Setting a public health research agenda for Down syndrome: Summary of a meeting sponsored by the Centers for Disease Control and Prevention and the National Down Syndrome Society

Published 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:2998–3010 (2008){This article is a US Government work and, as such, is inthe public domain in the United States of America.

Conference Report

Setting a Public Health Research Agenda forDown Syndrome: Summary of a Meeting Sponsored by the

Centers for Disease Control and Prevention and theNational Down Syndrome Society

Sonja A. Rasmussen,1* Nedra Whitehead,2 Sarah A. Collier,1,3 and Jaime L. Frı́as1,4

1National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia2RTI International, Atlanta, Georgia

3Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee4McKing Consulting Corporation, Atlanta, Georgia

Received 24 September 2008; Accepted 3 October 2008

On November 8–9, 2007, a meeting entitled ‘‘Setting a PublicHealth Research Agenda for Down Syndrome’’ was heldto review current knowledge, identify gaps, and developpriorities for future public health research related to Downsyndrome. Participants included experts in clinical andmolecular genetics, pediatrics, cardiology, psychiatry, psy-chology, neuroscience, epidemiology, and public health.Participants were asked to identify key public healthresearch questions and discuss potential strategies that couldbe used to address those questions. The following wereidentified as priority areas for future public health research:identification of risk and preventive factors for physicalhealth and cognitive outcomes, focusing on understandingthe reasons for previously recognized disparities; improvedunderstanding of comorbid conditions, including theirprevalence, clinical variability, natural history, and optimalmethods for their evaluation and treatment; better character-ization of the natural history of cognition, language, andbehavior; identification of mental health comorbidities and

of risk and protective factors for their development;identification of strategies to improve enrollment in researchstudies; development of strategies for conveying up-to-dateinformation to parents and health professionals; identifica-tion of interventions to improve cognition, language, mentalhealth, and behavior; understanding the impact of educa-tional and social services and supports; identification ofimproved methods for diagnosis of and interventions forAlzheimer disease; and understanding the effects of differenttypes of health care on outcomes. Participants stronglysupported the development of population-based resourcesfor research studies and resources useful for longitudinalstudies. This agenda will be used to guide future publichealth research on Down syndrome.Published 2008 Wiley-Liss, Inc.{

Key words: Down syndrome; public health; researchagenda; population-based; comorbidities

How to cite this article: Rasmussen SA, Whitehead N, Collier SA, Frı́as JL. 2008. Setting a public health researchagenda for Down syndrome: Summary of a meeting sponsored by the Centers for Disease Control and

Prevention and the National Down Syndrome Society. Am J Med Genet Part A 146A:2998–3010.

INTRODUCTION

On November 8-9, 2007, the National Center onBirth Defects and Developmental Disabilities at theCenters for Disease Control and Prevention (CDC)and the National Down Syndrome Society sponsoreda meeting entitled ‘‘Setting a Public Health ResearchAgenda for Down Syndrome’’ to identify prioritiesfor public health research on Down syndrome(DS). Sixty-seven experts in the areas of clinical andmolecular genetics, pediatrics, cardiology, psychiatry,

psychology, neuroscience, education, epidemio-logy, and public health among others, participatedin the meeting. The meeting commenced with a

The findings and conclusions in this report are those of the authors anddo not necessarily represent the official position of the Centers forDisease Control and Prevention.

*Correspondence to: Sonja A. Rasmussen, M.D., M.S., 1600 CliftonRoad, MS E-86, Atlanta, GA 30333. E-mail: [email protected]

Published online 11 November 2008 in Wiley InterScience(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.32581

discussion of what constitutes public health researchled by Dr. Coleen Boyle, who emphasized that akey characteristic of public health research is itspopulation-based perspective. Activities in publichealth focus on three key areas: surveillance,epidemiological research, and prevention [Instituteof Medicine Committee on Assuring the Health ofthe Public in the 21st Century, 2002]. Surveillanceactivities promote understanding of the magnitudeof a health problem and how it changes over time,including monitoring the impact of preventionprograms. A major goal of epidemiological researchis to identify risk factors for health problems, with anemphasis on those that are modifiable. Preventionactivities include the development of strategiesto prevent health problems and testing of thosestrategies to evaluate their effectiveness. Develop-ment or enhancement of activities such as these isan important area for future research on DS.

Several experts then summarized the current stateof knowledge in major areas related to DS, includingepidemiology, physical and mental health, cognitiveand linguistic profiles, aging, impact on the family,and current strategies for educating professionals,family members, and the general public. After thesepresentations, meeting participants were dividedinto three workgroups, each focusing on one ofthe following areas: (1) epidemiology and medicalissues, (2) cognitive and mental health issues, and(3) family and education issues. Each workgroupidentified gaps in knowledge and future researchpriorities using public health significance andfeasibility as criteria for setting priorities. Meetingparticipants then reconvened to develop a com-prehensive agenda to guide future public healthresearch related to DS.

CURRENT STATE OF KNOWLEDGE

Dr. Stephanie Sherman reviewed the current stateof knowledge of the epidemiology of DS [Shermanet al., 2007]. Although the characteristics of DS aredue to extra genetic material on chromosome 21,different mechanisms lead to this outcome. Theprimary mechanism for trisomy 21 is nondisjunction,which accounts for 95% of DS, with chromosomaltranslocations and mosaicism responsible for about4% and 1%, respectively. Most (93%) nondisjunc-tional events occur in the egg, and 4% occur in thesperm. Approximately three-fourths of nondisjunc-tional errors in the egg are caused by meiosis I errorsand one-fourth by meiosis II errors. To betterunderstand nondisjunction, studies need to deter-mine the source and timing of the nondisjunctionalerror [Oliver et al., 2008]. Thesedifferentmechanismsmight have distinct risk factors, and thus, should beconsidered separately in epidemiological studies.

