A Research Model for Investigating the Effects ofArtificial Food Colorings on Children With ADHD

abstractThe United Kingdom and European Union recently restricted the use ofartificial food colorings (AFCs) to improve the health of children. Thesedecisions provide an interesting case study of the role of scientificevidence in the assessment of food additives and risk to children’shealth and formulation of food policy. Although there continues to beuncertainty concerning the link between AFCs and attention-deficit/hyperactivity disorder (ADHD), policy decisions have been made thathave far-reaching implications. In addition, publicity surrounding thepolicy changes may shape public perceptions concerning effectivemanagement of ADHD. We believe that the balance of existing evidenceneither refutes nor supports the link between AFCs and ADHD, whichhighlights the need for carefully designed studies to further investigatethe link between AFCs and ADHD. In this article we describe a model forsuch studies. In developing our model, we drew from current investi-gative standards in ADHD research, such as those used in the landmarkMultimodal Treatment Study of Children With ADHD. These standardsencompass methodologic considerations including sample selection,outcome assessment, and data analyses. It is our hope that this modelresearch methodology may prove valuable in addressing design con-siderations in future studies of AFCs and ADHD with the goal of produc-ing reliable data that will enable policy-makers to better formulateeffective, evidence-based food-policy decisions. Pediatrics 2011;127:e1575–e1584

In recent years, debates concerning the safety to human health ofingredients and technologies used by the food industry have becomeincreasingly common. Examples include controversies surroundingthe role of irradiation in food-processing,1–3 health risks associatedwith plastics in drink and food containers,4–6 use of antibiotics andhormones by the meat industry,3,7–9 and development of geneticallymodified foods.10–12 Policy discussions related to these issues oftencenter on defining acceptable risk and its determinants, a process inwhich science plays a crucial role.13,14 The place of objective scientificevidence is especially important when one considers the tendency forstigmas about products or technologies to arise from popular percep-tions of risk, which are often driven by fears or misinformation.15,16

The ongoing debate concerning the link between artificial food coloring(AFC) and attention-deficit/hyperactivity disorder (ADHD) provides auseful case study of the role of scientific evidence in the assessment offood additives and risk to children’s health and formulation of foodpolicy. There is disagreement on the question of whether an associa-tion exists and, if it does, how strong such an association may be.17–26 A

AUTHORS: Ronald E. Kleinman, MD,a Ronald T. Brown,PhD,b Gary R. Cutter, PhD,c George J. DuPaul, PhD,d andFergus M. Clydesdale, PhDe

aDepartment of Pediatrics, Massachusetts General Hospital andHarvard Medical School, Boston, Massachusetts; bDepartment ofPsychology, Wayne State University, Detroit, Michigan;cDepartment of Biostatistics, University of Alabama,Birmingham, Alabama; dDepartment of Education and HumanServices, Lehigh University, Bethlehem, Pennsylvania; andeDepartment of Food Science, University of MassachusettsAmherst, Amherst, Massachusetts

KEY WORDSchildren, attention-deficit/hyperactivity disorder, artificial foodcolorings, elimination diet, food safety

ABBREVIATIONSAFC—artificial food coloringADHD—attention-deficit/hyperactivity disorderDSM—Diagnostic and Statistical ManualMTA—Multimodal Treatment Study of Children With ADHD

The UMass Amherst Food Science Strategic Policy Alliance has astrict policy stating that any and all Policy Alliance–sponsoredwork and publications related to that work must be free ofinfluence by corporate sponsors. In addition, the UMassAmherst Food Science Strategic Policy Alliance complies with allconflict-of-interest guidelines published in the American Journalof Clinical Nutrition and prepared by a working committee of theInternational Life Sciences Institute of North America. To furtherensure the highest standards of objectivity, all participatingresearchers and authors are required to state explicitly thatindustry funding has had no influence on the formulation oftheir work and to make full disclosure of relevant ties toindustry so that readers may judge any unintentional bias.

