Key Dates

Related Announcements

NOT-AG-20-055 - Notice of NIA Withdrawal from Participation in NOT-OD-20-129

PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)

PA-18-935 Urgent Competitive Revision to Existing NIH Grants and Cooperative Agreements (Urgent Supplement - Clinical Trial Optional)

NOT-OD-20-017 Notice of Special Interest to Encourage Development of Animal Models and Related Biological Materials for Research Related to Down Syndrome

NOT-OD-20-020 Notice of Special Interest (NOSI): Ruth L. Kirschstein National Research Service Award (NRSA) Fellowship Awards to Support Training in Research Related to Down Syndrome as Part of the INCLUDE Project

NOT-OD-20-021 Notice of Special Interest (NOSI): Mentored Career Development Awards To Support Training in Research Related to Down Syndrome as Part of the INCLUDE Project

NOT-OD-20-022 Notice of Special Interest: Administrative Supplements for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project to NIH-funded K12 and KL2 Institutional Career Development Awards

NOT-OD-20-023 Notice of Special Interest: Availability of Competitive Supplements/Revisions for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndromE) Project (Competitive Supplement/Revision Clinical Trial Optional)

NOT-OD-20-024 Notice of Special Interest: Availability of Administrative Supplements for the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project

NOT-OD-20-025 Notice of Special Interest: NIH Research Project Grants on Down Syndrome (R01)

RFA-OD-20-003 Clinical Trials Development for Co-Occurring Conditions in Individuals with Down syndrome: Phased Awards for INCLUDE (R61/R33 Clinical Trial Required)

RFA-OD-20-004 Nvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Clinical Trial Readiness (R21 Clinical Trial Not Allowed)

RFA-OD-20-005 Transformative Research Award for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project (R01 Clinical Trial Not Allowed)

RFA-OD-20-006 Small Research Grants for Analyses of Down Syndrome-related Research Data for the INCLUDE Project (R03 Clinical Trial Not Allowed)

RFA-OD-20-007 Development of the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndromE) Project Data Coordinating Center (U2C)

RFA-OD-21-007 - INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Exploratory/Developmental Research Grant Award (R21 Clinical Trial Not Allowed)

Issued by

Office of The Director, National Institutes of Health (OD)

National Heart, Lung, and Blood Institute (NHLBI)

National Human Genome Research Institute (NHGRI)

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute on Deafness and Other Communication Disorders (NIDCD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute of Environmental Health Sciences (NIEHS)

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute on Minority Health and Health Disparities (NIMHD)

National Center for Complementary and Integrative Health (NCCIH)

National Center for Advancing Translational Sciences (NCATS)

Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP)

National Cancer Institute (NCI)

Purpose

NIH is issuing this Notice of Special Interest (NOSI) to highlight the urgent need for research on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) in individuals with Down syndrome in conjunction with the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project. Because many people with Down syndrome are at increased risk of having co-occurring medical conditions, such as pulmonary disease, cardiac problems, obesity, diabetes, sleep apnea, and altered immune function that may predispose them to more severe infection with SARS-CoV-2, they may be particularly vulnerable to COVID-19 complications. Combined with shared living situations, and reduced access to testing and treatment services due to disparities in provision of resources, the impact of COVID-19 infection in people with Down syndrome is likely to be elevated. The overarching goal of this NOSI is to improve understanding and treatment of COVID-19 infection in individuals with Down syndrome and reduce COVID-19 associated morbidity and mortality for this population, which may be disproportionately affected by, have higher infection rates of, and/or be at elevated risk for adverse outcomes from contracting the virus.

Background

The Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project was developed in response to Fiscal Year 2018 and 2019 Consolidated Appropriations Acts, which encouraged the NIH to expand its current efforts on Down syndrome and common co-occurring conditions also seen in the general population while increasing the pipeline of Down syndromeinvestigators. Information about projects that were funded in 2018 and 2019, as well as the INCLUDE Project Research Plan, is available on the INCLUDE Project website.

