Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 https://doi.org/10.1186/s11689-022-09435-z REVIEW Open Access Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group Nicole T. Baumer1, Mara L. Becker2, George T. Capone3, Kathleen Egan4, Juan Fortea5,6,7, Benjamin L. Handen8, Elizabeth Head9, James E. Hendrix10, Ruth Y. Litovsky11,12, Andre Strydom13,14, Ignacio E. Tapia15 and Michael S. Rafii16* Abstract The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled lead- ing clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019. Keywords: Down syndrome, Intellectual disability, Clinical trials, Clinical research, Research engagement, Recruitment Background/introduction commitment, and generous support from Congress. This The INCLUDE (INvestigation of Co-occurring conditions program is developing a portfolio of scientific opportuni- across the Lifespan to Understand Down syndromE) ties that span the spectrum from basic science to clini- project was launched in June 2018 in support of a Con- cal research. Important insights are being gained from gressional directive in the fiscal year (FY) 2018 Omnibus INCLUDE studies, and the capacity building (especially Appropriations. The directive called for a new trans- training for a cadre of investigators who will advance the NIH research initiative on critical health and quality- field) that the program has accelerated provides confi- of-life needs for individuals with Down syndrome (DS) dence that this research trajectory will enhance the lives and resulted from advocacy from the community, NIH of people with DS. The NIH INCLUDE project hosted a workshop titled “Planning a Virtual Down Syndrome Cohort Across the *Correspondence: mrafii@usc.edu 16 Lifespan Workshop.” Groups interacted via teleconfer- Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA ences and email during a 3-month preparation period. A Full list of author information is available at the end of the article 2-day face-to-face meeting was held virtually, September © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Journal of Neurodevelopmental Disorders (2022) 14:22 Page 2 of 9 23 and 24, 2019, at which all working groups presented Barriers faced by families their findings and participated in additional discussion The biggest barrier is trust in most cases and/or the lack and refinement of the initial work. At the workshop, spe- of exposure to the benefits of research. This results from cialists, including clinicians, researchers, advocates (par- limited community awareness and interest and therefore ents and individuals with DS), as well as data scientists involvement in research, particularly in racially and eth- and biostatisticians, were brought together to discuss the nically diverse populations. Those who face disadvantage, creation of a virtual DS cohort across the lifespan. A final be it due to factors such as disability, socioeconomic sta- overview of the status of best practices for engaging and tus, and/or ethnic/minority background, have expressed conducting clinical trials in the DS population was devel- that it can be difficult for them to take part in research oped by the Clinical Trial Readiness Working group and activities, and report their views and experiences are less is presented in the following sections. The focus of this often heard and addressed [8]. paper is to outline current challenges and opportunities The logistical burden of participating in clinical tri- in clinical trial research in people with DS and to present als is also cited as a challenge for families of individuals recommendations for future work in this area. with DS, with families concerned about scheduling bur- den, family availability, overall time commitment, travel distance, out-of-pocket expenses, and frequency of visits Current state of clinical trials in the Down syndrome [9]. These challenges are likely exacerbated in older indi- population viduals for whom caregivers are also older, or for indi- Ongoing clinical trials with individuals with DS address viduals who are living in settings outside of the family a wide range of conditions and issues, such as Alzhei- home. Exploration of parent attitudes reveals that while mer’s disease (AD) dementia, cardiac disease, metabolic many parents of individuals with DS generally support disorders and obesity, autoimmune disorders, obstruc- pharmacological trials, there are concerns about safety tive sleep apnea (OSA), leukemia, behavioral, and mental and long-term implications, potentially limiting partici- health issues. Advances in medical care have improved pation [9, 10]. Decisions regarding participation in clini- overall health and extended the life span of individuals cal trials may be dependent on the intervention target, with DS. Current research is focused on development, such as medical versus developmental conditions/cogni- cognition, with the goal of maximizing functional out- tion or high priority symptoms such as communication comes and improving their quality of life. or behavior [9]. People with DS may also have difficulty Great strides have been made in observational and complying with study demands due to motor limitations, behavioral research in DS, with thorough characteri- impulsivity, and limited attention span, and may require zation of development and cognition [1, 2], as well as specialized testing administration, and customization. development of new tools to detect AD-related cogni- tive decline in adulthood [3, 4]. Working groups have also evaluated