www.pediatrics.org/cgi/doi/10.1542/peds.2009-2206

doi:10.1542/peds.2009-2206

Accepted for publication Feb 25, 2011

Address correspondence to Ronald E. Kleinman, MD, Department ofPediatrics, Massachusetts General Hospital, CPZS 578, 175Cambridge St, Boston, MA 02114. E-mail: rkleinman@partners.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: With reference to this article, only DrClydesdale has a working relationship with a company involvedin the manufacture of food colorings. The UMass Amherst FoodScience Strategic Policy Alliance receives funding from Cargill,Inc, Coca-Cola Company, ConAgra Foods, Inc, Kraft, Mars, Inc,Nestle R&D Center, Inc, Pepsi Cola, Inc, Tate and Lyle NorthAmerica, Unilever NA, Massachusetts Department ofAgricultural Resources (grant), and University ofMassachusetts Amherst. Dr Kleinman has served on thescientific advisory boards of General Mills, Beechnut, HeroFoods, the Grain Foods Foundation, and Burger King and

(Continued on last page)

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recent meta-analysis of existing stud-ies concluded that the link betweenADHD and AFCs was supported bybetter-designed studies. Furthermore,findings from a recent large and care-fully designed study conducted in theUnited Kingdom by researchers at theUniversity of Southampton have re-vealed a link between consumption ofAFCs and/or preservatives and in-creased symptoms of ADHD amongchildren in the general population.27

These results and findings from anearlier study by the same group28

prompted changes in food regulationsin the United Kingdom and EuropeanUnion and proposed federal and statelegislation in the United States.29–34 TheUK Food Standards Agency has calledfor voluntary bans on 6 AFCs.31 In addi-tion, the European Parliament hascalled for warnings on products thatcontain AFCs.35 However, findings fromthe Southampton study, which focusedon a general population sample, stilldo not shed light on the question ofwhether AFCs may contribute to ADHDas a clinical syndrome. In addition, thestudy was not designed to separatelyassess the potential effects of individ-ual compounds in the test mixture,which contained both AFCs and sodiumbenzoate, a point that illustrates justone of the intricacies involved in inves-tigations in this area. New regulationsin the United Kingdom and the Euro-pean Union reflect the judgment thatthe risk of developing symptoms ofADHD as a result of AFC exposure out-weighs the considerable problems as-sociated with replacing AFCs with nat-ural substitutes, as well as the benefitsof existing colorings (eg, culturalperceptions of food appearance, ef-fect of colorings on perception oftaste36) or the unexpected conse-quences of such rule-making, be theypositive or negative.

Recent advances in our understandingof the etiology of ADHD have important

implications for the question ofwhether AFCs play a causative role inADHD. Results from numerous studieshave indicated that ADHD is largelyheritable.37 On the basis of these find-ings, it is possible that AFCs may inter-act with underlying genetic factorsand act to trigger the disorder.Whether this hypothetical phenome-non involves no cases, only a smallfraction of cases, or a larger per-centage of cases remains to be de-termined and should be the subjectof further investigation. If AFCs do in-crease the risk of developing ADHD ina subgroup of children, it is impor-tant to identify the risk group thatmay benefit from a modified diet, asis done for phenylketonuria andother diseases. Thus, there is a needfor more studies that focus on possi-ble associations between AFCs andADHD to build on results from exist-ing studies.

Current food-policy developments inthe United Kingdom, European Union,and United States, with respect to thelink between AFCs and ADHD, supportthe need for amodel researchmethod-ology to inform food-policy decisions.In this article we present such amodel.Our results represent the consensusopinion of a group of experts con-vened by the University of Massachu-setts (UMass) Amherst Food ScienceStrategic Policy Alliance, a public-and industry-sponsored policy insti-tute located at UMass Amherst. Theopinions and positions taken in thisconsensus report are scientificallybased and not influenced by theUMass Amherst Food Science Strate-gic Policy Alliance or its members.We take no position on the effects ofAFCs on ADHD but recognize thatthere is a need for more well-designed research to examine thelink between AFCs and the clinicalsyndrome of ADHD.

OVERVIEW OF EXISTING RESEARCHON FOOD ADDITIVES AND ADHD

To establish a context for our recom-mendations, we conducted a review ofthe existing literature on food addi-tives and ADHD through 2009 by usingseveral biomedical and psychologicaldatabases (Ovid Medline, PsycINFO,Google Scholar, and PubMed). In addi-tion, we searched the bibliographies ofkey articles.