Individuals with Down syndrome face significant and changing health challenges but have often been excluded from participation in research that could improve their health outcomes and quality of life. This population is understudied even though Down syndrome is the most common genetic cause of intellectual and developmental disabilities (IDD) and, in the past 25 years, the average lifespan has doubled from 30 to 60 years. In addition to intellectual disability, Down syndrome is associate with an increased prevalence of autism and epilepsy. About 75% of individuals with Down syndrome experience cognitive decline in a syndrome that resembles Alzheimer’s disease, but with onset a decade or two earlier than typical Alzheimer’s disease. Individuals with Down syndrome also have high rates of congenital heart defects, sleep apnea, pulmonary hypertension, obesity, gastrointestinal malformations, thyroid disease, diabetes, leukemia, and other autoimmune or immune dysregulation disorders.

The leading causes of mortality in individuals with Down syndrome are pneumonias, respiratory failure, and dementia. In particular, given that many interferon receptor genes map to chromosome 21, and people with Down syndrome have three copies of chromosome 21, the result is a hyperactive immune system with elevated levels of inflammatory markers that results in a baseline cytokine storm status that may predispose them to infection with viruses such as SARS-CoV-2, increasing their risk of severe respiratory tract involvement, respiratory failure and mortality from this virus. In addition, they may be at increased risk of contracting COVID-19 due to residence in congregate housing settings and may experience more severe illness and death given the increased mortality due to the infection in those with IDD. They also have potential to experience health disparities related to access to diagnostic testing, treatment, and interventions. Understanding this unique combination of risk factors will inform testing and treatment for those with Down syndrome who may contract COVID-19 infection.

Research Objectives

In order to rapidly improve our understanding of SARS-CoV-2 and COVID-19 infection, NIH is encouraging the submission of applications for administrative supplements and urgent competitive revisions to active NIH grants to address the pathology, prevention, diagnosis, sequelae, or treatment of COVID-19 in people with Down syndrome. This funding opportunity is intended to support applications that focus on immediate needs to help address the COVID-19 pandemic in a timely manner.

Applications should address whether ongoing or potential future public health restrictions (e.g., closures, physical distancing) might affect the research approach, and if so, include a plan to prevent or mitigate any effect on the proposed study.

General Objectives (relevant to more than one Institute or Center (IC) at NIH):

• Relationships of individual factors, including co-existing conditions and medications, to resilient or adverse outcomes to SARS-CoV-2 exposure in individuals with Down syndrome.
• Studies in pre-hospital, emergency, or critical care settings to improve screening, risk stratification, diagnostic testing, care delivery decisions, resource allocation, and clinical outcomes for those with Down syndrome exposed to SARS-CoV-2.
• Studies of prevention practices (hand washing, effectively covering a cough, social distancing, etc.) and factors that influence adherence, including individual and age differences and social network effects for populations with cognitive impairment such as Down syndrome.
• Evaluation of pharmacological or health care delivery intervention strategies in those with Down syndrome after exposure to SARS-CoV-2 to prevent or mitigate morbidity and/or improve post-infection health and function.
• Evaluating strategies used by health systems to reallocate resources, rapidly train practitioners, communicate preventative practices, and maintain adherence to public health and clinical guidelines, with a particular interest in those that serve high-risk groups (e.g., group homes, nursing homes) and resulting racial, ethnic, or regional disparities in access/care.
• Leveraging longitudinal studies to elucidate how COVID-19-related changes in the social, economic, institutional, and policy environments differentially impact the health and welfare of people across the life course and in vulnerable social groups, such as those with Down syndrome; comparative studies of regional and national approaches are encouraged.

