Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE)

Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) is sponsored by National Institute on Aging (NIA). Supports short courses training the next generation of Down syndrome researchers in clinical research skills.

The National Institutes of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project: Accelerating research discoveries for people with Down syndrome across the lifespan - PMC As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.

Am J Med Genet C Semin Med Genet . Author manuscript; available in PMC: 2025 Mar 1. Published in final edited form as: Am J Med Genet C Semin Med Genet.

2024 Jan 10;196(1):e32081. doi: 10. 1002/ajmg.

c. 32081 The National Institutes of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project: Accelerating research discoveries for people with Down syndrome across the lifespan 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD.

Find articles by Sujata Bardhan 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. Find articles by Huiqing Li 3 National Institute on Aging (NIA), NIH, Bethesda, MD. Find articles by Erika Tarver 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD.

Find articles by Charlene Schramm 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. Find articles by Marishka Brown 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD. Find articles by Linda Garcia 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD.

Find articles by Bryanna Schwartz 4 Office of the Director, NIH, Bethesda, MD. Find articles by Anna Mazzucco 4 Office of the Director, NIH, Bethesda, MD. Find articles by Nikila Natarajan 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD.

Find articles by Elizabeth Walsh 3 National Institute on Aging (NIA), NIH, Bethesda, MD. Find articles by Laurie Ryan 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. Find articles by Gail Pearson 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD.

Find articles by Melissa A Parisi 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD. 2 National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. 3 National Institute on Aging (NIA), NIH, Bethesda, MD.

4 Office of the Director, NIH, Bethesda, MD. All of the authors have made substantial contributions to the conception and design of this paper. They have been involved in drafting the manuscript, creating the figures and tables, and/or revising it critically for important intellectual content, and they have given final approval of the version to be published.

Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content and has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. No original data were collected for use in this document.

PMCID: PMC10939900 NIHMSID: NIHMS1951487 PMID: 38197535 The publisher's version of this article is available at Am J Med Genet C Semin Med Genet Keywords: Down syndrome, National Institutes of Health, research, INCLUDE Project, DS-Connect, clinical trials Down syndrome (DS) is the most common genetic cause of intellectual disability, the most common autosomal trisomy, and one of the most visible and universally recognized genetic syndromes.

Each year there are approximately 6000 babies born in the United States with DS each year ( https://www. cdc. gov/ncbddd/birthdefects/downsyndrome.

html ; ( Centers for Disease Control and Prevention, 2023 )), with an estimated national prevalence of 1 in 635 births when adjusted for maternal age ( Mai et al. , 2019 ). Within the past 60 years, the median life expectancy for a person with DS has increased nearly 15-fold, from 4 years in 1950 to 58 years in 2010 ( de Graaf et al.

, 2017 ). Despite this increase in lifespan, individuals with DS and their families face significant and changing health challenges with age, and they have often been excluded from participation in research that could improve their health outcomes and quality of life.

It is also important to note that there are significant disparities in the life expectancy for people with DS from underrepresented groups, although multiple factors likely contribute ( Iulita et al. , 2022 ; Santoro et al. , 2016 ).

While all people with DS are connected by the common feature of a complete or partial copy of chromosome 21 (trisomy 21), there are significant physical and cognitive differences among them, indicating that inter-individual variability exists. DS is associated with an increased prevalence of autism and epilepsy.

Moreover, it is estimated that over 70% of individuals with DS develop dementia due to Alzheimer’s disease (AD), often with symptom onset a decade or two earlier than AD in the general population ( Iulita et al. , 2022 ).

Individuals with DS also have high rates of hearing loss, eye abnormalities, congenital heart defects, sleep apnea, pulmonary hypertension, gastrointestinal malformations, thyroid disease, leukemia, and other autoimmune or immune dysregulation disorders, including celiac disease ( Antonarakis et al. , 2020 ).

However, people with DS infrequently develop solid tumors such as breast or prostate cancer, and despite multiple risk factors for coronary artery disease and high rates of obesity, sleep apnea, and type 1 diabetes, they rarely develop atherosclerosis or have myocardial infarctions ( Chicoine et al. , 2021 ).