Our literature search identified 25blinded, controlled human studiespublished from 1970 through April200938–62 and 2 meta-analyses of hu-man studies.22,24 All studies reviewedwere controlled, double-blind trials,many of which involved a crossover de-sign. Several important conclusionscan be drawn on the basis of our re-view of the existing literature on AFCsand ADHD. First, there is a relativelysmall body of controlled human re-search in this area, and most studieswere relatively small. With themajorityof studies conducted before 1990, di-agnostic criteria used for sample selec-tion were largely outdated, which raisesconcernsabout thegeneralizability of re-sults to an ADHD population.38–55,57–59,61,62

The outcome assessment methodol-ogy used in the majority of studieslacks consistency with current stan-dards for ADHD assessment, whichrequire measuring change in bothsymptoms of the disorder and func-tional impairments associated withthe disorder and ensuring that mea-surements are made in multiple set-tings with multiple informants anddifferent methodologies.63 These dis-crepancies raise questions concern-ing the reliability of the conclusionsdrawn in these studies. Because themajority of studies involved smallsamples, insufficient power mayhave affected results from studiesthat failed to detect differences be-tween groups.

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ADVANCES IN OURUNDERSTANDING OF ADHD

Because most extant research on thelink between AFCs and ADHD predates1990, it is important to be aware of keydevelopments that have taken placeregarding ADHD since this researchappeared. Since its first appearance inthe Diagnostic and Statistical Manualof Mental Disorders (DSM), ADHD hasbecome the most common cognitive,behavioral, and emotional disordertreated in children.63 ADHD was first in-cluded in the DSM in 1968 as “hyperki-netic disorder of childhood.” Duringthe 1970s, the symptoms of inatten-tion, impulsivity, and hyperactivity be-gan to be recognized as core symp-toms and integral to the disorder.However, not until 1980 was thedisorder recategorized (DSM-III) asattention-deficit disorder with or with-out hyperactivity. With the DSM-III-R in1987, criteria for diagnosis of the dis-order required the presence of 8 of 14symptoms related to the 3 core symp-tom clusters (inattention, impulsivity,hyperactivity) and onset before theage of 7 years.64 Currently, accordingto DSM-IV-TR criteria, a diagnosis ofADHD is made on the basis of devel-opmentally inappropriate symptomsof inattention and/or hyperactivity-impulsivity. Three ADHD subtypes arerecognized, including inattentive, hy-peractive/impulsive, and a combinedsubtype. For a valid diagnosis of ADHD,there must be evidence of symptomsearly in life (before the age of 7 years),symptoms must be pervasive acrossdifferent settings, they must be persis-tent over time, and they must lead toclinically significant impairment in so-cial, academic, or occupational func-tioning.65 Although not used in isola-tion to diagnose ADHD, rating scaleshave become useful for documentingsymptoms and measuring responsesto treatment. These scales haveevolved along with our understanding

of the disorder and changes in diag-nostic requirements.66 Although therehave been advances in the manage-ment of ADHD since the 1960s, no treat-ment study has had more impact thanthe landmark Multimodal TreatmentStudy of Children With ADHD (MTA).67–70

The MTA has evaluated the relative ef-ficacy of the stimulant medicationmethylphenidate, behavioral treat-ment, and community-based care inthe treatment of ADHD in children,which led the way in establishingmethodologic standards in ADHD re-search. Many of the research stan-dards established in the MTA are re-flected in the model that we describehere.

PROPOSED MODEL RESEARCHMETHODOLOGY

The objective of our model researchmethodology is to identify and addresskey considerations in the design of re-search projects that examine associa-tions between AFCs and ADHD. It is ourhope that results from such projectswill inform food-policy decisions thataffect children with ADHD.

Specifying the Research Question

Our research model is intended to ad-dress specific questions that concernthe relationshipbetweenAFCsandADHD.The primary research question for ourmodel is whether consumption of di-etary AFCs is associated with changes inADHD symptoms and functioning in chil-drenwith ADHD. An important secondaryquestion is whether consumption ofAFCs is associated with the occurrenceof ADHD symptoms in typically develop-ing control subjects.