potential outcome measures that can be used Ethical and logistical barriers faced by researchers in clinical trials in the areas of cognition and behavior [5]. Challenges with recruitment, retention, consenting/ However, despite these advances, clinical trial research, assenting, and logistics, safety, and efficacy have also long particularly that focused on cognition, has been slow impacted clinical trial research in DS and special consid- to progress and poses unique challenges [6, 7]. Several erations are needed for success [6, 7]. Given the histori- issues have impacted the success of clinical trials in DS, cal context of exploitation, there are issues surrounding and more broadly within neurodevelopmental disabilities the ethical and legal implications for conducting research (NDDs). These include barriers that individuals with DS with individuals with intellectual disability (ID) [11, and their families experience, ethical and logistical barri- 12]. For example, some researchers may be reluctant to ers that researchers face, and challenges with clinical trial include people with ID in their research for several rea- research design and interpretation. sons: they may inappropriately presume inability; they may be concerned about the capacity of the individual to understand risks and benefits and provide consent or Challenges and barriers for conducting clinical trials assent to participate; or they may consider those with ID The number of families and individuals with DS who par- to be vulnerable and in need of protection from poten- ticipate in research and clinical trials is not sufficient to tial harms of research. While DS researchers may be well obtain valid and reliable results. NIH has created a DS trained and experienced, and have comfort in address- Registry and while the numbers have increased over the ing these issues, researchers less familiar with DS or ID, past years, there is still a need for greater involvement of but who study health issues relevant to DS may not be. a larger number of participants. Choice of participants can also be problematic, as those Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 3 of 9 with more severe impairments who may not be able to over the lifespan further influence neurodevelopment comply with study demands may not be well represented and outcomes. by findings originating from study participants with While a longitudinal lifespan approach would help to milder impairments who are better able to participate in answer important clinical questions that address both research. neurodevelopmental and neurodegenerative aspects of DS, there are many challenges to a lifetime approach as Challenges specific to clinical trials targeting cognition brain development, organization, maturation, and func- There are specific challenges to clinical trials that tar- tioning evolve over time, and there may be critical win- get cognition, neurodevelopment, and neurodegenera- dows for potential treatments to have desired effects. tion. These include heterogeneity within the population, Additionally, pharmacological treatments targeting cog- interindividual variability, lack of standard endpoints to nition or learning may need to be paired with structured assess efficacy, placebo effects, reliance on informant- therapy/teaching paradigms and study impact over longer based questionnaires that require the same informant at time periods to adequately assess effectiveness of a drug multiple time points, and complexity in interpretation that has the potential to enhance the learning process. of findings. Current research most commonly involves those who have mild-moderate ID, and findings may not be generalizable to those with more severe impairment. Clinical trials readiness working group objectives Clinical trials in DS have faced similar challenges to The Clinical Trial Readiness Working Group was provided clinical trials in other NDDs. For example, in Fragile with key questions and tasked with developing responses X, despite great success in understanding genetic and that could serve as a roadmap for efforts going forward in mechanistic causes of cognitive impairments and posi- advancing clinical research efforts in DS and increasing par- tive findings in mouse models, human studies of targeted ticipation among persons with DS in future clinical trials. pharmacologic treatments for cognition have not yet The questions focused on (1) identification of approaches to shown significant improvement in outcomes, and some facilitate recruitment and retention of research participants, pharmaceutical companies have discontinued further including underrepresented groups, (2) cohort preparation drug development [13]. However, there are many com- for clinical trials with special considerations for clinical tri- plexities to interpreting the available findings. It may be als across the lifespan, and (3) building a pipeline of inves- that studies are too quick to conclude that negative find- tigators with DS clinical trial experience. In exploring these ings in a trial prove that a treatment is ineffective under questions, several themes emerged and fostered develop- all conditions or that the presumed underlying patho- ment of the recommendations that follow. physiological mechanisms are not valid [14]. For example, some treatments may be effective in certain subgroups Key questions: 1. Recruitment and retention: what approaches can facilitate recruit- of the population, at a different time in development, or