Areas of specific interest by participating Institutes, Centers, and Offices include, but are not limited to, the following:

National Cancer Institute (NCI):

• To better understand the impact of SARS-CoV-2 infection and its impact on disease progression, response to therapy, care delivery, or survivorship in infants and children with Down syndrome and co-occurring cancer, such as leukemia.
• Of particular interest are studies that take advantage of unique cancer model systems or analytical tools to study the consequences of SARS-CoV-2 infection and COVID-19 disease progression. Supported research is expected to inform future efforts to diagnose, prevent, mitigate, or treat this viral infection in children with Down syndrome who have leukemia or transient myeloproliferative disorder (or pre-cancer), undergoing treatment for cancer, or are in remission.

National Heart, Lung, and Blood Institute (NHLBI):

• To elucidate the clinical trajectory of cardio-respiratory illness, response to therapy, and outcomes in individuals with Down syndrome and COVID-19, including, but not limited to, sudden death, respiratory insufficiency progressing to failure, arrhythmias, myocardial dysfunction, coagulation disorders (including, but not limited to, predisposition to venous thromboembolism),and pulmonary hypertension; and also in individuals with Down syndrome and co-existing conditions such as obstructive sleep apnea, obesity, and congenital heart disease (pre- and post-surgery).
• To assess and refine approaches to the management of critically ill individuals with Down syndrome and COVID-19 including, but not limited to, the assessment and optimization of different ventilatory strategies in acute respiratory distress syndrome (ARDS), the risks and benefits of prone positioning in management of these individuals considering their habitus and airways, and their susceptibility and/ or resilience to end-organ damage as a consequence of profound hypoxemia.
• To better understand the pathogenesis of pneumonia and the basic mechanisms of cytokine surge from COVID-19 closely-coupled and/or specific to Down syndrome, e.g., gamma-interferon mediated mechanisms, with the goal of identifying druggable biological pathways for these mechanisms.
• To understand the effect of COVID-19 on central ventilatory control and response to hypoxemia in individuals with Down syndrome.
• To assess clinical trajectory and response to therapies in people with Down Syndrome presenting with the recently described Multisystem Inflammatory Syndrome in Children (MIS-C) with left ventricular dysfunction and/or coronary artery aneurysms.

National Human Genome Research Institute (NHGRI):

• Develop novel methods using genomic techniques to identify signatures of infection, prognosis, and/or severity of disease for individuals with Down syndrome in a medical setting.
• Use of electronic health information, or other relevant clinical, environmental, demographic and social determinants of health data, and accompanying genomic data, to aid in tracking and understanding the genetic epidemiology of SARS-CoV-2, and the individual susceptibility and resistance to infection and disease severity in those with Down syndrome.
• Studies addressing the ethical, legal, and social implications of the use of genetic and genomic information and technologies to diagnose, track, monitor, treat, and triage SARS-CoV-2 and COVID-19 infected individuals and populations with Down syndrome in clinical and public health settings.

National Institute of Allergy and Infectious Diseases (NIAID):

• Studies to understand critical aspects of viral infection and pathogenesis in individuals with Down syndrome.
• The development of SARS-CoV-2 infection in Down syndrome animal models suitable for therapeutic candidate and/or pathogenesis studies.
• Identification and evaluation of the innate, cellular, and humoral immune responses to SARS-CoV-2 infection and/or candidate vaccines, in individuals with Down syndrome.

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS):

• Research on SARS-CoV-2 and COVID-19 in the Down syndrome population relevant to the areas of arthritic (and other rheumatic), musculoskeletal, and skin anomalies and disorders.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

• Research on whether children with Down syndrome are more susceptible to Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 infection.
• Studies to understand whether infection with SARS-CoV-2 is more severe in children with Down syndrome and underlying health conditions such as congenital heart disease, pulmonary hypertension, or frequent respiratory infections than in those without such co-occurring conditions.
• Studies to determine whether past infection or vaccination, if available, to SARS-CoV-2 provides lasting immunity in children with Down syndrome.
• Research to determine if COVID-19 infection in adolescents and young adults impacts risk of cognitive decline, behavioral or mental health conditions, and/or regression.
• Incorporation of COVID-19 elements into existing registries for the purpose of tracking the testing, diagnosis, and/or treatment of the infection in people with Down syndrome.