Understanding this unique combination of risks and resiliencies will inform medical advances for individuals with DS, and for individuals who do not have DS but share these co-occurring conditions. In 2011, NIH created a Down syndrome Consortium with governmental and private organizations interested in Down syndrome.

The consortium included NIH’s Down Syndrome Working Group (DSWG) members representing several Institutes and Center’s within NIH. The goal of the DS Consortium is to encourage the exchange of information about Down syndrome research and foster communication and idea-sharing among NIH, individuals with Down syndrome and their families, national organizations interested in Down syndrome, and pediatric and other groups.

The Down syndrome consortium group’s support has been instrumental in many key activities led by NIH such as creation of the first national registry called DS-Connect ® , providing input for the Down Syndrome Research Plan (Down syndrome Directions (2014) and the updated Down syndrome Research Plan (2023)).

Finally, in 2017, Special Olympian Mr. Frank Stephens (Spokesman for the Global Down Syndrome Foundation-member of the DS Consortium) gave a powerful testimony to the members of Congress on the importance of inclusion and Down syndrome research and encouraged them to continue their support for research on Down syndrome.

Following Mr. Stephen’s testimony, in fiscal year (FY) 2018, the United States (U.S.) Congress noted that “the presence of a third copy of human chromosome 21, which causes Down syndrome, predisposes individuals to significant immune system dysregulation.

This dysregulation is associated with the occurrence of Alzheimer’s disease as individuals with Down syndrome age and the high incidence of autoimmune disease as well as protections against most solid tumor cancers and cardiovascular disease” and encouraged the National Institutes of Health (NIH) to “pursue a multi-year, trans-NIH research initiative examining immune system dysregulation and trisomy 21, with the aim of yielding scientific learnings that could significantly improve the health of individuals with Down syndrome as well as millions of typical individuals” ( https://www.

govinfo. gov/content/pkg/CRPT-115hrpt244/html/CRPT-115hrpt244. htm ; ( Committee on Appropriations, 2018a )).

In response to this language and comparable directive from the U.S. Senate ( Committee on Appropriations, 2018b ), NIH launched the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE; https://www. nih. gov/include-project ) Project (National Institutes of Health).

Led by the Office of the Director (OD) of NIH, the INCLUDE Working Group comprises 23 different institutes, centers, and offices across the NIH, reflecting the pleiotropic nature of the condition.

The INCLUDE Steering Committee is co-chaired by the directors of the National Institute on Aging (NIA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Heart, Lung, and Blood Institute (NHLBI), and the Deputy Director of NIH.

This Project set out to study conditions that affect individuals with DS and the general population, including but not limited to Alzheimer’s disease (AD), autism, attention deficit hyperactivity disorder (ADHD), celiac disease, congenital heart disease, and diabetes.

The NIH developed three components of focus for the INCLUDE Project ( Figure 1 ): The three components of the INCLUDE Project and their overlapping areas of focus with funding initiatives and goals relevant to each component.

CT, clinical trial; DCC, Data Coordinating Center; DEIA, Diversity, equity, inclusion, and accessibility; DS-CDP, Down Syndrome Cohort Development Program; iPSC, induced pluripotent stem cells; JAX, Jackson Laboratory; R21, R01, R61/R33 represent particular grant mechanisms at NIH.

Component 1: Targeted high risk - high reward basic science studies in areas highly relevant to DS Component 2: Assembly of a large cohort of individuals with DS across the lifespan to perform deep phenotyping and study co-existing conditions Component 3: Inclusive clinical trials of existing and future treatments and interventions for co-occurring conditions in individuals with DS Since the initial INCLUDE research goals were announced, the Project has worked to expand the number and diversity of investigators engaged in DS research and to create an international resource for data management, collection and sharing on DS through the INCLUDE Data Coordinating Center (DCC).

In addition, the first 5 years have contributed to major investments in DS research across the lifespan, including support of training initiatives and clinical trials, all with the goal of increasing participant diversity. INCLUDE has also benefited from the NICHD-supported DS-Connect ® Registry ( https://dsconnect. nih.

gov/ ) (National Institutes of Health) to assist investigators in their recruitment efforts, including working towards increasing the number of participants in the registry from diverse backgrounds. An NIH INCLUDE research plan published in 2023 also establishes objectives for the future of the INCLUDE Project, and paves the way for future investments in a large cohort study and other initiatives. 2.