ment and retention of families or participants to build a DS cohort and under different conditions. understand natural history, including underrepresented groups? Without potential biomarkers of treatment response, 2. Cohort development across the lifespan: how can we ensure that cohorts are prepared for those with DS across the lifespan for future human trials need to rely on behavioral outcomes, which clinical trials? reflect combined effects of many different factors such 3. Building an investigator pipeline: how can we build the pipeline of as learning and environment. Additionally, the behav- investigators who have DS clinical trial experience? ioral outcome measures may not be sensitive enough to treatment effects, or best suited to the population stud- ied or what is most relevant to families and people with Recruitment and retention: strategies to promote DS. Standardized behavioral-based assessments have engagement and inclusion floor and ceiling effects and direct measurement testing Engagement with individuals with DS, their families/care batteries may over- or underestimate participant’s skills partners, and community advocacy organizations because they are not geared to their specific profile. Reli- Ensuring that research teams include members from the ance on informant-based questionnaires is also particu- groups studied has been increasingly recognized as an larly susceptible to strong placebo effects in NDDs [15]. important aspect of research involving individuals with Variability in cognition, behavior, language, and adap- disabilities [7, 15]. The shift from “researching on” to tive skills is seen in people with DS, and skills in these “researching with” has helped investigators understand domains evolve across the lifespan, with environmental the types of outcomes that are perceived to be useful influences playing a role in ways that are not well char- within the community and can contribute valuable infor- acterized or understood. Furthermore, how medical and mation to study design and implementation [16]. mental health conditions that occur at different times Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 4 of 9 The Working Group identified areas of need and sug- of clinical care, with both clinical and research cultures gestions for recruitment and retention of research par- existing synergistically. It is necessary to continue to ticipants, with particular focus on engaging and involving build a strong network of clinical care centers for people groups often underrepresented in medical research. with DS, and for researchers to collaborate closely with Involving individuals with DS and their families at clinicians and to collaborate in study recruitment and all phases of research and fostering and maintaining study conduct, such as for collecting data from the clinic research collaborations are necessary to promote engage- sample. Researchers should engage clinicians as partners ment and advance clinical research while helping to fur- and respect their involvement (e.g., the face of the study, ther the understanding of needs and priorities. collaborators on publications). Surveys, focus groups, and consultation and advisory Partnerships between academic researchers and feedback from families and participants can be par- industry are needed to conduct large scale randomized, ticularly helpful when developing study questions and placebo-controlled clinical trials. Collaborations with designing clinical trials. This can help to ensure under- researchers who focus on other areas of developmen- standability and feasibility of study assessments, outcome tal disabilities may be useful to broaden the scope of measures, information and consent materials, and will endpoints. Continued collaborations with NIH and the help researchers understand the relevance of the study Down Syndrome Medical Interest Group (DSMIG-USA), question to participants and how they would like infor- collaborations with researchers and clinicians, basic sci- mation conveyed. Some family members may have pro- entists, and clinical researchers are needed to further this fessional expertise that aligns with clinical and scientific effort. goals. Investigators should take a community-engaged/ community-based participatory research approach Engagement of underrepresented groups (CBPR), in which they collaborate with the community, Engagement and involvement of minority groups who and incorporate stakeholders’ expertise, values, and pri- are underrepresented in biomedical research is a par- orities in all steps of the research process [17]. ticular challenge. It is necessary to incorporate strate- Community engagement and outreach events may gies that address cultural and language barriers, such as enhance outreach and education and can be conducted adapting information, providing translations for written in person or virtually. Social media, websites, and documents and interpreters for oral communications, newsletters from advocacy organizations can be used and targeting recruitment. It will be necessary to identify to advertise studies. Partnering with DS associations strategies to gain information about the ages, ethnici- and societies (e.g., National Down Syndrome Society ties, and races of people with DS in research catchment (NDSS), Global Down Syndrome Foundation (GDSF), areas and clinical research sites and to work closely with LuMind Foundation, National Down Syndrome Congress the community to engage participants. Recruiting people (NDSC), Trisomy 