National Institute on Deafness and Other Communication Disorders (NIDCD):

• Research on SARS-CoV-2 and COVID-19 in the Down syndrome population relevant to the areas of hearing, balance, taste, smell, voice, speech, and language.
• Specific impacts on communication for those with Down syndrome in the context of a pandemic with enforced social distancing, including impacts to services or interventions.

National Institute of Dental and Craniofacial Research (NIDCR):

• Topics that would be of immediate and high impact to protect and ensure the safety of personnel in dental practices and their patients comprised of individuals with Down syndrome:

  • Modifications to dental practice and/or treatment space to prevent aerosol and droplet pathogen transmission

  • Determination of the extent to which viral pathogens are transmitted via aerosol and droplet routes during treatment in dental settings

  • Design and implementation of strategies to achieve the Centers for Disease Control and Prevention (CDC) second-tier Transmission-Based Precautions in dental practice

  • Implementation of disinfection processes to ensure treatment spaces and equipment are devoid of transmissible viral pathogens

  • Development of interventions to protect health care workers, other front-line professionals, and patients from viral transmission
• Assessment of the impact of dental care delivery delays upon oral health needs and access to care, especially for vulnerable Down syndrome populations and those affected by health disparities.

• Development or implementation of strategies to triage and manage those with Down syndrome who have oral care needs, including via remote or virtual means.

• Examination of the role of oral/nasal microbiota and ACE2 receptor on SARS-CoV-2 infectivity and carriage in oral fluids and nasal secretions in the Down syndrome population, as gateways to the spread of infection into the respiratory tract via proof of principle studies.

• Pilot testing of existing therapeutic modulators of oral microbiota that may limit infectivity of SARS-CoV-2 in those with Down syndrome.

• Performance of research conducted within the National Dental Practice-Based Research Network (PBRN), which supports clinical research studies in dental practices with dental practitioners and their consenting patients as well as survey studies of practitioners and/or their patients which include individuals with Down syndrome. Potential applicants are strongly encouraged to review the process for potential grant applicants to interact with and utilize National Dental PBRN resources.

• Implementation of FDA-approved detection and screening tests for SARS-CoV-2 virus and antibodies to improve triage and early disease management strategies for those with Down syndrome.

National Institute on Minority Health and Health Disparities (NIMHD):

• Including individuals with Down syndrome from NIH-designated health disparity populations (Blacks/African Americans, Hispanics/Latinos, American Indians/Alaska Natives, Asians, Native Hawaiians and Other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities) into existing clinical or community-based studies in sufficient number to study:
  • Intersectional stigma and discrimination and their impact on health and healthcare utilization.
  • Coping strategies, social support, and other protective factors related to chronic disease risk and outcomes.
  • Access to and quality of healthcare, including primary, specialty, and behavioral health care.
  • Evaluating the transition from child to adult healthcare and other service systems.

National Institute on Neurological Disorders and Stroke (NINDS):

• Studies to understand the biologic effects of SARS-CoV-2 infection on the brain, spinal cord, and nerves in individuals with Down syndrome. This includes acute neurological symptoms, with symptoms ranging from the relatively mild (anosmia and dysgeusia) to the more extreme (encephalitis, ataxia, seizures, and cerebrovascular events such as stroke). This also includes potential delayed effects of COVID-19, such post-viral complications (e.g., acute disseminated encephalomyelitis and Guillain-Barre syndrome).
• Establishment and maintenance of a database designed to collect clinical information on the neurological manifestations of SARS-CoV-2 in individuals with Down syndrome. Such a database should address the objectives outlined in NOT-NS-20-046 and align with centralized NINDS data collection efforts.
• Studies using telemedicine in the diagnosis and treatment of neurological symptoms in individuals with Down syndrome.