EVOLUTION OF THE INCLUDE PROJECT Down syndrome funding at NIH (in U.S. dollars), 2011–2023. The blue band represents INCLUDE funding, while the lime green band represents baseline funding for DS research, with the total represented by the addition of both colored bands together.

Total Down NIH Down syndrome research investment and number of INCLUDE projects by year Number of INCLUDE Projects NIH investment amount in millions of U.S. dollars ($M), including amount spent on the INCLUDE Project, non-INCLUDE DS research, and the total DS research investment. The final column indicates the total number of new projects funded each year by INCLUDE.

FY, fiscal year Title of Funding Opportunity (URL) Application Due Date(s) * Notice of Intent to Publish Notice of Funding Opportunity Announcements for Down Syndrome Cohort Research Sites (DS-CRS) for the Down Syndrome Cohort Study Program (DS-CDP) across the lifespan for the INCLUDE Project ( https://grants. nih. gov/grants/guide/notice-files/NOT-OD-23-134.

html) ( https://www. nih. gov/include-project/frequently-asked-questions ) November 01, 2023 (estimated) Cohort research sites for planned large-scale cohort effort across the lifespan Notice of Intent to Publish Notice of Funding Opportunity Announcements for a Down Syndrome Clinical Cohort Coordinating Center (DS-4C) for the INCLUDE Project ( https://grants.

nih. gov/grants/guide/notice-files/NOT-OD-23-135. html) ( https://www.

nih. gov/include-project/frequently-asked-questions ) November 01, 2023 (estimated) Coordinating center for planned large-scale cohort effort across the lifespan Notice of Intent to Publish Notice of Funding Opportunity Announcements for a Federated Biobanking resource for the Down Syndrome Cohort Study Program (DS-CDP) across the lifespan for the INCLUDE Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-23-136. html) ( https://www. nih.

gov/include-project/frequently-asked-question ) November 01, 2023 (estimated) Federated biobank for planned large-scale cohort effort across the lifespan and other INCLUDE studies Animal Model Development and Basic Science Development of Animal Models and Related Biological Materials for Down Syndrome Research (R24 Clinical Trials Not-Allowed) ( https://grants. nih. gov/grants/guide/pa-files/PAR-22-247.

html ) 4-year awards to develop animal models and biological materials Development of Animal Models and Related Biological Materials for Down Syndrome Research (R21 Clinical Trials Not Allowed) ( https://grants. nih. gov/grants/guide/pa-files/PAR-23-067.

html ) 2-year awards to develop or improve animal models Transformative Research Award for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project (R01 Clinical Trial Not Allowed) ( https://grants. nih. gov/grants/guide/rfa-files/RFA-OD-22-009.

html ) High-risk, high-reward basic and clinical studies in DS INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Clinical Trial Readiness (R21 Clinical Trial Not Allowed) ( https://grants. nih. gov/grants/guide/rfa-files/RFA-OD-22-007.

html ) 2-year awards to develop biomarkers and outcome measures for clinical trials Clinical Trials Development for Co-Occurring Conditions in Individuals with Down syndrome: Phased Awards for INCLUDE (R61/R33 Clinical Trial Required) ( https://grants. nih. gov/grants/guide/rfa-files/RFA-OD-22-010.

html ) Ruth L. Kirschstein National Research Service Award (NRSA) Fellowship Awards to Support Training in Research Related to DS as Part of the INCLUDE Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-126. html ) Support predoctoral and postdoctoral fellows in DS research Mentored Career Development Awards to Foster the Careers of Investigators Pursuing Research Related to Down syndrome as Part of the INCLUDE Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-124. html ) Support mentored career development of junior investigators Administrative Supplements to NCATS CTSA Program KL2/K12 Institutional Career Development Awards as part of the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-192. html ) July 1, 2024; July 1, 2025 Supplements for career development awards for trainees at CTSA programs Administrative Supplements to NCATS CTSA Program T32/TL1 Institutional Training Program as part of the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-191. html ) July 1, 2024; July 1, 2025 Supplements for career development awards for trainees at CTSA programs INCLUDE (Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Predoctoral to Postdoctoral Fellow Transition Award (F99/K00 Clinical Trial Not Allowed) ( https://grants. nih.

