHDandacontrolgroupofsubjectswithoutADHD.Patientsarerandomlyassignedto1of5groups,eachreceivingAFC-freemealspluscapsulescontaining5differentconcentrationsofAFCs(0%,50%,100%,150%,200%),basedonconcentrationsofAFCsintypicalmeals.aSamplesizeisbasedon1effectivedosefoundfromphaseII.150%,and200%(Fig2).AFCcapsulesallyresultinasamplewithamorese-ferentbrainstructuresthanthosein-willbeadministeredwithAFC-freeverepresentationofdisease.AnothervolvedinADHDcombinedtype.63mealsatbreakfast,lunch,anddinner,considerationinsampleselectionisInclusionofsubjectswithothercomor-andAFC-freesnacksandbeverageswhetherthestudyshouldfocuson1orbidpsychiatricdiagnosesinadditionwillalsoprovided.moreADHDsubtypes.WeproposeusingtoADHD,includingotherexternalizingADHDcombinedtypeonlyforoursample(eg,conductdisorder,oppositionalde-StudySampleratherthanincludingall3subtypes.fiantdisorder)andinternalizing(eg,Theselectionofsubjectsforanyre-CombinedtypeistheADHDsubtypethatanxietydisorders,depression)disor-searchprojectdependsonthepopula-ismostcommoninclinicalpracticeandderswillallowustodetermineifAFCtiontowhichresultswillbegeneralized.hasbeenstudiedmostwidely.63Itisas-effectsarespecifictoADHD.Ourproposedstudywillbeconductedinsociatedwiththegreatestclinicalim-asampleofchildrenwithADHD.How-pairment.63Also,previousstudieshaveAgeisacriticalvariableintheselectionever,withinthisgeneralgroupthereareprimarilylinkedAFCswithhyperactivity,ofourstudysample.Becauseinclusionsomeimportantconsiderationsintermsnotinattention,*andthereissomecon-ofpreschool-agedchildrenposescer-offurtherdefiningthestudysample.FortroversyintheADHDfieldastotainchallenges(ie,difficultyinestablish-instance,usingaschool-basedpopula-whetherADHDinattentivetypeisactu-ingaccuratediagnosis63),weproposetionwillresultinasamplewithlessallyaseparatedisorderinvolvingdif-usingaschool-basedsamplethatcon-severedisease,whereasusingasistsofboysandgirlsaged6to12years.psychiatric-basedpopulationwillgener-*Refs24,27,28,42,44,46,51,56,and59.InclusioncriteriaarebasedoncurrentPEDIATRICSVolume127,Number6,June2011e1579Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download diagnosticcriteriaforADHD.Partici-Measurementspsychopathology,anddemographicpantsmustmeetdimensionalcriteriaBecausemostexistingcontrolledstud-characteristics.StepsshouldbeforADHDbasedonparentandteacheriesofAFCsandADHDwereconductedtakentoensureconsistencyofas-ratingscalescoresthatexceedspecifiedinthe1970sand1980s,outcomesaresessments,includingcentralprepa-criteria(eg,beyondthe93rdpercentilenotconsistentwiththecurrentstan-rationofassessmentanddataformsforchild’sageandgender)andfullre-dardsrequiredofresearchonADHD.24andconsistencyintrainingacrosssearchdiagnosticcriteriaforADHD,Toensurevalidresults,anystudythatstudysitesandpersonnel.combinedtype,onthebasisofastruc-investigatesthelinkbetweenAFCsandSample-SizeIssuestureddiagnosticinterviewwiththepar-ADHDmustadoptameasurementent(s).Exclusioncriteriaarecurrentstrategythatincorporatespsychomet-Insteadofadoptinganeffectsizeof0.4,hospitalization,participationinanotherricallysoundoutcomemeasuresthatsuchasintheMTAstudy,weproposetreatmentstudy,havingnotelephone,focusonsymptomchangeaswellasusingalowereffectthresholdof0.28lowIQ(80),majorneurologicormedi-functionalimpairment.72,73Outcomeforourprimaryoutcome(changeincalillness,orongoingorpreviouslyun-assessmentmustencompassmultipleADHDsymptoms)andasthebasisfordisclosedchildabuse.Forstudyentry,functionaldomains(school,peerrela-powercalculationsforourphaseIIIweproposeusingamultiplegatingpro-tionships,familyfunctioning),andstudy.Thisthresholdisbasedonthecedure(4phases)similartothatusedinchangesinADHDsymptomsmustbeas-findingsatarecentmeta-analysisof15theMTAstudy(Table1).72sociatedwithconcomitantchangesintrialsfromwhichapositiveassocia-functionalimpairments.73Inaddition,tionbetweenAFCsandincreasedTheuseofacontrolgroupofchildrentheremustbemeasuresinmultipleset-symptomsofADHDwasreported(ef-withoutADHDwillallowourstudytoad-tingsfrommultipleinformantsthatusefectsize:0.28[95%confidenceinterval:dressthequestionofwhetherAFCcon-differentmethodologies(ratings,direct0.079–0.488]).24InthemostrecenttributestoADHDsymptomsamongtypi-tests,observations,measuresofaca-Southamptonstudy,McCannetal27callydevelopingsubjects.Thiscontroldemicandsocialfunctioning).72,73(2007)foundsimilarlymodesteffectgroupwillbesubjecttothesameinter-Studymeasuresforourproposedsizesamongageneralpopulationofventionandassessmentplanassub-studiesarelistedinTable2.Fullas-children.SmallereffectsizesarejectswithADHDintheprimarystudy.alsoappropriatewhenseeninthesessmentsforthephaseIIIstudy,bothControl-groupparticipantswillnotmeetcontextofexposuresthatmayhaveforsubjectswithADHDandcontrolcriteriaforanyDSM-IV-TRdiagnosisonsignificantpublichealthconse-subjectswithoutADHD,willbemadeatthebasisofparentinterviewandwillbequences.Althoughlargereffectsizesscreening,atbaseline,andattheclosematchedbyageandgenderwiththepar-ofthestudy,andselectedassess-maybeappropriatefortrialsofmed-ticipantswithADHD.mentswillbemadeatspecifictimeications,suchasisthecasewiththepointsduringthestudy.ThetimingofMTA,moremodesteffectsmaybetheseassessmentswilldependontim-seenascriticalwheninvestigatingingofresponseasdeterminedduringwidespreadexposuressuchasfoodTABLE1StudyEntry:MultipleGatingthepreliminaryphaseIIstudy.Intheadditivesorcolorings.Procedure(4-Phase)laboratorystage(stage1),assess-ForourphaseIIstudy,ourdesignobjec-PhaseProcedurementswillbemadeatbaselineandtiveistodetectaclinicallyimportantATelephoneintake:initialinclusionandexclusioncriteriadaily.Duringstage2(free-living),as-changeinsubjects(30%)inparent-BMailedratingscalessessmentswillbemadedaily.andteacher-ratedsymptomsandbehav-Parent,teacher:Conners’RatingInadditiontodirectmeasurementsofiors/attentionobservedinastructuredScales;ADHDRatingScale-IVCIn-personassessmenttheeffectoftheproposedintervention,setting.Toachievethisgoal,wewillre-Parent:DiagnosticInterviewwewillalsoassesspotentialmodera-cruit200participants:100subjectswithScheduleforChildren;ColumbiaADHDand100controlsubjectswithouttorsandmediatorsofoutcomes,ImpairmentScaleChild:mentalstatusexamination,whichincludeadherence/complianceADHD,whichwillprovide20subjectsWechslerIntelligenceScalefortotreatment/intervention,foodintakewithADHDand20controlsubjectsforChildren-III,physicalexaminationapartfromtheintervention(assessedeachofthe5AFCtreatmentgroups(0%,Child:mentalstatusexamination,WechslerIntelligenceScaleforbyusingfooddiaries),consumer50%,100%,150%,200%).ThethresholdChildren-III,physicalexaminationsatisfactionwiththeintervention,ofresponseforadoseinproceedingtoDFullbaselineassessmentcomorbidityofdisorder,parentalthephaseIIIstudyissomewhatarbitrarye1580KLEINMANetalDownloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download