Study Funding

In any research project, it is importantto ensure freedom from real or per-ceived biases.71 Therefore, all fundingsources must be clearly identified, andassurances that the study design andmethods are appropriate for address-

ing the research question(s) in an un-biased manner must be made.

Experimental Design

A carefully designed and sufficientlypowered randomized controlled trial(RCT) was considered the best meansof investigating the potential effects ofAFCs on ADHD. Our main phase III RCTwill be preceded by a preliminary,small phase II study (Fig 1) designed toestablish proof of concept and exam-ine issues of dosing and timing. We de-termined that before proceeding to alarge, expensive phase III RCT study, itwould be prudent to have at least someevidence of causality in the link be-tween consumption of AFCs and symp-toms of ADHD.

Our phase II study will be conducted in2 stages: stage 1, in a laboratory(classroom) setting, which will allowfor structured assessments; and stage2, in the home setting (free-living).Each phase will last for 1 week. Provid-ing our phase II study establishes atleast limited evidence of causality, itwill be followed by a large-scale, short-term (6-week), phase III, double-blind,randomized, controlled, parallel-groupstudy designed to measure the acuteeffects of AFCs on ADHD symptoms insubjects with ADHD (Fig 2). This studywill also have an extension phase (6months) for assessing maintenance.During this extension, study interven-tions will remain the same, and peri-odic assessments will be made. Forboth the phase II and III studies, we pro-pose using a control group of childrenwithout ADHD to assess the secondaryquestion of whether AFCs are associ-ated with the occurrence of ADHDsymptoms in the general population.

Treatment/Intervention

Although it may be possible to struc-ture a naturalistic intervention inwhich subjects are randomly assignedto receive blinded, specially prepared

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meals that are similar in appearancebut contain either AFCs or natural col-orings as a means of determining theeffects of AFCs on ADHD symptoms, webelieve that considerations of logisticsand cost make this type of interventionunfeasible. Therefore, we propose anintervention in which participants willbe randomly assigned to a range ofdouble-blind treatment arms with AFC-free meals plus opaque capsules thatcontain different concentrations ofAFCs above and below the amountsfound in typical meals. We proposetesting AFC concentrations that rangefrom AFC-free (0%) to twice the normalor typical AFC concentration (200%) toobtain results that represent a widerange of dietary exposures. An average

level of AFCs per meal (breakfast,lunch, dinner, drinks, and snacks) willbe determined on the basis of analysisof a representative sample of meals.

The phase II study is designed to provideproof of concept and to guide treatmentselection and assessment timing for thelarger phase III study. It is also designedto test specific AFCs alone and in combi-nation at different concentrations to de-termine if an effect is associated with anindividual AFC or a combination of them.Participants in the phase II study, sub-jects with ADHD and thosewithout ADHD,will be randomly assigned to 1 of 5groups; groups will receive capsulesthat contain 0%, 50%, 100%, 150%, or200% concentrations of a mixture of

AFCs (Fig 1). If an effect is seen with theAFCmixture at 1 ormore dosage levels,then the study will be repeated, andindividual colorings will be withdrawnin a staged manner to determine if theeffect results from 1 or a combinationof the colorings.

In the larger phase III study, subjectswith ADHD and those without ADHDwill be randomly assigned to thesame 5 treatment arms as in thephase II study (assuming that all 4active doses produce a result, andfewer will be used if no effects areseen at a given dose or doses) to testthe AFC or AFC mixture as deter-mined in the phase II study at concen-trations including 0%, 50%, 100%,

FIGURE 1Phase II, proof-of-concept study to establish a causal link between AFC consumption and change in ADHD score (ADHD subjects) or increase in ADHDsymptoms (control subjects without ADHD) and to determine the dose of AFCs to be tested in the phase III study. Patients will be randomly assigned to 1 of5 groups, each receiving AFC-free meals plus capsules that contain 5 different concentrations of AFCs (0%, 50%, 100%, 150%, 200%), based on concentra-tions of AFCs in typical meals.

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150%, and 200% (Fig 2). AFC capsuleswill be administered with AFC-freemeals at breakfast, lunch, and dinner,and AFC-free snacks and beverageswill also provided.