Older maternal age is a well-known risk factor forDS, but other risk factors have not been consistently

identified. Changes in the maternal age distributionin the United States, with more women delayingchildbearing [Martin et al., 2007], have resulted in anincreased frequency of nondisjunctional errors in theegg, which are a leading cause of pregnancy loss,developmental disability, and birth defects [Hassoldand Sherman, 2000; Oliver et al., 2008].

DS is one of the most commonly occurringcongenital anomalies in the United States, with aprevalence of 13.7 per 10,000 (1/732) live births, or5,429 births per year [Canfield et al., 2006]. Addition-ally, about 80% of fetuses with DS are lost beforebirth [Hassold and Jacobs, 1984]. The maternal-ageadjusted birth prevalence varies by race-ethnicity,with a lower prevalence reported among infantsborn to black mothers and a higher prevalenceamong infants born to Hispanic mothers, comparedto infants born to non-Hispanic white mothers[Canfield et al., 2006]. The reasons for this racial-ethnic variation are not understood, but couldinclude differences in completeness of ascertain-ment, access to prenatal care, use of prenataldiagnostic services or pregnancy termination, orgenetic factors or environmental exposures.

The prevalence of DS among adults has beenincreasing in recent years as a result of improvedsurvival [Besser et al., 2007]. Theprevalenceby ageofpersons with DS is relatively constant amongchildren born to non-Hispanic white mothers, butdecreasing prevalence in older age groups has beenobserved among children born to black mothers,related to decreased survival [Besser et al., 2007].Reasons for the decreased survival among infantswith DS born to black mothers are unknown[Rasmussen et al., 2006].

Estimates of the prevalence of associated defectspresent at birth are available. For example, about44% of all infants with DS have a cardiac defect[Freeman et al., 2008]. Some risk factors for thesedefects are known (e.g., race-ethnicity) [Freemanet al., 2008], but others are yet to be identified.The genetic mechanisms involved with some DS-associated disorders (e.g., transient leukemia) arebeginning to be elucidated [Vyas and Crispino, 2007],but more information is needed.

Key research gaps in this area identified byDr. Sherman included a need for understandingthe underlying cause of the association betweenadvanced maternal age and nondisjunction, as wellas understanding the risk factors (genetic andenvironmental) for different mechanisms that causetrisomy 21. Identification of risk factors associatedwith morbidity and mortality among persons with DSand a better understanding of the reasons for thedisparities in survival by race-ethnicity are needed.Improved understanding of the effects of associatedbirth defects (e.g., congenital heart defects) oncognition and behavior is also an important area. Abetter understanding of the frequency of later-onset

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disorders and risk factors for their occurrence isneeded. Development of strategies to minimize theadverse effects of birth defects and health conditionsassociated with DS is another important area forfuture research.

A presentation on the current knowledge of issuesrelated to physical health and wellness amongpeople with DS was provided by Dr. Nancy Roizen.The goal of research in this area is to maximize thehealth and functioning of persons with DS. Althoughsurvival has improved in recent years, the mortalityrate among persons with DS remains more thanfive times that of the general population [Day et al.,2005]. In addition, persons with DS are at increasedrisk for many health conditions. Thus, new signsor symptoms in a person with DS need carefulevaluation to determine the underlying healthcondition, rather than attributing the findings asbeing secondary to DS, so that a timely diagnosis canbe made and appropriate treatment can be instituted.

The approach to medical care of persons with DScan be organized into three main areas: (1) evalua-tion for certain frequent conditions; (2) monitoringor increased vigilance for less frequent, but stillcommonly occurring conditions, with the goal ofearly identification and institution of treatment; and(3) prevention of conditions for which modifiablerisk factors have been identified.

Defects of the cardiovascular systemandof hearingand vision are sufficiently frequent that routineevaluation of these systems is recommended [DownSyndrome Medical Interest Group (DSMIG), 1999;American Academy of Pediatrics, 2001]. Whilerecommendations for evaluation of these systemshave been developed, the data on which theserecommendations have been based are often scant.For example, the optimal evaluation for congenitalheart defects, which occur in nearly half of infantswith DS [Freeman et al., 2008], has yet to be deter-mined [Shashi et al., 2002; McElhinney et al., 2003].In addition, once a child is identified with a healthproblem, the data on which to determine optimaltreatment strategies are often not available. Forexample, cross-sectional studies have suggested ahigh prevalence of hearing loss among personswith DS, and thus routine evaluation of hearingis recommended. Although some studies havesuggested that placement of pressure equalizationtubes can improve outcomes, other studies have hadmixed results [Selikowitz, 1993; Iino et al., 1999;Shott, 2006]. Evaluation and appropriate interventionhave been shown to have an impact in somecircumstances. For example, as many as 78%of children with DS have been shown to havevision impairment, and this high frequency has ledto guidelines issued by the DSMIG calling forexamination in the neonatal period by a pediatricophthalmologist, followed by a comprehensiveophthalmologic evaluation (including refraction and

orthoptic examination) before 36 months of age,with preschool follow-up as needed [Stephen et al.,2007]. One study has shown that these guidelineshave led to earlier identification and institution ofappropriate treatment of vision problems [Stephenet al., 2007].