National Center for Complementary and Integrative Health (NCCIH):

• In in vivo animal models of Down syndrome, conduct assessments of natural product therapeutic candidates or repurposed existing or candidate natural product therapeutics initially developed for other indications against SARS-CoV-2, and study the mechanisms of action of the candidates in treatment and prevention of COVID-19, such as suppressing virus transmission, infection (loading, entry, fusion), and replication; and/or regulating innate, adaptive, cellular, and humoral immune systems including immune-mediated pathologies or host interactions (molecular pathways, cytokine storms, free radicals, etc.).

Office of Research Infrastructure Programs (ORIP):

• ORIP is interested in supporting projects aimed at enhancing existing and creating new animal models of Down syndrome for studying mechanisms underlying COVID-19 in the context of Down syndrome. Preference will be given to applications that develop informative animal models and demonstrate their potential for investigating multiple phenotypic features of COVID-19 in the context of Down syndrome, rather than focusing on a specific phenotype of the disease.
• Note that ORIP will only consider applications submitted under PA-18-591 or subsequent reissued equivalents.

Considerations

To maximize comparisons across datasets or studies, and facilitate data integration and collaboration, researchers funded through this NOSI are strongly encouraged to use the following resources:

• Data Harmonization for Social Determinants of Health via the PhenX Toolkit: Investigators involved in human-subject studies are strongly encouraged to employ a common set of tools and resources that will promote the collection of comparable data on social determinants of health (SDOH) across studies. In particular, human-subject studies should incorporate SDOH measures from the Core and Specialty collections that are available in the Social Determinants of Health Collection of the PhenX Toolkit (www.phenxtoolkit.org).
• NIH is encouraging researchers to explore the use of the HL7 FHIR (Fast Healthcare Interoperability Resources) standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data (NOT-OD-19-122). FHIR resources may be particularly useful in the development of computational tools used in COVID-19 research and data sharing.
• Additional emerging data terminologies, ontologies, and standards should be considered in describing semantic content of data and metadata for COVID-19 research (e.g., LOINC, SNOMED, ICD-10, and others described here: https://covid.cd2h.org/forms_and_standards).
• A trans-NIH working group is making existing COVID-19 survey items and investigator contact information publicly available through two NIH-supported platforms: the NIH Public Health Emergency and Disaster Research Response (DR2) [https://dr2.nlm.nih.gov/] and the PhenX Toolkit [https://www.phenxtoolkit.org/index.php]. Researchers addressing COVID-19 questions, whether population-based or for clinical research, are strongly encouraged to consider these COVID-19 specific survey item repositories and select existing survey items or protocol modules currently being fielded.
• Additionally, researchers with funding through this NOSI will be strongly encouraged to share their survey items to make them public for other researchers to consider by submitting their surveys to NIHCOVID19Measures@nih.gov.
• Projects that propose to recruit subjects with Down syndrome are encouraged to promote enrollment of research subjects in the Down syndrome patient registry supported by NIH,DS-Connect . For other data and biospecimens from human genetic or non-genetic studies, awardees are encouraged to use biorepositories designated by INCLUDE staff that meet requirements for broad sharing.

In addition to the review criteria described in PA-18-591 and PA-18-935, and as applicable for the project proposed, reviewers will also evaluate:

• To what extent does the application address the goals of the INCLUDE Project?
• How relevant is the proposed research in regard to addressing the key areas identified as priorities for COVID-19 research in Down syndrome?
• How likely is it that the investigators will have immediate access to the necessary resources (e.g., patient samples, isolates, test kits, laboratory access, etc.) to achieve the aims of the proposed research?
• How strong are the proposed plans for the execution of the proposed work if laboratory access is limited or restricted due to the COVID-19 pandemic?
• How likely is it that the proposed research will generate unique resources or data that could impact the public health response?
• How adequate is the resource sharing plan?