Study Sample

The selection of subjects for any re-search project depends on the popula-tion to which results will be generalized.Our proposed study will be conducted ina sample of children with ADHD. How-ever, within this general group there aresome important considerations in termsof further defining the study sample. Forinstance, using a school-based popula-tion will result in a sample with lesssevere disease, whereas using apsychiatric-based population will gener-

ally result in a sample with a more se-vere presentation of disease. Anotherconsideration in sample selection iswhether the study should focus on 1 ormore ADHD subtypes. We propose usingADHD combined type only for our samplerather than including all 3 subtypes.Combined type is the ADHD subtype thatis most common in clinical practice andhas been studied most widely.63 It is as-sociated with the greatest clinical im-pairment.63 Also, previous studies haveprimarily linked AFCs with hyperactivity,not inattention,* and there is some con-troversy in the ADHD field as towhether ADHD inattentive type is actu-ally a separate disorder involving dif-

ferent brain structures than those in-volved in ADHD combined type.63

Inclusion of subjectswith other comor-bid psychiatric diagnoses in additionto ADHD, including other externalizing(eg, conduct disorder, oppositional de-fiant disorder) and internalizing (eg,anxiety disorders, depression) disor-ders will allow us to determine if AFCeffects are specific to ADHD.

Age is a critical variable in the selectionof our study sample. Because inclusionof preschool-aged children poses cer-tain challenges (ie, difficulty in establish-ing accurate diagnosis63), we proposeusing a school-based sample that con-sists of boys and girls aged 6 to 12 years.Inclusion criteria are based on current*Refs 24, 27, 28, 42, 44, 46, 51, 56, and 59.

FIGURE 2Phase III randomized controlled trial to evaluate the acute effect of consumption of different concentrations of AFCs on ADHD symptom scores in subjectswith ADHD and a control group of subjects without ADHD. Patients are randomly assigned to 1 of 5 groups, each receiving AFC-free meals plus capsulescontaining 5 different concentrations of AFCs (0%, 50%, 100%, 150%, 200%), based on concentrations of AFCs in typical meals. a Sample size is based on 1effective dose found from phase II.

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diagnostic criteria for ADHD. Partici-pants must meet dimensional criteriafor ADHD based on parent and teacherrating scale scores that exceed specifiedcriteria (eg, beyond the 93rd percentilefor child’s age and gender) and full re-search diagnostic criteria for ADHD,combined type, on the basis of a struc-tured diagnostic interview with the par-ent(s). Exclusion criteria are currenthospitalization, participation in anothertreatment study, having no telephone,low IQ (�80), major neurologic or medi-cal illness, or ongoing or previously un-disclosed child abuse. For study entry,we propose using a multiple gating pro-cedure (4 phases) similar to that used inthe MTA study (Table 1).72

The use of a control group of childrenwithout ADHD will allow our study to ad-dress the question of whether AFC con-tributes to ADHD symptoms among typi-cally developing subjects. This controlgroup will be subject to the same inter-vention and assessment plan as sub-jects with ADHD in the primary study.Control-group participants will not meetcriteria for any DSM-IV-TR diagnosis onthe basis of parent interview and will bematchedbyageandgenderwith thepar-ticipants with ADHD.

Measurements

Becausemost existing controlled stud-ies of AFCs and ADHD were conductedin the 1970s and 1980s, outcomes arenot consistent with the current stan-dards required of research on ADHD.24

To ensure valid results, any study thatinvestigates the link between AFCs andADHD must adopt a measurementstrategy that incorporates psychomet-rically sound outcome measures thatfocus on symptom change as well asfunctional impairment.72,73 Outcomeassessment must encompass multiplefunctional domains (school, peer rela-tionships, family functioning), andchanges in ADHD symptoms must be as-sociated with concomitant changes infunctional impairments.73 In addition,there must be measures in multiple set-tings from multiple informants that usedifferent methodologies (ratings, directtests, observations, measures of aca-demic and social functioning).72,73

Study measures for our proposedstudies are listed in Table 2. Full as-sessments for the phase III study, bothfor subjects with ADHD and controlsubjects without ADHD, will be made atscreening, at baseline, and at the closeof the study, and selected assess-ments will be made at specific timepoints during the study. The timing ofthese assessments will depend on tim-ing of response as determined duringthe preliminary phase II study. In thelaboratory stage (stage 1), assess-ments will be made at baseline anddaily. During stage 2 (free-living), as-sessments will be made daily.