Conditions for which persons with DS are atincreased risk, but which occur less frequently,require regular monitoring or increased vigilance.Such conditions include celiac disease, thyroiddisorders, type 1 diabetes, atlanto-axial instability,otitis media, and obstructive sleep apnea. Moreresearch is needed to identify optimal methods ofmonitoring for these conditions. In addition, pre-vention strategies need to be developed for thoseconditions amenable to prevention. For example,obesity is commonly observed among adults withDS [Rubin et al., 1998], yet little is known regardingeffective prevention strategies.

Key research gaps in this area include the need todetermine the best approaches to evaluation, treat-ment, and prevention of common health problemsobserved among people with DS. Research toidentify the optimal methods for screening for lesscommon conditions is also needed. Certain condi-tions (e.g., cancer, coronary artery disease) appear tooccur less frequently among persons with DS; con-firmation of these findings and understanding of theprotective mechanisms that lead to their decreasedoccurrence can benefit persons with DS and thepopulation at large. Research on the development ofstrategies to prevent conditions, such as obesity, inpersons with DS is needed, as well as evaluation todetermine if these strategies are effective.

Dr. Leonard Abbeduto reviewed the state ofknowledge regarding cognitive and linguistic pro-files of children with DS. Most persons with DS haveIQs between 35 and 65 [Chapman, 2003], but IQscores are only a rough estimate of cognitive andlinguistic impairments. Mean IQ declines as ageincreases [Carr, 2005]. IQ, however, masks the factthat delays vary in degree across different cognitiveand linguistic skills. Thus, behavioral phenotypemaybe a more useful construct than IQ. The behaviorphenotype of a syndrome can be defined as a profileof behaviors or developmental strengths and weak-nesses across functional domains that are exhibitedmore frequently by persons with the syndrome thanthose without it [Dykens and Cassidy, 1995]. Theprofile is dynamic, however, and it is not alwaysunderstood how it changes over time. Problem-solving skills in children and toddlers with DS arerelatively weak, but skills in imitation are relativelystrong [Pueschel et al., 1987; Pitcairn and Wishart,1994; Ruskin et al., 1994; Rast and Meltzoff, 1995;Fidler et al., 2005a; Wright et al., 2006]. Beginningin childhood and continuing into adolescence,areas of relative strength include visual processing,particularly the ability to analyze visual patterns,

3000 RASMUSSEN ET AL.


and implicit long-term memory [Haxby, 1989; Harriset al., 1997; Hodapp et al., 1999; Chapman, 2003].Auditory memory, explicit long-term memory, hip-pocampal function, and reasoning about epistemicstates are areas of relative weakness [Meyers et al.,1961; Rohr and Burr, 1978; Wang and Bellugi, 1994;Zelazo et al., 1996; Carlesimo et al., 1997; Yirmiyaet al., 1998; Seung and Chapman, 2000; Abbedutoet al., 2001; Jarrold et al., 2002; Pennington et al.,2003].

There is a close relationship between cognitive andlanguage development. Hearing loss contributes tolanguage problems, but accounts for relatively littleof the variation between individuals. Toddlers withDS begin canonical (speech-like) babbling onlyslightly later than their typically developing peers.They experience severe impairments in speecharticulation, however, and have high rates ofunintelligible speech. The lack of intelligibilityincreases with more difficult tasks [Kumin, 1994;Chapmanet al., 1998; Barnes et al., 2006]. Vocabularyis relatively strong, but syntax is relatively weak,especially in the expressive modality [Cardoso-Martins et al., 1985; Chapman et al., 1991, 2000,2002; Vicari et al., 2000; Stoel-Gammon, 2001; Eadieet al., 2002; Abbeduto et al., 2003; Miolo et al., 2005;Williams et al., 2005; Miles et al., 2006; Price et al.,2007].

Pragmatic development in children with DS isassociated with delayed onset of intentional com-munication, especially requests, during the prelin-guistic period [Fidler et al., 2005b]. During laterchildhood and adolescence, persons with DS aredelayed in meeting the informational needs oftheir listeners and in becoming ‘‘active’’ listeners[Abbeduto et al., 2006, 2008]. Expressive languagehas been shown to be more severely affected amongpersons with DS than nonverbal cognition orreceptive language [Abbeduto et al., 2001]. Theirrates of certain behaviors, such as perseveration,off-topic/tangential language, and stereotyped lan-guage, are similar to or only slightly higher than thoseof typically developing children at the same level ofcognitive development [Roberts et al., 2007].

Caregivers of childrenwithDS talk to themasmuchas caregivers of children with typical development,and caregivers adjust their language to the child’slevel of competence [Rondal, 1978; Petersen andSherrod, 1982; Maurer and Sherrod, 1987; Tannock,1988; Mahoney et al., 1990]. However, parents ofchildren with DS tend to be more directive and morelikely to focus the discussion on mother-initiatedtopics than parents of typically developing children.Children with DS had greater receptive languagegains when child-initiated topics received moreattention and when mothers less often redirectedattention from child-selected foci [Petersen andSherrod, 1982; Maurer and Sherrod, 1987; Tannock,1988; Mahoney et al., 1990; Harris et al., 1996].