21 Research Society (T21RS)), and reli- from various backgrounds and minority groups can also gious and community groups, government, and advocacy be enhanced by inclusion of people on the research team groups will also support this effort. Importantly, an indi- that captures this diversity. vidual and family’s experience in a trial not only impacts retention for that trial but impacts recruitment for future Providing accessible information trials. Partnerships can be further strengthened and pro- A careful and thorough process of communication is moted by engagement in which materials and informa- needed when conducting research in individuals with DS. tion about ongoing studies can be disseminated. These Use of accessible information and repeated opportunities efforts can help to promote partnerships, buy-in, and to communicate information and check for understand- willingness for individuals to be contacted in the future ing are needed. Novel ways to address informed consent, for research opportunities. such as through picture-based consents and electronic consenting platforms (eConsenting), are needed. For Collaboration between researchers, clinicians, stakeholder example, the U.S. Food and Drug Administration has groups, and advocacy organizations guidance on use of electronic consents [18]. Involve- In addition to strong community engagement, success- ment of individuals with DS and their families in review- ful recruitment will rely on collaboration among clini- ing consent materials is especially important. Individuals cians and researchers, stakeholder groups, and advocacy with DS may be inclined to give socially desired answers, organizations. Strong relationships with referring clinical so checking for understanding and use of visually acces- programs, and in collaboration with clinicians who have sible information is needed. pre-existing relationships with potential participants, Timely and accurate dissemination of important will enable research to be considered as an extension findings, including safety information and results, is Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 5 of 9 imperative. New and creative ways to acknowledge partici- research studies, thus the informed consent process, in pation in research and to share and distribute study results particular, demands careful planning. are crucial. Information should be shared in formats that Given the ID associated with DS, as well as potential are appropriate to the audience, such as through a newslet- emotional/behavioral conditions that influence deci- ter or infographic, rather than a journal article. For exam- sions, individuals with DS must be supported in research ple, T21 RS COVID-19 infographic summaries, vetted decision-making. In many cases, and depending on the through stakeholders and advocacy groups, have proved to legal framework, a surrogate or proxy decision maker is be a successful method for dissemination of key research involved, and a legally authorized representative makes findings [19]. Providing a platform for patients and decisions about participation. Many individuals are com- research participants to share their experience in research fortable receiving assistance from trusted family and with others may also be a valuable tool for all stakeholders. friends to help them with decisions. Even for individu- als who cannot provide legal consent, they may be able Reducing study burden to express their thoughts and feelings about participat- Trial burden may be decreased by using telemedicine ing and exercise some choice. Assent—or willingness of and home visits, or by coordinating research with clinic the prospective participant to go along with or not object visits or on nights or weekends, so as not to interfere to the study—is essential, even when there is a surrogate with school, work and other activities and appoint- decision-maker. ments. Budgets should reflect the additional cost Special consideration is also needed for recruitment/ required to bring in research staff on off-hours. It is consenting of aging adults with DS or adults living in also important to ensure that families, participants and group homes who may lack a legally authorized repre- care partners are appropriately supported to attend vis- sentative or family informant. The legally authorized rep- its (e.g., travel arrangements and reimbursement, com- resentatives of adults with DS often change over time, for pensation for use of care hours, flexibility in timing of example, from an aging parent to a sibling or professional visits, adequate breaks during study visits.) Travel for caregiver. Each state or country has different regulations adult participants, especially, can be a barrier to partic- around consent for individuals with disabilities. This ipation, and travel expenses should be included in the must be determined in advance to inform clinical trial budget. Group travel for individuals with Down syn- development, with particular consideration of multisite/ drome living together in a group home can save money multiregional studies, and local/state regulations must be and be enriching for participants. In addition, remote taken into consideration. visits, such as via telemedicine, could also reduce travel burden for participants and expand research catchment Cohort development across the lifespan areas. Direct to patient trials in which study treatments Cohort development across the lifespan is critical for and procedures are delivered in the participant’s