In addition to direct measurements ofthe effect of the proposed intervention,we will also assess potential modera-tors and mediators of outcomes,which include adherence/complianceto treatment/intervention, food intakeapart from the intervention (assessedby using food diaries), consumersatisfaction with the intervention,comorbidity of disorder, parental

psychopathology, and demographiccharacteristics. Steps should betaken to ensure consistency of as-sessments, including central prepa-ration of assessment and data formsand consistency in training acrossstudy sites and personnel.

Sample-Size Issues

Instead of adopting an effect size of 0.4,such as in the MTA study, we proposeusing a lower effect threshold of 0.28for our primary outcome (change inADHD symptoms) and as the basis forpower calculations for our phase IIIstudy. This threshold is based on thefindings at a recentmeta-analysis of 15trials from which a positive associa-tion between AFCs and increasedsymptoms of ADHD was reported (ef-fect size: 0.28 [95% confidence interval:0.079–0.488]).24 In the most recentSouthampton study, McCann et al27

(2007) found similarly modest effectsizes among a general population ofchildren. Smaller effect sizes arealso appropriate when seen in thecontext of exposures that may havesignificant public health conse-quences. Although larger effect sizesmay be appropriate for trials of med-ications, such as is the case with theMTA, more modest effects may beseen as critical when investigatingwidespread exposures such as foodadditives or colorings.

For our phase II study, our design objec-tive is to detect a clinically importantchange in subjects (�30%) in parent-and teacher-rated symptoms and behav-iors/attention observed in a structuredsetting. To achieve this goal, we will re-cruit 200 participants: 100 subjects withADHD and 100 control subjects withoutADHD, which will provide 20 subjectswith ADHD and 20 control subjects foreach of the 5 AFC treatment groups (0%,50%, 100%, 150%, 200%). The thresholdof response for a dose in proceeding tothephase III study is somewhat arbitrary

TABLE 1 Study Entry: Multiple GatingProcedure (4-Phase)

Phase Procedure

A Telephone intake: initial inclusion andexclusion criteria

B Mailed rating scalesParent, teacher: Conners’ RatingScales; ADHD Rating Scale-IV

C In-person assessmentParent: Diagnostic InterviewSchedule for Children; ColumbiaImpairment ScaleChild: mental status examination,Wechsler Intelligence Scale forChildren-III, physical examinationChild: mental status examination,Wechsler Intelligence Scale forChildren-III, physical examination

D Full baseline assessment

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but should be chosen in advance. If weaccept that the threshold for proceedingto thephase III studyshouldbeamajority(�50%) with a clinically significant re-sponse, then a response in �14 of 20subjects would occur by chance only5.8%of the time if the true rate of impactis 50%. Thus, we choose as our decisionrule for proceeding to the phase III study�14 of 20 subjects with a�30% changeon the symptom scale as a level suffi-cient to show that this is more thanmight be expected by pure chance be-cause of measurement error. If onejudged that a response in 12 of 20 sub-jects was sufficient for moving forwardrather than �14 of 20, then either thesample size would need to increase orwe would need to accept a lower limit ofthe threshold for what proportion re-sponses would warrant continuing tothe phase III study. For example, if onewere willing to proceed to the phase IIIstudy if only 10 of 20 subjects responded,then the threshold value for this decisionwouldbe�35%ofsubjectsexperiencinga significant (�30%) change in symp-toms. That is, when 10 of 20 subjects re-spond, the probability of it happening bychance is only .053 when the true re-sponse rate is 35%; thus, the responserate is more likely to be higher than35%, a value sufficient to warrant alarge and expensive phase III study.This within-dose selection rule wouldbe used to determine if any effectivedose should be tested further. If �2

doses are chosen, then those levelswould be used in a subsequent de-sign bolstered by more analyses onthe basis of the continuous re-sponses of changes in the symptomscale, analyzed by using regressionand analysis-of-variance techniques(discussed below) and multiple com-parisons against a control as well asdose-response analyses.