Little is known about the trajectory of cognitive andlanguage development or the mechanisms thatproduce cognitive and linguistic profiles, and moreresearch in these areas is critically needed. Factorsthat moderate cognitive and linguistic developmentand the effects of comorbid conditions on cognitiveand language development need to be better under-stood. More information is needed on how impair-ments in one domain lead to, are affected by, andinteract with impairments in other domains. Data areneeded to understand the relation between impair-ments in language and cognition and later academicoutcomes, quality of life, and development ofAlzheimer disease. The effects of educational pro-grams and treatments on the cognitive and languagephenotype need to be better appreciated. Further,effective interventions and treatments for improvingcognitive and linguistic functioning, including waysin which non-professionals (e.g., parents, siblings,and peers) might be used to deliver these interven-tions, need to be identified. In addition, a betterunderstanding of the ethnic, racial, social, andcultural language differences observed is needed.Virtually all studies of language development to datehave been conducted among white, middle income,well-educated families. Language development maydiffer among children in families with less educationor of different cultural backgrounds. Future researchneeds to include families of all sociodemographicbackgrounds.

Dr. Elisabeth Dykens discussed the current knowl-edge of the mental health and wellness of peoplewithDS.Most peoplewithDSdonot havepsychiatricor behavioral disorders, but some behavior orpsychiatric problems are more common amongpersons with DS than among typically developingchildren or adults. However, behavioral problemsare less common among children with DS (�18–23%) than among those with other intellectualdisabilities (�40%) [Reiss and Freund, 1990; Myersand Pueschel, 1991; Einfeld and Tonge, 1996;Dykens and Kasari, 1997; Dykens, 2001]. Peoplewith DS can also have other developmental dis-abilities, such as autism spectrum disorders orattention deficit hyperactivity disorder [Gath andGumley, 1986; Myers and Pueschel, 1991; Cuskellyand Dadds, 1992; Coe et al., 1999; Kent et al., 1999;Pary and Hurley, 2002]. The only available estimatesof the prevalence of comorbidity are from studiesusing convenience samples rather than well-designed epidemiological studies. Epidemiologicalstudies to examine autism rates in children with DSare currently underway.

The increased risk of Alzheimer disease amongadults with DS is well documented [Zigman andLott, 2007]. The incidence of depression (6–8%) isincreased as well [Dykens, 2007]. The symptoms ofdepression and Alzheimer disease have consider-able overlap. In persons with DS, unlike other



adults, behavioral and personality manifestations ofAlzheimer disease often occur before cognitive ormemory changes. Other conditions such as obsessive-compulsive disorder, obsessional slowing, andatypical psychosis, also occur in adults with DS, butthese conditions have been less well-studied[Capone et al., 2006; Dykens, 2007]. Diagnostic over-shadowing (defined as attributing all symptoms tothe individual’s intellectual disability) [Reiss et al.,1982] is a major barrier to the diagnosis of psychiatricor behavioral disorders in this population.

Four major research gaps in this area wereidentified by Dr. Dykens. First, virtually no informa-tion exists on the development and trajectory ofpsychopathology across the lifespanof a personwithDS. The focus has been on young children and olderadults, but data on adolescents and young adults thatwould connect these developmental periods arelimited. Second, improved measurement of psycho-pathology is needed, including but not limited totraditional DSM psychiatric nosology or maladaptivebehavior checklists. Third, to allow for early identi-fication of persons at high risk and to informtreatment, risk and protective factors for thesecomorbidities need to be identified. Finally, the effi-cacy of treatments to reduce symptoms and nurturepositive states among persons with DS is unknown.While evidence-based best practices exist for psychi-atric care in general, these interventions have yet tobe systematically studied in persons with DS.

Dr. Marsha Mailick Seltzer provided an overviewof the effects of having a child with DS on families.The experience of families of children with DS canvary dramatically, even when children have similarphenotypes. The goal of research on the effects onfamilies is to identifyways to optimize theexperiencefor families. Families of children with DS report lessparenting stress and better relationships with siblingsthan families of children with other developmentaldisabilities, and this pattern extends well into adult-hood [Kasari and Sigman, 1997; Seltzer and Krauss,2001; Hodapp et al., 2003; Greenberg et al., 2004;Hodapp and Urbano, 2007; Orsmond and Seltzer,2007]. This advantage may be due to the behavioralphenotype of DS or to social and demographicfactors, such as older maternal age or the fact that thefamily usually has only one child with a disability.However, families of children with DS experiencemore stress than those of typically developingchildren [Rodrigue et al., 1992; Scott et al., 1997;Roach et al., 1999]. Significant difficulties areobserved in 25–35% of families with a child withDS [Cunningham, 1996]. Factors that predict whichfamilies of children with DS experience distress needto be identified.

Four demographic factors affect the quality of lifefor persons with DS and their families: maternal ageat the child’s birth, life expectancy of the person withDS, individual’s residential status across his or her

life, and number of siblings in the family. Maternalage at the child’s birth has both positive and negativeeffects: oldermothers often copebetter than youngermotherswith the challenges of having a childwithDS[Ha et al., 2008], but older maternal age may alsoresult in the child being younger when the motherdies. Because of the increasing life expectancy forpeople with DS [Bittles and Glasson, 2004], adultswith DS are now more likely to experience movingfrom their parents’ home to a community placement,the death of a parent, and/or a sibling taking overas caregiver, than in previous generations. Most(�60%) persons with DS live with their parents wellinto adulthood [Fujiura, 1998]. Adults with devel-opmental disabilities who move out of their parents’home increase their functional abilities, but alsohave a transient increase in behavioral problems[Esbensen et al., 2008]. Behavioral problems alsoincrease after a parent’s death, and this increasepersists throughout the length of follow-up.