Review and Selection Process: Applications to both PA-18-591 and PA-18-935 will be evaluated for scientific and technical merit by an appropriate internal review panel convened by staff of the NIH INCLUDE Project Team, in accordance with the stated review criteria and any additional review criteria specified.

Application and Submission Information

Application Due Dates: July 13, 2020, November 12, 2020, March 12, 2021, and July 12, 2021 by 5:00 PM local time of applicant organization.

Applications for this initiative must be submitted electronically using one of the following target opportunities or their subsequent reissued equivalents:

• PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
• PA-18-935 Urgent Competitive Revision to Existing NIH Grants and Cooperative Agreements (Urgent Supplement - Clinical Trial Optional)

NIH anticipates that most applications in response to this NOSI will be expanding the scope of the parent award and will be submitted in response to PA-18-935. The definition of scope can be found in the NIH Grants Policy Statement. The funding instrument, or activity code, will be the same as the parent award.

Applicants must follow all instructions in the SF424 (R&R) Application Guide and in the selected target funding opportunity announcement (PA-18-591 or PA-18-935), with the following additions:

• Budget:
  • For applications targeting PA-18-591 (Administrative Supplement), application budgets are limited to no more than the amount of the current parent award or $1,000,000 in direct costs, whichever is less, and must reflect the actual needs of the proposed project.
  • For applications targeting PA-18-935 (Urgent Competitive Revision), application budgets are limited to no more than $1,000,000 in direct costs, and must reflect the actual needs of the proposed project.
  • Exceptions to these budget limits may be made with NIH pre-approval and will only be approved under the very rare circumstances where the work may immediately impact public health.
• Project Period: Applicants may request a budget period for only one year of support and that year must align with the existing parent award. The parent award must be active when the supplement application is submitted (e.g. within the originally reviewed and approved project period), regardless of the time remaining on the current project.
• Abstract: The Abstract section should describe the proposed supplement.
• Research Strategy: The Research Strategy section should provide a summary or abstract of the funded parent award or project and describe the relevance of the proposed project to the funded parent award and the INCLUDE project. Describe the component(s) and any IC-specific priorities that the supplement is addressing. The Research Strategy is limited to 6 pages
  • Applicants should address whether ongoing or potential future public health restrictions (e.g., closures, physical distancing) might affect the research approach and, if so, include a plan to prevent or mitigate any effect on the proposed study.
• Administrative supplement applications to PA-18-591must use the application form package with theCompetition ID that contains "FORMS-F-ADMINSUPP." In addition, the process forStreamlined Submissions using the eRA Commons cannot be used for this initiative.
• Competitive revision applications to PA-18-935 must use the application form package with the Competition ID that contains "FORMS-F-COMP-REV."
• All applications (including those for multi-project activity codes) must be submitted electronically using a single-project application form package.
• For funding consideration, applicants must include NOT-OD-20-129 in the Agency Routing Identifier field (Box 4.b) of the SF 424 (R&R) Form. Applications without this information in Box 4b will not be considered for this initiative.

Pre-award costs may be incurred from January 20, 2020 through the public health emergency period and prior to the date of the federal award.

The process for Streamlined Submissions using the eRA Commons cannot be used for this initiative.

The INCLUDE Program Office will not consider applications that fail to meet the terms of this NOSI.

Applicants are strongly encouraged to notify the program contact at the Institute supporting the parent award that a request has been submitted in response to this FOA in order to facilitate efficient processing of the request.

This NOSI expires on July 13, 2021. An application submitted in response to this NOSI that is received on/after the expiration date will be withdrawn.

Inquiries

Please direct all inquiries to the contact at the Institute, Center or Office supporting the parent award as indicated on the funding page of the INCLUDE Project website.

Financial/Grants Management Contact(s)

Ryan Talesnik
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Telephone: 301-435-6976
Email: talesnikr@mail.nih.gov