home readiness for future clinical trials. These trial ready could also be considered to optimize recruitment and cohorts might accelerate research for several clinical minimize burden to patients and families [19]. needs (e.g., AD and OSA), thus reducing the costs of per- Data collection in research areas of high interest (e.g., forming different clinical interventions. Further devel- sleep, behavior, cognition, mental health) are extremely opment of reliable and valid clinical outcome measures labor- and time-intensive to conduct. Development of across the lifespan and across a wide range of develop- select web-based, interactive assessment tools (point- mental abilities are needed. Longitudinal studies are click-scroll) will be helpful to partially replace the need for needed to better understand the natural history of DS in-person visits. Some studies are also completed entirely and its associated conditions, to identify DS-related online, such as the Alzheimer’s Prevention Trials web- norms, to help identify subgroups with characteristics, based research study [20]. Efforts are needed to begin to to understand what childhood factors may predispose to validate these tools and compare to gold-standard assess- risk or resilience, and who may be good candidates for ments, and also to collect data longitudinally to determine preventative interventions. test-retest reliability. Feasibility trials/pilot studies are Many medical issues for adults with DS such as obe- likely to be needed before larger scale trials are conducted. sity and sleep apnea begin in childhood and childhood antecedents may play an important role in how these, Legal and ethical considerations and other adult-onset conditions, evolve. For example, Autonomy and self-determination must be respected AD, which is one of the most prevalent and challeng- and balanced with the responsibility to protect vulner- ing conditions for adults with DS, has genetic but also able individuals from potential risks of participation in likely environmental origins early in childhood [21]. Some research in the general population has shown Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 6 of 9 associations between AD and increased exposure to share these in DS conferences to convey results and find- adverse childhood experiences (including living in cus- ings to the population. tody and difficult experiences with teachers) [22, 23]. The timing of interventions will be critical to con- In addition to research trials in older adults, longitudi- sider. In younger children, developmental change will nal studies in DS will be needed in DS to understand be expected in the absence of intervention, and in older early risk factors and the potential impact of childhood individuals, there may be points at which aberrant neu- experiences. Additionally, the association between rodevelopment or the later neurodegenerative cascade, OSA in adults with AD is currently under investiga- are too far underway such that neurobiological con- tion in the general population [24]. With high rates of sequences are irreversible and functioning cannot be OSA in people of all ages with DS, it will be important altered. Additionally, specific brain areas impacted in to understand whether OSA in childhood might impact DS mature at different rates and manifestations of their later risk of AD. Similarly, research in typically develop- disrupted development change across the lifespan, sug- ing children has shown that persistent sleep problems gesting that some pharmacological targets may be most through childhood are associated with worse behavio- effective at different time points in development. For ral outcomes and quality of life. A longitudinal study in these reasons, targeting younger individuals for treat- individuals with DS might be able to provide important ment and prevention trials, in addition to older adults, insight into the association between sleep and health may be an additional important approach. outcomes across the lifespan [25]. Furthermore, there Clarity is needed on a regulatory pathway for new drugs are conditions that arise specifically in childhood, for for DS, as the typical progression of drug development example DS-associated arthritis that can affect long- that is initiated in neurotypical adults, then children, term physical outcomes. DS-associated arthritis is may be problematic. It is not clear that demonstration of under-recognized, has a more severe phenotype, and is safety in a neurotypical population would predict safety difficult to treat. It can result in disruptions in motor in DS. In addition, individuals with DS are at increased development, unpredictable medication toxicity and risk for numerous co-occurring conditions that require significant long-term physical disability [26]. chronic medications and very little is understood about Ongoing work to accelerate the development, evalu- drug biotransformation in DS, despite observed differ- ation, and validation of new trial-enabling standard- ences in drug response and toxicity [28–30]. Dedicated ized outcome measures for use over the lifespan is also pharmacodynamic and pharmacokinetic studies, such needed. Many measures currently used in neurotypical as those conducted through the Pediatrics Trials Net- children and adults cannot be used in those with DS. work—currently investigating metabolism of Guanfacine Cognitive measures are needed that are normed for indi- in Down syndrome—are needed more broadly in DS to viduals