Areas that need further investigation includefactors that predict which families of children withDS will experience distress, factors that influence thequality of sibling relationships in adulthood and thelikelihood that a sibling will take on the caregivingresponsibility for their brother or sister with DS, andthe bi-directional effects between family well-beingand the characteristics and development of a childwith DS. Given the longer life expectancy for peoplewith DS, research with a focus on later life (using alongitudinal approach when possible) is needed.More research on the effects on family members,including effects on parental health and well-being,is needed, as well as a better understanding of theexperience of family members other than mothers.

Dr. Wayne Silverman discussed the current knowl-edge related to adulthood and aging in persons withDS. DS is associated with premature aging, includingchanges in the skin, graying or loss of hair, earlymenopause, increased frequency of senile cataractsandhearing loss, increasedhypothyroidismand seiz-ures, a greatly increased risk of Alzheimer disease,and substantially reduced life expectancy [Lott,1982]. On the other hand, persons with DS appearto have a reduced risk of solid tumors [Hasle et al.,2000; Yang et al., 2002] and possibly of cardio-vascular and cerebrovascular disease [Murdochet al. 1977; Lott and Head, 2005; Goi et al., 2006],compared to the general population. The course ofDS throughout adulthood, including the age-specificprevalence, risk factors for key morbidities, andresources necessary to maintain quality of life, needto be better understood.

Amyloid deposition in the brain is believed to beinvolved in the pathogenesis of Alzheimer diseasein the general population by triggering a complexpathological cascade that leads to the broad spec-trum of neuropathological changes [Lott et al.,2006]. The amyloid precursor gene is located on



chromosome 21, and virtually all people with DShave neuropathological changes consistent with adiagnosis of Alzheimer disease, including extensivedeposition of amyloid b, by the time they are35–40 years of age [Schupf and Sergievsky, 2002].Not all individuals develop dementia, however.The mechanisms that cause neuropathology toprecede dementia in DS or that make some personsmore vulnerable than others are not known.

Key gaps identified by Dr. Silverman includeunderstanding the impact of aging, including theage-specific prevalence and risk factors for relevantconditions, possible birth cohort effects, and sup-ports necessary to maintain quality of life. Thegenetic and nongenetic factors that contribute toindividual differences in aging need to be under-stood. Specific criteria for the diagnosis of Alzheimerdisease among populations with pre-existing cogni-tive impairments need to be developed, anddiagnostic tools will need to include assessment ofboth functional and cognitive impairments [Silver-man et al., 2004]. Differential diagnosis can beparticularly difficult, and guidelines for distinguish-ing Alzheimer disease from other conditions, espe-cially those that are easily treated, are needed. Betterinformation is needed on why dementia developswell after substantial neuropathology is presentand on what factors are related to developmentof dementia among persons with DS. Identificationof factors that influence the age of onset and rate ofprogression of dementia could lead to successfulinterventions. Pharmaceutical interventions fordementia tested in the general population may differin efficacy among persons with DS who havedementia; therefore, well-controlled clinical trials ofpromising pharmaceuticals are also needed.

Dr. Harold Kleinert discussed education of healthcare providers, families, and the community aboutDS. He noted the need to ensure that health careproviders, families, and the public are aware ofcurrent knowledge about DS, and highlightedspecific knowledge gaps about how to communicateinformation in the context of prenatal screening anddiagnostic testing. Information is needed on howprofessionals, families and the community view DS,and on how those views affect patient care, parentalreaction to a diagnosis of DS, and treatment ofpersons with DS at school and in the community.Effective strategies are needed to ensure that healthcare providers and families understand the needfor timely referral for early intervention [Fidler andNadel, 2007], and that the positive impact of having achild with an intellectual disability such as DS can beas great as that of having a child without disabilities[Blacher and Baker, 2007].

Family stability, structure and support mechanismsand life transitions need continued research. A recentstudy found that divorce rates were lower amongparents of children with DS (7.6%) than among

parents of children without disabilities (10.8%)[Urbano and Hodapp, 2007]. Information and sup-port are critical to parental adjustment; Taanila [2002]found that parents who reported receiving littleinformation and practical advice about raising theirchild on initial disclosure of a diagnosis reportedfeelings of insecurity and helplessness five times asoften as those parents who felt they had receivedadequate information and support [Taanila, 2002].Effective strategies are needed to communicatebalanced, accurate information to parents abouthealth concerns and challenges in raising a child withDS, instead of the ‘‘worst-case scenario’’ that is oftenpresented [Hedov et al., 2002]. Three promisingstrategies for educating members of the broadercommunity about DS are high school peer buddies[Hughes et al., 2001], interactions at work and inother social roles [Bryant et al., 2006; Lindh et al.,2007], and training for school teachers that combinesclassroom instruction with structured fieldwork[Campbell et al., 2003].