gov/grants/guide/rfa-files/RFA-OD-23-016. html ) Support graduate students to transition to postdoctoral fellowships INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Clinical Research Short Course (R25 Independent Clinical Trial Not Allowed) d ( https://grants. nih.

gov/grants/guide/pa-files/PAR-22-195. html ) June 27, 2024; June 27, 2025 5-year awards for short courses for skills development in DS research Developing Academic Research Enhancement Award (AREA) and Research Enhancement Award Program (REAP) for Institutions with an emphasis on Down syndrome research (R15 Clinical Trial Not Allowed) d ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-136. html ) Support training at institutions without substantial NIH funding Community-Based Participatory Research (CBPR) Initiative in Reducing and Eliminating Health Disparities with a focus on addressing diverse representation in research on Down syndrome (R21 Clinical Trial Optional) d ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-142. html ) Support community-based research with a diversity focus Notice of Special Interest (NOSI): Use of Digital Technology and Mobile Health (mHealth) to Improve Diagnosis, Assessments, Interventions, Management and Outcomes for Individuals with Down Syndrome Across the Lifespan (R21 Clinical Trial Not Allowed) ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-21-092. html ) 2-year awards to develop mobile technologies and mHealth applications NIH Research Project Grants on Down Syndrome (R01) for the INCLUDE Project Standard 5-year awards with a DS focus INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Exploratory/Developmental Research Grant Award (R21 Clinical Trial Not Allowed) ( https://grants. nih.

gov/grants/guide/rfa-files/rfa-od-21-007. html ) 2-year exploratory awards for DS research Small Research Grants for Analysis, Curation, and/or Sharing of Down syndrome-related Research Data for the INCLUDE Project (R03 Clinical Trial Not Allowed) ( https://grants. nih.

gov/grants/guide/rfa-files/RFA-OD-22-008. html ) 2-year awards for data analysis, curation, and/or sharing Availability of Administrative Supplements for the INCLUDE Project ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-22-137. html ) 1-year supplements to existing funded awards # Earliest Estimated Award Date is indicated in this column rather than Expiration Date for these 3 notices. @ The F99/K00 mechanism had a single receipt date in July 2023 but is intended to be renewed.

d Diversity-related funding opportunity. CTSA, Clinical and Translational Science Awards; INCLUDE, INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE; NCATS, National Center for Advancing Translational Sciences INCLUDE support by component for each year of the program by (a) funding amount and (b) number of new awards 3. FINANCIAL INVESTMENT IN INCLUDE 4.

THE INCLUDE DATA COORDINATING CENTER (DCC) The INCLUDE (DCC), awarded in September 2020, is led by a trio of sites (Children’s Hospital of Philadelphia, University of Colorado School of Medicine/Linda Crnic Institute for Down Syndrome, and Sage Bionetworks).

The DCC is composed of an Administrative and Outreach Core that provides program management, outreach, and education; a Data Management Core that oversees and manages data collection, processing, and harmonization; and a Data Portal Core that facilitates access to and analysis of data via an online web portal. On October 1, 2021, the DCC website was first unveiled ( https://includedcc. org/ ).

On March 21, 2022 (World Down Syndrome Day), the INCLUDE Data Hub ( https://portal. includedcc. org/login ) launched with clinical and genomic data from 5 studies: DS-Connect ® registry; Crnic Institute Human Trisome Project ® ( https://www.

trisome. org/ ); and three separate groups that contributed over 2000 samples to the Study of Congenital Heart Defects and Acute Lymphoblastoid Leukemia in Children with DS: DS360 ( Rosser et al. , 2018 )), the Children’s Oncology Group, and the Pediatric Cardiac Genomics Consortium.

Currently, the INCLUDE Data Hub contains 11 studies with 65 terabytes of data, including 8400 harmonized clinical profiles from de-identified participants, 30,500 biospecimens, over 2600 whole genomes, and over 400 transcriptomes, proteomes, and metabolomes ( National Institutes of Health, 2023c ).