For the phase III study, the primary ob-jective is to detect a clinically impor-tant change in ADHD symptoms on thebasis of a minimal effect size of 0.28 insubjects with ADHD. The secondary ob-jective is to detect a change in behav-iors in control subjects without ADHDwith the same minimal effect size. Asample size of 270 subjects in eachgroup at the time of analysis will have90% power to detect an effect size of0.28 using a 2-group t test with a type Ierror of .05 (2-sided). This sample sizedoes not account for dropouts andcrossovers or the possibility of morethan 1 effective dose found from phaseII. Assuming a dropout rate of 10% anda crossover or noncompliance rate of10%, 420 subjects per group, for boththe ADHD and control groups, wouldneed to be randomly assigned. If �2groups are used, adjustments wouldbemade formultiple comparisons andthe expected differences among the in-dividual groups, estimated from thephase II results.

Data Analysis

Existing ADHD treatment studies suchas the MTA investigation provide amodel for data analysis.69 The objectiveis to predict outcomes on the basis ofmeasurement of continuous variables.Analysis of combined metrics shouldbe avoided. For our phase III study,data analysis will be conducted on theintent-to-treat population. The mainanalytic approach will be mixed-effects repeated-measures regressionmodeling, a method that allows for in-clusion of subjects with incompletedata across time and accounts forwithin-subject correlations betweenrepeated observations. Analysesshould report effects separately foreach measure and setting withappropriate statistical controls forexperiment-wise type I error. Our pri-mary intent-to-treat analysis will fo-cus on change in ADHD symptoms asdetermined by outcome measuresacross multiple domains (Table 2).We use multiple outcome variablesrather than a single outcome in antic-ipation of our intervention having a dif-ferential impact across various areasof functioning. Regression modelingwill allow us to adjust for multiple co-variates in determining the effect of in-dividual variables. Outcomes will beassessed at baseline and during andafter the active intervention period.

Publishing and Related Issues

Trial registration is an importantmeans of achieving full transparencyand public confidence and should berequired of any study that investigatesnutritional exposures and ADHD.74 Reg-istration also provides a mechanismfor addressing publication bias.75

DISCUSSION AND CONCLUSIONS

The model research methodology wehave proposed here is an attempt tooutline the essential features of astudy that investigates the role of AFCs

TABLE 2 Phase II and III Study Measures

Domain/Type Measure

School/academic WIATPeer social SSISBroadband measures of psychopathologyExternalizing symptomatology Classroom observations, Conners’ Rating Scales, Child

Behavior Checklist, ADHD Rating Scale-IVInternalizing symptomatology MASC, Child Depression Inventory, Conners’ Rating

Scales, Child Behavior ChecklistFamily functioning Parent-Child Relationship QuestionnaireCognitive/attentional Continuous Performance Test, Posner Visual OrientingImpairment Impairment Rating ScaleDirect observation of functioning Videotaped classroom task engagement

WIAT indicatesWechsler Individual Achievement Test; SSIS, Social Skills Information System;MASC, Multidimensional AnxietyScale for Children.

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in contributing to symptoms of ADHD.ADHD has a high prevalence76,77 and isassociated with a variety of negativeoutcomes if not managed effectively.78–81

Therefore, making available effectivemanagement strategies, includingelimination of harmful nutritional ex-posures as evidence warrants, is a na-tional public health priority.

Food-policy decisions that affect childhealth should be based on the bestpossible scientific evidence. Examplesaboundof instances inwhich policy deci-sions in a given area that lacked a solidevidential foundationhavebeen followedby unintended negative consequences.In the 1970s, industries in the easternUnited States adopted the use of tallsmokestacks to better disperse factoryemissions. The unintended consequencewas the transport of sulfur pollutionhigher in the airshed, where it mixedwithwater vapor andwas dispersed to awider geographic area, which resultedin acid-rain destruction in northeasternand Canadian forests.82 In the area of nu-trition, dietary recommendations in the1970s and 1980s emphasizing the impor-tance of lowering dietary fat intake re-sulted in the introduction of numerousfat-free and low-fat food products, manyof which contained high amounts ofsugar and refined carbohydrates.83,84 Al-though the low-fat campaign decreased

dietary fat intake in the United States,during the same period there was an in-crease in the prevalence of diabetes andobesity. It is now increasingly recognizedby experts in nutrition that there was lit-tle scientific evidence supporting thelow-fat campaign and that it may haveled to unintended negative healthconsequences.85

In developing our model research meth-odology, we have drawn from currentstandards in ADHD researchandhave in-cluded what we view to be essential de-sign features. It is our hope that thismodel methodology may inform the de-sign of future studies of the effects ofAFCs on children with ADHD and enablepolicy-makers to formulate effective,evidence-based food-policy decisions.