What health professionals know and can explainabout prenatal and postnatal testing for DS and theavailable options at each point of testing need furtherstudy. Health professional education may be neededto ensure that couples are adequately informed[Sharma et al., 2007] and to assist providers inunderstanding families’ decision-making concernsregarding these tests [Zindler, 2005]. Theneed for thisinformationwill increase substantially in the future asnew technologies for prenatal screening and diag-nosis of DS, such as testing of maternal blood forfetal nucleic acids [Saller and Canick, 2008], becomeavailable. In addition, as access to such testingbecomes more broadly available, the education ofother health care professionals beyond pediatriciansandobstetricianswill benecessary. In a recent surveyof obstetricians and gynecologists, almost half (45%)felt their training regarding prenatal diagnosis ofDS was barely adequate or nonexistent [Cleary-Goldman et al., 2006]. Evidence-based strategies areneeded to educate couples about the meaning andlimits of screening tests and to convey that this testingmay not be for everyone [Kuppermann et al., 2006].Providers need to use language couples can under-stand, stress that testing is voluntary, and acknowl-edge that they may approach decision-making froma different perspective than the couples they counsel[Hunt et al., 2005].

Vehicles to provide knowledge aboutDS to currentpractitioners and those in training are needed. Acomponent that provides experience interactingwith persons with DS in addition to a didacticcomponent may be beneficial. Interactive virtualcase scenarios developed with the input of personswith developmental disabilities and their familymembers can also be useful. Use of virtual patientswith DS has increased the knowledge and comfortlevel of student dentists, physician assistants, and



nurse practitioners [Kleinert et al., 2007a,b; Sanderset al., 2008]. An interactive tool for resident physi-cians that allowed them to view and respond tovirtual patient-doctor sessions regarding a newdiagnosis of DS resulted in increased knowledge ofand comfort in responding to questions about DS[Ferguson et al., 2006].

Dr. Ira Lott discussed the progress made and thechallenges encountered by the Down SyndromeResearch Coalition in setting a research agenda [Lottet al., 2007]. These challenges include the complexnature of DS research, the fact that there is no publichealth DS ‘‘crisis’’ to motivate people, and thatcurrent research is often isolated by field. Progresstowards a common research agenda has beenmade, however, including recent NIH programannouncements on synaptic functioning and cogni-tive functioning and the recent special volume ofMental Retardation and Developmental DisabilitiesResearch Reviews [Lott et al., 2007]. The process ofsetting an agenda must be transparent and includestakeholder review.

Dr. Mary Lou Oster-Granite presented the NationalInstitutes of Health draft research plan for DS. Theplan sets short, medium and long-term researchobjectives for five research areas: pathophysiologyand disease progression; diagnosis, screening, andfunctional measures; treatment and management;living with DS; and building research infrastructure.The plan is available at http://www.nichd.nih.gov/publications/pubs/upload/NIH_Downsyndrome_plan.pdf.

PRIORITIES FOR FUTURE PUBLICHEALTH RESEARCH

Workshop participants in the three breakoutgroups identified a total of 20 priority topics forfurther research. After they were presented to thegeneral group, these topics were combined andprioritized by non-CDC participants to create a finallist. The topics are listed below in order of prioritybeginning with the research area that received themost support from participants. Several of the itemsoverlap others, reinforcing the gaps in research. Thegroup also recognized as a critical need, develop-ment of infrastructure that will facilitate population-based and longitudinal approaches to study personswith DS and their families and encourage broaderparticipation in clinical research.

Identification of Risk and Preventive Factorsfor Physical Health and Cognitive Outcomes,Focusing on Understanding the Reasons for

Previously Recognized Racial-Ethnic Disparities

More information is needed on risk factors forphysical health and cognitive outcomes associatedwith DS throughout the lifespan. These outcomes

include mortality, comorbid health conditions, andcognitive, linguistic and mental health outcomes.High priority was given to this area because researchstudies have identified racial-ethnic disparities insurvival and in prevalence of DS-associated morbid-ities, but the reasons for these disparities areunknown. More research is needed to understandhow underlying disease mechanisms and differentialaccess to services relate to disparities in outcomes.The priority areas for physical health research arethose that contribute significantly to individual orpublic health burden or for which disparities havebeen shown to exist. These include, but are notlimited to cardiovascular disease, including congen-ital heart defects and pulmonary hypertension;immune dysfunction, such as recurrent infectionsand autoimmune disease; obesity, nutrition, andmetabolism; sleep dysfunction and apnea; compli-cations from Alzheimer disease; and malignancy.Identification of environmental exposures andbiomarkers that might identify increased risks forcomorbidities is needed. The goal of this research isto identify risk and protective factors for comorbidconditions that would be amenable to the develop-ment of prevention strategies. The importance ofpopulation-based ascertainment of persons with DSand of the development of research databases andregistries to facilitate research in this area wasemphasized.

Improved Understanding of ComorbidConditions, Including their Prevalence,Clinical Variability, and Natural History,

and Optimal Methods for TheirEvaluation and Treatment

The prevalence, clinical variability, and naturalhistory of comorbid conditions need to be betterdescribed. In addition, studies that could lead toevidence-based methods for screening, diagnosis,and management of comorbid conditions are neces-sary. Such research is particularly needed forconditions for which the prevalence relative to thegeneral population and appropriate treatment rec-ommendations are unclear. For example, manyquestions remain about screening for, diagnosing,and managing thyroid disease in persons with DS.The goal of this research is to ensure that once acomorbid condition occurs, a timely diagnosis ismade and appropriate treatment is instituted.

Better Characterization of Natural History ofCognition, Language, and Behavior

A better understanding of the natural history ofDS is needed, particularly related to factors that affectthe range of phenotypes with respect to language,cognition, and behavior. Development of a com-mon, age-specific protocol for measuring outcomes



in the functional domains of cognition, language,and behavior would facilitate research in this area.