Committed to the FAIR data principles (Findable, Accessible, Interoperable, Reusable), the Data Hub provides a portal for the open exchange of data and resources to facilitate interdisciplinary collaboration and evaluation of omics data designed to lead to improved understanding of the co-occurring conditions in DS. In addition, the Data Hub provides a cloud-based platform called CAVATICA ( https://www. cavatica.

org/ ), which enables cloud-based analyses to accelerate scientific discoveries related to DS and facilitates the Data Hub’s interoperability with other major NIH data resources.

The value of open science has been driven home by the success of initiatives such as the COVIDome Project that increased the understanding of the COVID-19 pandemic at a rapid speed previously unfathomable due to pre-publication data sharing of de-identified data ( Sullivan et al. , 2021 ).

The INCLUDE DCC is promoting data sharing through its cohort-building efforts and by creating tools for data visualization and analysis through the INCLUDE Data Hub. A virtual biorepository links information about biospecimens available from studies that have data available on the portal.

It also hosts an investigator registry that lists INCLUDE-funded investigators and their publications, providing a forum for researchers to identify potential collaborators.

The DCC launched a training initiative in data science in summer 2022 through a 2-week immersive summer program directed at diverse graduate students and post-doctoral fellows; in its 2nd year, it supported training experiences for 25 domestic and international scholars.

Finally, a pilot project is exploring the option of adding non-human DS study data such as that generated by animal models, induced pluripotent stem cells (iPSCs), and brain organoid cultures to the resource, to truly make it comprehensive. 5.

INCLUDE INVESTMENTS IN DS RESEARCH ACROSS THE LIFESPAN The first six years of INCLUDE Project funding have established a strong foundation to continue discovery science for this important population. For example, one of the goals of the Project is to ensure that the co-occurring conditions across the lifespan are recognized and addressed, to optimize health outcomes for all with DS.

The INCLUDE Project has made possible a wide array of research.

There are studies examining prenatal diagnosis and development; neonatal conditions such as congenital heart disease, gastrointestinal complications, and leukemia; neurodevelopmental challenges including autism and ADHD; childhood issues such as speech articulation challenges and sleep apnea; visual conditions such as strabismus and keratoconus; and many other conditions, including recent recognition of the link between Down syndrome regression disorder (DSRD) and neuroimmune complications in some individuals ( J.

D. Santoro et al. , 2023 ).

In recognition that transitions to adulthood can be challenging, several research projects are addressing issues of employment, relations, and sexuality. Some research projects also supported studies of the impact of the COVID-19 pandemic on individuals with DS and their caregivers, including the consequences of their unique immunological profile on response to infection ( Espinosa, 2020 ).

A well-known association between early onset AD and DS has been established in aging adults; in fact, about half of adults with DS have evidence of AD in their 50s, and as the population with DS has aged, AD and its complications have been shown to be a leading cause of mortality for adults with DS ( Landes et al. , 2023 ).

To address the need for improved information about the evolution of AD in DS, the NIA and NICHD jointly funded the Alzheimer’s Biomarkers Consortium-Down Syndrome (ABC-DS) program ( National Institute on Aging, 2023 ) starting in 2015 ( https://www. nia. nih.

gov/research/abc-ds ). This initiative studies a longitudinal cohort of nearly 500 adults over the age of 25 years with DS to identify early biomarkers based on cognitive tests, neuroimaging, genetic studies, and blood and cerebrospinal fluid biomarkers that may predict the onset of dementia due to AD ( Handen et al. , 2020 ).

A 2019 workshop hosted by the Alzheimer’s Association, Global Down Syndrome Foundation (GDSF), and LuMind IDSC Foundation, with scientific input from NIH, affirmed similar patterns of pathology between DS and AD through neuroimaging studies, although AD may begin at an earlier age in those with DS, and called for further research to advance the field ( Snyder et al. , 2020 ).

More recently, plasma metabolites such as tau and neurofilament light chain have been identified as diagnostic biomarkers of AD in adults with DS ( Petersen et al. , 2021 ). The ABC-DS program, renewed in FY2020, continues to follow the cohort of adults with DS and aims to increase representation of populations historically underrepresented in DS clinical research.