ACKNOWLEDGMENTSThis article was prepared at a meetingconvened by the University of Massa-chusetts (UMass) Amherst Food Sci-ence Strategic Policy Alliance on April1–3, 2009, to address the issue of thecurrent state of research in food policyand ADHD and was supported by theUMass Amherst Food Science Strate-gic Policy Alliance and its members, in-cluding the Massachusetts Depart-ment of Agricultural Resources(grant) and UMass Amherst. The meet-ing gathered thought leaders in the ar-eas of food science and policy and clin-

ical psychology with emphasis on thedesign and conduct of clinical trialsthat assess the effects of pharmaco-therapeutic and behavioral interven-tions for ADHD, pediatric nutrition withemphasis on assessing the bioavail-ability and metabolism of nutritionalexposures, and biostatistics and thedesign and conduct of clinical trialsand research projects. Participantswere selected on the basis of large-scale screening and in-depth personalinterviews. Moderators were selectedto facilitate discussion, and a writerwith expertise in medical publicationswas chosen to work with panel mem-bers to develop a consensus reportbased on expert panel recommenda-tions. The UMass Amherst Food Sci-ence Strategic Policy Alliance is a pol-icy program based at UMass Amherstwith members from industry, govern-ment (including the US Food and DrugAdministration and US Department ofAgriculture), and university facultyand students. The opinions and posi-tions taken in this consensus reportare scientifically based and not influ-enced by the UMass Amherst Food Sci-ence Strategic Policy Alliance or itsmembers. Editorial assistance for thisproject was provided by BioScienceCommunications with financial sup-port from the UMass Amherst Food Sci-ence Strategic Policy Alliance.

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consulted for Elanco, Mead Johnson, and Cantox; Dr Brown has served on a scientific advisory board for Shire Pharmaceuticals and has received grant supportfrom Eli Lilly; Dr Cutter has served on data and safety monitoring committees for AntiSense Pharmaceuticals, Sanofi-Aventis, Bayhill Pharmaceuticals Inc, BayerPharmaceuticals, BioMS Pharmaceuticals, Daichi-Sankyo Pharmaceuticals, Enzo Pharmaceuticals, Esai Pharmaceuticals, GlaxoSmithKline Pharmaceuticals,Genentech Pharmaceuticals, Genmab Biopharmaceuticals, Incyte Pharmaceuticals, Medivation Pharmaceuticals, Millennium Pharmaceuticals, NovartisPharmaceuticals, Peptimmune Pharmaceuticals, PTC Therapeutics, Teva Pharmaceuticals, Vivus Pharmaceuticals, the National Heart, Lung, and BloodInstitute, the National Institute of Neurological Disorders and Stroke, and the [National Multiple Sclerosis Society] NMSS and has served as a consultantto Alexion Pharmaceuticals, Accentia Pharmaceuticals, Bayer Pharmaceuticals, Barofold Pharmaceuticals, Biogen Idec Pharmaceuticals, CibaVision,Millenium Pharmaceuticals, Consortium of MS Centers, an MS-CORE- and NMSS-funded research group, Novartis Pharmaceuticals, Klein-BuendelIncorporated, and Somnus Pharmaceuticals; Dr DuPaul receives research grant support from Shire Pharmaceuticals; and Dr Clydesdale has served onthe scientific advisory boards of General Mills, Mars Snackfood US, McCain Foods, Tate and Lyle, ConAgra, Unilever, and the Coca-Cola Company, hasconsulted with Cantox, and serves on the board of directors of Sensient Technologies, Inc (a manufacturer of both artificial and natural food colorings).

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