Identification of Mental Health Comorbiditiesand of Risk and Protective Factors for

Their Development

The mental health conditions and problem behav-iors that occur over the lifespan of persons with DSneed to be identified. More information is needed onmedical and other risk and protective factors thatinfluence the risk of mental health conditions in DS.Further, how these factors differ relative to the risk ofmental health conditions in persons without intel-lectual disabilities or with intellectual disabilitiescaused by conditions other than DS needs to beunderstood. One area of particular concern is theprevalence of mental health problems, such asdepression and anxiety, among young adults withDS and how these conditions affect the transitioninto adulthood and planning for the future. Theimpact of these conditions on quality of life needsfurther research. The effect of autonomy and self-determination on mental well-being and mentalhealth outcomes for persons with DS needs to beelucidated.

Identification of Effective Strategies to ImproveEnrollment in Research Studies

Effective strategies to encourage persons with DSand their families to enroll in registries and clinicalresearch studies, including brain and tissue banks,and to minimize barriers to participation need tobe identified. One challenge for studies is ensuringthat enrollment is population-based so the entirespectrum of persons with DS is represented,allowing results to be generalized. As part of thiseffort, development of a standardized dataset ofinformation to be collected as part of DS registriesis needed.

Development of Improved Strategies forConveying Up-To-Date Information to

Parents and Health Professionals

Research is needed to identify the most effectivestrategies for providing prospective and currentparents with up-to-date information about DS andthe best practices to enhance their child’s develop-ment. More information is also needed on effectivestrategies for educating medical and allied healthprofessionals on the latest information about DS andthe best practices for conveying this information.Such information needs to be targeted for eachprofessional audience and appropriate educationalmaterials need to be developed and evaluated.Importantly, information for both parents and healthprofessionals needs to be culturally sensitive.

Identification of Effective Interventions toImprove Cognition, Language, Mental Health,

and Behavioral Outcomes

Interventions to be implemented at appropriatepoints throughout the lifespan need to be identifiedto improve cognition, language, mental health,behavior, and academic outcomes. Evidence-basedcurrent best practices and new interventions need tobe identified, and strategies need to be developed topromote, disseminate, implement, and sustain theseinterventions in communities, to ensure that profes-sionals working with children and adults with DS areaware of these interventions. Participants stressedthe need for research on improving the well-being ofadults with DS. Existing data sources may provideinformation on the effects of interventions, but thelack of standardized data collection methods mayreduce the usefulness of existing data.

Understanding the Effects of Educational andSocial Services and Supports

More research is needed on the educationalservices provided to children with DS, the extentto which they experience inclusion in the schoolcommunity and classrooms, and the effects of theseservices and inclusions on their physical andpsychological health. Similarly, the effects of com-munity inclusion and community-based socialservices and the effect of the transition betweenschool-based and community-based services on thewell-being of persons with DS need further study.More information is also needed on the effect ofservices and supports, such as health insurance,day care, education, and developmental services,on the quality of life (e.g., well-being, functioning,and finances) of families and persons with DS. Theeffects of school and community-based interactionsbetween persons with DS and typically developingindividuals on family and community members needfurther research.

Identification of Better Methods for Diagnosisand Treatment of Alzheimer Disease

Research is needed to identify early signs (e.g.,language impairment) and biomarkers that wouldpredict later development of Alzheimer disease andrelated dementia. Development of a standardizedevaluation for persons with DS that focuses onmental health screening and risk factors for dementiawas recommended. Research on the effectiveness ofinterventions for Alzheimer disease developed forthe general population among persons with DS isneeded. An understanding of the nature and timingof interventions that can delay the onset of Alzheimerdisease among persons with DS is also needed. Aclinical trial network similar to the consortium of



treatment centers for Alzheimer disease in thegeneral population should be considered for futuredevelopment.

Better Understanding of the Effects of DifferentTypes of Health Care on Outcomes

More information is needed on the availability ofdifferent types of care, such as DS clinics, centers ofexcellence, and primary care, to persons with DS andtheir families, and the effect of types of care on short-and long-term outcomes. It is unknown to whatextent persons with DS receive the preventive carerecommended for the general population. Barriersfaced by persons with DS in obtaining appropriatehealth care and disparities in access to care need tobe elucidated. Alternative health care systems thatmight better serve persons with DS should beidentified. Research is also needed on the issuesand barriers that arise as persons with DS make thetransition from pediatric to adult healthcare. Theseissues may include difficulty in finding a physicianwilling to care for adults with DS and difficulty ingetting care reimbursed.

CONCLUSIONS

The public health research priorities identified atthis meeting focus on the causes of physical andmental comorbid conditions and health outcomesamongpersonswithDS andof population disparitiesin those conditions and outcomes, the natural historyof cognition and behavior and of medical conditionsin DS, effective strategies for research enrollmentand for conveying information about DS to parents,effective intervention to improve cognitive out-comes, the effect of support services and communityinclusion, strategies for early identification andinterventions for Alzheimer disease, and access tohealth care for adults with DS. For each research gapto be filled, participants strongly recommended thedevelopment of population-based resources foridentifying patients for research and resources thatcould be useful for longitudinal research.