SPECIALARTICLESTABLE2PhaseIIandIIIStudyMeasuresDataAnalysisDomain/TypeMeasureExistingADHDtreatmentstudiessuchSchool/academicWIATastheMTAinvestigationprovideaPeersocialSSISBroadbandmeasuresofpsychopathologymodelfordataanalysis.69TheobjectiveExternalizingsymptomatologyClassroomobservations,Conners’RatingScales,ChildistopredictoutcomesonthebasisofBehaviorChecklist,ADHDRatingScale-IVmeasurementofcontinuousvariables.InternalizingsymptomatologyMASC,ChildDepressionInventory,Conners’RatingScales,ChildBehaviorChecklistAnalysisofcombinedmetricsshouldFamilyfunctioningParent-ChildRelationshipQuestionnairebeavoided.ForourphaseIIIstudy,Cognitive/attentionalContinuousPerformanceTest,PosnerVisualOrientingdataanalysiswillbeconductedontheImpairmentImpairmentRatingScaleintent-to-treatpopulation.ThemainDirectobservationoffunctioningVideotapedclassroomtaskengagementanalyticapproachwillbemixed-WIATindicatesWechslerIndividualAchievementTest;SSIS,SocialSkillsInformationSystem;MASC,MultidimensionalAnxietyScaleforChildren.effectsrepeated-measuresregressionmodeling,amethodthatallowsforin-clusionofsubjectswithincompletebutshouldbechoseninadvance.Ifwedosesarechosen,thenthoselevelsdataacrosstimeandaccountsforacceptthatthethresholdforproceedingwouldbeusedinasubsequentde-within-subjectcorrelationsbetweentothephaseIIIstudyshouldbeamajoritysignbolsteredbymoreanalysesonrepeatedobservations.Analyses(50%)withaclinicallysignificantre-thebasisofthecontinuousre-shouldreporteffectsseparatelyforsponse,thenaresponsein14of20sponsesofchangesinthesymptomeachmeasureandsettingwithsubjectswouldoccurbychanceonlyscale,analyzedbyusingregressionappropriatestatisticalcontrolsfor5.8%ofthetimeifthetruerateofimpactandanalysis-of-variancetechniquesexperiment-wisetypeIerror.Ourpri-is50%.Thus,wechooseasourdecision(discussedbelow)andmultiplecom-maryintent-to-treatanalysiswillfo-ruleforproceedingtothephaseIIIstudyparisonsagainstacontrolaswellascusonchangeinADHDsymptomsas14of20subjectswitha30%changedose-responseanalyses.determinedbyoutcomemeasuresonthesymptomscaleasalevelsuffi-ForthephaseIIIstudy,theprimaryob-acrossmultipledomains(Table2).cienttoshowthatthisismorethanjectiveistodetectaclinicallyimpor-Weusemultipleoutcomevariablesmightbeexpectedbypurechancebe-tantchangeinADHDsymptomsontheratherthanasingleoutcomeinantic-causeofmeasurementerror.Ifonebasisofaminimaleffectsizeof0.28inipationofourinterventionhavingadif-judgedthataresponsein12of20sub-subjectswithADHD.Thesecondaryob-ferentialimpactacrossvariousareasjectswassufficientformovingforwardjectiveistodetectachangeinbehav-offunctioning.Regressionmodelingratherthan14of20,theneithertheiorsincontrolsubjectswithoutADHDwillallowustoadjustformultipleco-samplesizewouldneedtoincreaseorwiththesameminimaleffectsize.Avariatesindeterminingtheeffectofin-wewouldneedtoacceptalowerlimitofsamplesizeof270subjectsineachdividualvariables.Outcomeswillbethethresholdforwhatproportionre-groupatthetimeofanalysiswillhaveassessedatbaselineandduringandsponseswouldwarrantcontinuingto90%powertodetectaneffectsizeofaftertheactiveinterventionperiod.thephaseIIIstudy.Forexample,ifone0.28usinga2-groupttestwithatypeIwerewillingtoproceedtothephaseIIIPublishingandRelatedIssuesstudyifonly10of20subjectsresponded,errorof.05(2-sided).ThissamplesizethenthethresholdvalueforthisdecisiondoesnotaccountfordropoutsandTrialregistrationisanimportantwouldbe35%ofsubjectsexperiencingcrossoversorthepossibilityofmoremeansofachievingfulltransparencyasignificant(30%)changeinsymp-than1effectivedosefoundfromphaseandpublicconfidenceandshouldbetoms.Thatis,when10of20subjectsre-II.Assumingadropoutrateof10%andrequiredofanystudythatinvestigatesspond,theprobabilityofithappeningbyacrossoverornoncompliancerateofnutritionalexposuresandADHD.74Reg-chanceisonly.053whenthetruere-10%,420subjectspergroup,forbothistrationalsoprovidesamechanismsponserateis35%;thus,theresponsetheADHDandcontrolgroups,wouldforaddressingpublicationbias.75rateismorelikelytobehigherthanneedtoberandomlyassigned.If235%,avaluesufficienttowarrantagroupsareused,adjustmentswouldDISCUSSIONANDCONCLUSIONSlargeandexpensivephaseIIIstudy.bemadeformultiplecomparisonsandThemodelresearchmethodologyweThiswithin-doseselectionrulewouldtheexpecteddifferencesamongthein-haveproposedhereisanattempttobeusedtodetermineifanyeffectivedividualgroups,estimatedfromtheoutlinetheessentialfeaturesofadoseshouldbetestedfurther.If2phaseIIresults.studythatinvestigatestheroleofAFCsPEDIATRICSVolume127,Number6,June2011e1581Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download incontributingtosymptomsofADHD.dietaryfatintakeintheUnitedStates,icalpsychologywithemphasisontheADHDhasahighprevalence76,77andisduringthesameperiodtherewasanin-designandconductofclinicaltrialsassociatedwithavarietyofnegativecreaseintheprevalenceofdiabetesandthatassesstheeffectsofpharmaco-outcomesifnotmanagedeffectively.78–81obesity.Itisnowincreasinglyrecognizedtherapeuticandbehavioralinterven-Therefore,makingavailableeffectivebyexpertsinnutritionthattherewaslit-tionsforADHD,pediatricnutritionwithmanagementstrategies,includingtlescientificevidencesupportingtheemphasisonassessingthebioavail-eliminationofharmfulnutritionalex-low-fatcampaignandthatitmayhaveabilityandmetabolismofnutritionalposuresasevidencewarrants,isana-ledtounintendednegativehealthexposures,andbiostatisticsandthetionalpublichealthpriority.consequences.85designandconductofclinicaltrialsIndevelopingourmodelresearchmeth-andresearchprojects.ParticipantsFood-policydecisionsthataffectchildodology,wehavedrawnfromcurrentwereselectedonthebasisoflarge-healthshouldbebasedonthebeststandardsinADHDresearchandhavein-scalescreeningandin-depthpersonalpossiblescientificevidence.Examplescludedwhatweviewtobeessentialde-interviews.Moderatorswereselectedaboundofinstancesinwhichpolicydeci-signfeatures.Itisourhopethatthistofacilitatediscussion,andawritersionsinagivenareathatlackedasolidmodelmethodologymayinformthede-withexpertiseinmedicalpublicationsevidentialfoundationhavebeenfollowedsignoffuturestudiesoftheeffectsofwaschosentoworkwithpanelmem-byunintendednegativeconsequences.AFCsonchildrenwithADHDandenableberstodevelopaconsensusreportInthe1970s,industriesintheeasternpolicy-makerstoformulateeffective,basedonexpertpanelrecommenda-UnitedStatesadoptedtheuseoftallevidence-basedfood-policydecisions.tions.TheUMassAmherstFoodSci-smokestackstobetterdispersefactoryenceStrategicPolicyAllianceisapol-emissions.TheunintendedconsequenceACKNOWLEDGMENTSicyprogrambasedatUMassAmherstwasthetransportofsulfurpollutionThisarticlewaspreparedatameetingwithmembersfromindustry,govern-higherintheairshed,whereitmixedconvenedbytheUniversityofMassa-ment(includingtheUSFoodandDrugwithwatervaporandwasdispersedtoachusetts(UMass)AmherstFoodSci-AdministrationandUSDepartmentofwidergeographicarea,whichresultedenceStrategicPolicyAllianceonAprilAgriculture),anduniversityfacultyinacid-raindestructioninnortheastern1–3,2009,toaddresstheissueoftheandstudents.Theopinionsandposi-andCanadianforests.82Intheareaofnu-currentstateofresearchinfoodpolicytionstakeninthisconsensusreporttrition,dietaryrecommendationsintheandADHDandwassupportedbythearescientificallybasedandnotinflu-1970sand1980semphasizingtheimpor-UMassAmherstFoodScienceStrate-encedbytheUMassAmherstFoodSci-tanceofloweringdietaryfatintakere-gicPolicyAllianceanditsmembers,in-enceStrategicPolicyAllianceoritssultedintheintroductionofnumerouscludingtheMassachusettsDepart-members.Editorialassistanceforthisfat-freeandlow-fatfoodproducts,manymentofAgriculturalResourcesprojectwasprovidedbyBioScienceofwhichcontainedhighamountsof(grant)andUMassAmherst.Themeet-Communicationswithfinancialsup-sugarandrefinedcarbohydrates.83,84Al-inggatheredthoughtleadersinthear-portfromtheUMassAmherstFoodSci-thoughthelow-fatcampaigndecreasedeasoffoodscienceandpolicyandclin-enceStrategicPolicyAlliance.REFERENCES1.MartinA.Spinachandpeanuts,withadash7.HallT.Interestgrowingin“natural”beef.13.KuiperHA,KleterGA.Thescientificbasisforofradiation.TheNewYorkTimes.FebruaryTheNewYorkTimes.March1,1989;C:1riskassessmentandregulationofgeneti-2,2009;A:108.BurrosM.Brand-nameleanbeef:isitreallybet-callymodifiedfoods.TrendFoodSciTech-2.Safersalad.TheNewYorkTimes.August28,ter?TheNewYorkTimes.January31,1990;C:1nol.2003;14(5–8):277–2932008;A:269.Trendagainstantibioticuseinmeats.TheKip-14.KuiperHA,KleterGA,NotebornHP,KokEJ.3.NaygaRMJr.SociodemographicinfluencesonlingerAgricultureLetter.March8,2002;73(5)Assessmentofthefoodsafetyissuesre-consumerconcernforfoodsafety:thecaseof10.KanterJ.Proposedbanongeneticallymod-latedtogeneticallymodifiedfoods.PlantJ.irradiation,antibiotics,hormones,andpesti-ifiedcorninEurope.TheNewYorkTimes.2001;27(6):503–528cides.RevAgricEcon.1996;18(3):467–475November23,2007;C:315.GregoryRS,SatterfieldTA.Beyondpercep-4.117yearsofBPA.TheWashingtonPost.April11.RosenthalE.Ageneticallymodifiedpotato,nottion:theexperienceofriskandstigmain27,2008;A:10foreating,isstirringsomeoppositioninEu-communitycontexts.RiskAnal.2002;22(2):5.Higherurinarylevelsofcommonlyusedrope.TheNewYorkTimes.July24,2007;C:3347–358chemical,BPA,linkedwithcardiovasculardis-12.CockburnA.Assuringthesafetyofgeneti-16.GregoryRS,SlavicP,FlynnJ.Riskpercep-ease,diabetes.DrugWeek.October3,2008callymodified(GM)foods:theimportancetions,stigma,andhealthpolicy.Health6.Movetobarsomebabycups.Newsday(Newofanholistic,integrativeapproach.JBio-Place.1996;2(4):213–220York).March4,2009;A3technol.2002;98(1):79–10617.Dietandattentiondeficithyperactivitydis-e1582KLEINMANetalDownloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthCh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ralfoodcolorings).e1584KLEINMANetalDownloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download AResearchModelforInvestigatingtheEffectsofArtificialFoodColoringsonChildrenWithADHDRonaldE.Kleinman,RonaldT.Brown,GaryR.Cutter,GeorgeJ.DuPaulandFergusM.ClydesdalePediatrics;originallypublishedonlineMay16,2011;DOI:10.1542/peds.2009-2206UpdatedInformation&includinghighresolutionfigures,canbefoundat:Serviceshttp://pediatrics.aappublications.org/content/early/2011/05/11/peds.2009-2206Permissions&LicensingInformationaboutreproducingthisarticleinparts(figures,tables)orinitsentiretycanbefoundonlineat:http://pediatrics.aappublications.org/site/misc/Permissions.xhtmlReprintsInformationaboutorderingreprintscanbefoundonline:http://pediatrics.aappublications.org/site/misc/reprints.xhtmlPEDIATRICSistheofficialjournaloftheAmericanAcademyofPediatrics.Amonthlypublication,ithasbeenpublishedcontinuouslysince1948.PEDIATRICSisowned,published,andtrademarkedbytheAmericanAcademyofPediatrics,141NorthwestPointBoulevard,ElkGroveVillage,Illinois,60007.Copyright©2011bytheAmericanAcademyofPediatrics.Allrightsreserved.PrintISSN:0031-4005.OnlineISSN:1098-4275.Downloadedfrompediatrics.aappublications.orgbyguestonFebruary17,2012SouthChinaNormalUniversity(183.63.102.253)-2016/4/3Download