In addition, ABC-DS facilitates the co-enrollment of a trial-ready cohort to test an anti-amyloid agent as a preventive treatment to delay the onset of dementia in a subset of the sample, taking advantage of the Alzheimer’s Clinical Trial Consortium-Down syndrome (ACTC-DS; see clinical trial in Table 3 led by Rafii ( Rafii et al. , 2021 ).

INCLUDE-funded clinical trials and assigned NIH institute Medications for obstructive sleep apnea to improve cognition in children with Down syndrome Hartnick, Christopher/ Skotko, Brian Effects of hypoglossal nerve stimulation on cognition and language in Down syndrome Positive airway pressure for obstructive sleep apnea syndrome in children with Down syndrome Home Sleep Apnea Testing Compared to In-lab Polysomnography for the Evaluation of Obstructive Sleep Apnea in Children with DS Self-Supporting Nasopharyngeal Airway Treating Upper Airway Obstruction in Hypotonia A Personalized Surgical Approach for the Treatment of Children with Obstructive Sleep Apnea and Small Tonsils Randomized Controlled Trial of Oxygen Therapy in Children and Adolescents with Down Syndrome and Obstructive Sleep Apnea Alzheimer’s Disease & Aging Clinical trials to prevent Alzheimer’s Disease in Down syndrome Addition of GM-CSF/sargramostim treatment to improve cognition in Down syndrome The Impact of Weight Loss on Alzheimer’s Disease Risk in Adults with Down Syndrome Immune System Dysregulation JAK inhibition in Down syndrome Esbensen, Anna/ Froehlich Tanya Evaluating assessment and medication treatment of ADHD in children with Down syndrome Espinosa, Joaquin/ Santoro, Jonathan Mechanistic investigation of therapies for Down Syndrome Regression Disorder ADHD, Attention Deficit Hyperactivity Disorder; GM-CSF, granulocyte-macrophage colony-stimulating factor; INCLUDE, INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE; JAK, Janus kinase; NHLBI, National Heart, Lung, and Blood Institute; NIA, National Institute on Aging; NIAMS, National Institute of Arthritis and Musculoskeletal and Skin Diseases; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; OSA, obstructive sleep apnea.

Since the 2 nd year of the INCLUDE Project, there has been an emphasis on increasing opportunities for those with DS to participate in clinical trials.

Individuals with intellectual disabilities often have been summarily excluded from taking part in such trials because of misplaced concern that they may not have the decisional capacity to make an informed choice about participating, or the assent/consent process would be too onerous to ensure understanding ( Freedman, 2001 ; Shepherd, 2020 ).

These fallacies have been shattered by the robust participation in 13 clinical trials since the inception of the program ( Table 3 ). Seven are examining intervention strategies for obstructive sleep apnea, three are addressing aging and AD risk, one is evaluating immune modulatory treatments for autoimmune skin disorders, and two are studying neurodevelopmental interventions for ADHD and DSRD.

Moreover, an INCLUDE Working Group on Clinical Trials has supported two virtual seminars on clinical trial topics that have been made freely available ( https://www. nih. gov/include-project/events ).

One webinar held November 15, 2022, addressed issues of assent and consent; another held on April 25, 2023, entitled “Let’s Talk About Clinical Trials” discussed inclusion of individuals with DS in clinical trials and clinical research.

The Clinical Trial Readiness Working Group that evolved out of the INCLUDE-sponsored Workshop in fall 2019 also summarized some of the barriers to participating in clinical trials, including legal and ethical considerations involving assent/consent and the decision-making capacity of individuals with DS. ( Baumer et al. , 2022 ).

Several INCLUDE-funded investigators are also studying elements of informed consent and assent in people with DS across the age spectrum to ensure that they can be included in clinical research safely and ethnically. In addition, NIH recently convened a working group of the principal investigators engaged in INCLUDE-funded clinical trials.

The working group meets quarterly to share recruitment strategies, develop collaborative projects, and facilitate clinical research for DS. 7. THE DS-CONNECT ® REGISTRY AND OTHER RESOURCES THAT SUPPORT INCLUDE NIH has supported several resources to facilitate DS research, including a consortium to bring together the DS community ( Oster-Granite et al.