with DS and age appropriate, which are sensitive determine drug disposition and response relationships, to bidirectional change (i.e., can detect developmental and to establish safety and dosing recommendations growth and skill acquisition as well as decline), and that across the lifespan. Additionally, training and exper- can be used in individuals with a wide range of abilities, tise are needed for identifying and managing potential including those with more severe ID [5]. adverse events, particularly when participant reporting of While longitudinal lifespan studies are logistically chal- side effects and problems may not be straightforward. lenging, through close collaboration among the DS-com- Coordinated efforts across many sites will be needed munity and advocacy organizations, specialized pediatric to build large cohorts, and leverage existing infrastruc- and adult clinical DS programs, and researchers, large ture, including Alzheimer’s Disease Research Cent- registries and clinical databases of well-characterized ers (ADRCs), Centers for Excellence in Developmental cohorts can be created and shared. NIH-funded Data Disabilities (CEDDs), Intellectual and Developmental Coordinating Centers [27] can lead these efforts by serv- Disability Research Centers (IDDRCs) and others. Har- ing as a platform for linking investigators for collabora- monization of test batteries across studies and across tive research. Additionally, with opportunities for clinical age groups is desired so that results can be compared research throughout the lifespan, more touchpoints and and aggregated across studies. Several strategies can ongoing engagement can be fostered for future recruit- help with cohort development, including continued sup- ment into clinical trials. Exposure to research results and port of DSConnect and similar efforts to build a registry sharing the successes in a case study can help build trust. of interested participants, continued work to prepare Also, most publications are usually scientific and do not and maintain lists and coordination of existing cohorts reach the target population. The recommendation is to through the Data Coordinating Centers, and ensuring publish for the target population on their websites and that new research study design is tailored and compat- ible with existing cohorts. This involves ongoing work Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 7 of 9 to determine a minimum set of core data elements and The PTN also launched a PTN Down Syndrome 2020 informative measures, and to create standard operating Virtual meeting to introduce to the larger network and procedures to facilitate systematic collection of biological interested collaborators the therapeutic challenges faced and standardized and consistent behavioral data across by children with DS; opinions of community advocates, studies and sites. individuals, and parent/family on engaging in current and future research; lessons learned from current efforts Building an investigator pipeline in Down syndrome to enroll patients with Down syndrome into an active research PTN study; and input on a prospective randomize clini- Coincident with bolstering clinical trial participation by cal trial protocol in development. members of the DS community, there is a critical need Existing IDDRCs can also be leveraged to fund post- to have clinical research sites trained and resourced to docs and/or PhD positions in their labs to draw stu- conduct such studies. The Working Group offered several dents from other fields into the DS space. This can be recommendations to support this effort. The INCLUDE accomplished by offering CME activities and presenting infrastructure can be used to bring in early stage as well workshops/symposia at national meetings focused on as established investigators into the DS research space DS/ID [e.g., DSMIG-USA, DSMIG-UK, Child Neurol- by capitalizing on existing training mechanisms, such as ogy Society (CNS), American Academy of Neurology NIH Career Development and Training pathways (e.g., (AAN), AAIDD-Gatlinburg, and American Academy of K23, T32 training awards). Developmental Medicine and Dentistry (AADMD)] or Interest in DS research can be expanded and fostered with stakeholders not focused solely or primarily on DS by engaging clinicians, researchers, and trainees includ- or even IDD (e.g., AMA, APA, AAIC.) Finding ways to ing those who are not focused solely or primarily on DS support student/young investigator attendance at these or even ID and providing training and mentorship. To meetings will also be important. encourage DS clinicians to participate, it will be neces- sary to offer training bootcamps to provide skills in clini- cal trial design, implementation, and funding, as well as Discussion/key points ongoing mentoring opportunities. Advancing research in DS will require ambitious and In order to encourage other researchers to include collaborative efforts that reach across the lifespan and people with DS or other intellectual and developmental include researchers, clinicians, individuals with DS and disabilities in their research, it will be necessary to pro- their families, advocacy groups, and industry. The Clini- vide training on how to interact with and include people cal Trial Readiness Working Group has identified many with DS. challenges and opportunities for these efforts and has Training opportunities can be built into NIH clini- suggested approaches in developing some of the infra- cal trials infrastructure such as the Pediatric Trials Net- structure and methods needed to conduct clinical trials work (PTN) and Alzheimer’s Clinical Trials Consortium successfully in people with DS. (ACTC). For example, ACTC launched the IMPACT AD Specifically, the Working Group highlighted the impor- training course in 2020. Lectures are given by national tance of the following: leaders in Alzheimer’s Disease and Related Dementias (ADRD) trials, and attendees have the opportunity to 1- Stakeholder engagement from the inception of any work closely with the field’s top investigators in small research project. group workshops. Groups such as the ADRC can be 2- Ethical, accessible (culturally and cognitively appro- encouraged to recruit and help train investigators inter- priate) recruitment materials, ensure collection of ested in focusing on DS. There is now a DS module devel- assent as part of the consenting process if a legal oped by the National Alzheimer’s Coordinating Center guardian is providing consent, study materials, and (NACC) that can be implemented at all ADRCs. It will be dissemination of results available in different lan- important to develop international links and collabora- guages. tive networks via organizations such as the Alzheimer’s 3- A lifespan approach from time of diagnosis (includ- Association International Society to Advance Alzhei- ing prenatal diagnosis) to death both to evaluate mer’s Research and Treatment (ISTAART) and T21RS childhood antecedents of adult disease or decline and to capitalize on global expertise. All NIH funded ADRCs to evaluate effects of interventions. also now include a Research Education Component that 4- Development of appropriate tools to assess outcomes could be coordinated to provide training modules on the in health, quality of life, cognitive functioning and importance of research in people with DS and Alzheimer behavioral/mental health that can be used across disease. institutions and age ranges. Baumer et al. Journal of Neurodevelopmental Disorders (2022) 14:22 Page 8 of 9 5- Workforce development of a pipeline of research- 2 Department of Pediatrics, Duke University School of Medicine, Durham, USA. 3 Department of Pediatrics, Kennedy Krieger Institute, The Johns Hopkins ers and clinicians to collaborate in ongoing research School of Medicine, Baltimore, USA. 4 Parent/Advocate, Virginia, USA. 5 Sant Pau efforts. Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 6 CIBERNED, Madrid, Spain. 7 Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain. 8 Department Conclusions of Psychiatry, University of Pittsburgh, Pittsburgh, USA. 9 Department of Pathol- As we develop more advanced infrastructure to translate ogy & Laboratory Medicine, University of California, Irvine, USA. 10 LuMind IDSC Foundation, Burlington, USA. 11 Waisman Center, University of Wisconsin, research towards clinical benefit for individuals with DS, Madison, USA. 12 Department of Communication Sciences and Disorders, Uni- it will be critical to continue the efforts described by the versity of Wisconsin, Madison, USA. 13 Department of Forensic and Neurode- Working group to achieve the best possible outcomes velopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, London, UK. 14 King’s College London & South London and the Maudsley NHS and ensure that important research opportunities are Trust, London, UK. 15 Division of Pulmonary and Sleep Medicine, Children’s Hos- accessibility for all. pital of Philadelphia Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. 16 Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA. Abbreviations NIH INCLUDE: National Institute of Health INvestigation of Co-occurring Received: 22 October 2021 Accepted: 10 March 2022 conditions across the Lifespan to Understand Down syndromE; DS: Down syndrome; NDD: Neurodevelopmental disabilities; ID: Intellectual disability; NDSS: National Down Syndrome Society; GDSF: Global Down Syndrome Foundation; NDSC: National Down Syndrome Congress; T21RS: Trisomy 21 Research Society; DSMIG-USA: Down Syndrome Medical Interest Group-USA; References OSA: Obstructive Sleep Apnea; ADRC: Alzheimer’s Disease Research Centers; 1. Channell MM, Mattie LJ, Hamilton DR, Capone GT, Mahone EM, Sherman CEDD: Centers for Excellence in Developmental Disabilities; IDDRC: Intellectual SL, et al. Capturing cognitive and behavioral variability among individuals and Developmental Disability Research Centers; PTN: Pediatric Trials Network; with Down syndrome: a latent profile analysis. J Neurodev Disord. 2021. ACTC​: Alzheimer’s Clinical Trials Consortium; ADRD: Alzheimer’s Disease https://​doi.​org/​10.​1186/​s11689-​021-​09365-2. and Related Dementias; IMPACT-AD: Institute on Methods and Protocols for 2. Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with Down Advancement of Clinical Trials in ADRD; NACC​: National Alzheimer’s Coordinat- syndrome. Ment Retard Dev Disabil Res Rev. 2000;6:84–95. ing Center; ISTAART​: International Society to Advance Alzheimer’s Research 3. Startin CM, Lowe B, Hamburg S, Hithersay R, Strydom A. Validating the and Treatment; CNS: Child Neurology Society; AAN: American Academy of cognitive scale for Down syndrome (CS-DS) to detect longitudinal Neurology; AAIDD: American Association on Intellectual and Developmental cognitive decline in adults with Down syndrome. Front Psychiatry. 2019. Disabilities; AADMD: American Academy of Developmental Medicine and https://​doi.​org/​10.​3389/​fpsyt.​2019.​00158. 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