ACKNOWLEDGMENTS

The priorities outlined in this manuscript weredefined during a meeting entitled ‘‘Setting a PublicHealth Research Agenda for Down Syndrome’’ heldNovember 8–9, 2007. We are especially grateful tomembers of the steering committee for this meeting(Vince Campbell, CDC, Atlanta, GA; ElisabethDykens, Vanderbilt Kennedy Center for Researchon Human Development, Nashville, TN; GeorgeJesien, Association of University Centers on Dis-abilities, Silver Spring, MD; Ira Lott, University ofCalifornia Irvine School of Medicine, Irvine, CA; andStephanie Sherman, Emory University School ofMedicine, Atlanta, GA) who helped develop the

meeting agenda and identified meeting speakers andparticipants. We also thank Dr. Dykens, Dr. Lott, andDr. Sherman, and our other meeting speakers (LenAbbeduto, Waisman Center, University of Wisconsin-Madison, Madison, WI; Coleen Boyle, CDC, Atlanta,GA; Nancy Roizen, Rainbow Babies and Children’sHospital, Cleveland, OH; Marsha Mailick Seltzer,Waisman Center, University of Wisconsin-Madison,Madison, WI; Wayne Silverman, Kennedy KriegerInstitute, Baltimore, MD; Harold Kleinert, Universityof Kentucky, Lexington, KY; and Mary Lou Oster-Granite, National Institutes of Health, Bethesda, MD)who summarized the current knowledge in the areaand identified research gaps and/or served asmoderators for meeting sessions and discussions.We also would like to acknowledge George Capone(Kennedy Krieger Institute, Baltimore, MD) andRobert Hodapp (Vanderbilt University, Nashville,TN) for serving as moderators for meeting sessionsand discussions, and Scott Grosse, Cynthia Moore,Stuart Shapira, and Brenda Silverman (CDC, Atlanta,GA) for acting as rapporteurs during meetingsessions. Finally, we also thank the other meetingparticipants who contributed to this work: MarilynBull, Indiana University School of Medicine, Indian-apolis, IN; Brian Chicoine, Adult Down SyndromeCenter of Lutheran General Hospital, Park Ridge, IL;Laura Cifra-Bean, National Down Syndrome Con-gress, Mentor, OH; Bill Cohen, Children’s Hospitalof Pittsburgh, Pittsburgh, PA; Adolfo Correa, CDC,Atlanta, GA; Beth Finkelstein, National Down Syn-drome Society, New York, NY; William Freeman,Northwest Indian College, Bellingham, WA; JanFriedman, University of British Columbia, Vancou-ver, Canada; Paul Glassman, University of the PacificSchool of Dentistry, San Francisco, CA; LilliamGonzalez de Pijem, University of Puerto Rico Schoolof Medicine, San Juan, PR; Henrik Hasle, AarhusUniversity Department of Pediatrics, Aarhus, Den-mark; Charlotte Hobbs, College of Medicine at theUniversity of Arkansas for Medical Sciences, LittleRock, AR; Margaret Honein, CDC, Atlanta, GA;David Hoppe, National Down Syndrome Society,Washington, DC; Matthew P. Janicki, University ofIllinois at Chicago, Chicago, IL; Lisa Kaeser, NationalInstitutes of Health, Bethesda, MD; Bryan King,University of Washington, Seattle, WA; PriyaKishnani, Duke University Medical Center, Durham,NC; Barbara Levitz, Westchester Institute for HumanDevelopment, Valhalla, NY; Kevin Maher, EmoryUniversity, Atlanta, GA; Beth Marks, RehabilitationResearch Training Center on Aging with Develop-mental Disabilities, Chicago, IL; Dianne McBrien,University of Iowa Children’s Hospital, Iowa City, IA;Dennis McGuire, Adult Down Syndrome Center ofLutheran General Hospital, Park Ridge, IL; JoavMerrick, Division for Mental Retardation, Ministryof Social Affairs, Jerusalem, Israel; Lynn Nadel,University of Arizona, Tucson, AZ; Stephanie



Meredith, Down Syndrome Association of Atlanta,Atlanta, GA; David Patterson, University of Denver,Denver, CO; Bonnie Patterson, Cincinnati Children’sHospital Medical Center, Cincinnati, OH; RogerReeves, Johns Hopkins University School of Medi-cine, Baltimore, MD; John Reiss, University ofFlorida, Gainesville, FL; Cordelia (Corry) Robinson,University of Colorado Health Sciences Center,Denver, CO; Diana Schendel, CDC, Atlanta, GA;Nicole Schupf, Columbia University, New York, NY;Mikyong (Meekie) Shin, CDC, Atlanta, GA; BrianSkotko, Children’s Hospital Boston, Boston, MA;Stephanie Smith Lee, National Down SyndromeSociety, Washington, DC; Esther Sumartojo, CDC,Atlanta, GA; Claus Svaerke, University of Aarhus,Aarhus, Denmark; Poul Thorsen, University ofAarhus, Aarhus, Denmark; Tracy Trotter, SRV Pri-mary Care, San Ramon, CA; Jeannie Visootsak,Emory University School of Medicine, Atlanta, GA;Steven Warren, the University of Kansas, Lawrence,KS; Madeleine Will, National Down SyndromeSociety, Washington, DC; and Warren Zigman,New York State Institute for Basic Research inDevelopmental Disabilities, Staten Island, NY.

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Documents

Setting a public health research agenda for Down syndrome: Summary of a meeting sponsored by the Centers for Disease Control and Prevention and the National Down Syndrome Society