, 2011 ). In 2011, NIH first convened the DS Consortium ( https://downsyndrome. nih.

gov/ ) as a public-private-partnership to support the exchange of information about DS research and health care. Composed of 13 NIH Institutes and Centers, along with 17 professional, advocacy, and foundation members with a DS focus, and 3 adult self-advocates, this group provided critical input into the development of the first national registry for DS. The registry, DS-Connect ® : The Down Syndrome Registry ( https://dsconnect.

nih. gov/ ), was launched in 2013 by NICHD to create a secure online resource to enhance participation by connecting eligible families with research opportunities of interest to them ( Peprah et al. , 2015 ).

All participants have access to the aggregate de-identified data and can download their own survey responses to serve as a reference for families or medical providers.

Additional resources available for families are a crowd-sourced compilation of health care providers listed by specialty and location; links to health care guidelines appropriate for the age of the participant with DS; standardized DS-specific growth charts for monitoring height, weight, and body mass index of children with DS as they grow; a list of currently used medications; and a link to find NIH-supported clinical studies for people with DS on ClinicalTrials.

gov . DS-Connect has over 5800 registered participants currently, with the majority in the U.S. The registry content is also available in Spanish to increase access by Spanish-speaking families within the U. S and worldwide.

DS-Connect also has a professional portal where approved researchers can view the aggregate de-identified data and request recruitment support; the Registry coordinators serve as “trusted brokers” who send out study notifications to eligible participants or families, who can decide whether to take part in the advertised study.

Thus far, DS-Connect has promoted research enrollment for over 100 projects, 15 INCLUDE-funded, including 5 clinical trials. A list of studies that are currently recruiting through the registry can be found on the DS-Connect website . Among the projects supported by the registry are a survey of dietary supplement use in children with DS ( Lewanda et al.

, 2018 ), a survey of parents utilizing a validated tool to assess measures of global health in their children with DS ( S. L. Santoro et al.

, 2023 ), application of the Research Attitudes Questionnaire to over 1000 families in the DS-Connect Registry ( Lott et al. , 2022 ), the comfort of caregivers with the transition to adult care for their children with DS ( VanZant & McCormick, 2021 ), and a survey of preventive and gynecologic health care uptake by adult women with DS ( Smith et al. , 2020 ).

Another research tool supported by NIH is the Jackson Laboratory (JAX) Cytogenetic and Down Syndrome Models resource ( The Jackson Laboratory, 2023 ) ( https://www. jax. org/research-and-faculty/resources/cytogenetic-and-down-syndrome-models-resource ).

Subsidized by a contract from NICHD, this resource provides DS mouse models free of charge for federally funded investigators. In addition to many of the typical mouse models used in many basic science projects supported by INCLUDE, the resource has, in recent years, brought new models into the repository, including the TcMAC21 strain with a human chromosome 21q attached to a mouse centromere for stable segregation ( Kazuki et al.

, 2020 ). Several projects funded by INCLUDE are developing rat models for DS or other resources such as cell atlases or isogenic iPSC lines. 8.

A COMMITMENT TO DIVERSITY The INCLUDE Project Diversity, Equity, Inclusion, and Accessibility (DEIA) Workgroup was formed to address the need for NIH-led DS-related research activities to increase their diversity.

Although the DS-Connect ® registry has been a great resource for investigators when recruiting participants for their studies, most of the participants in the registry are not from diverse backgrounds with regard to race, ethnicity, level of education, and/or economic status, and many of the participants in INCLUDE-funded projects also do not reflect the racial and ethnic diversity of the U.S. The goal of the INCLUDE DEIA Workgroup is to learn about and implement strategies from other programs that have been successful in engaging underrepresented groups in their research activities.

The Workgroup has developed projects, initiatives, and an outreach plan to increase diversity and inclusion in NIH-supported DS research. One of the most significant events sponsored by the INCLUDE DEIA Workgroup was a 2-day virtual workshop, “Building a Diverse Community for Down Syndrome Research” ( National Institutes of Health, 2022 ) held September 20–21, 2022 ( https://www. nih.

gov/include-project/building-diverse-community-down-syndrome-research-virtual-workshop ). This workshop was the culmination of two listening sessions, one