NOT-OD-18-194: Notice of Availability of Administrative Supplements for NIH Grants that are NOT Focused on Down Syndrome to Address Specific Down Syndrome Research Objectives

Notice of Availability of Administrative Supplements for NIH Grants that are NOT Focused on Down Syndrome to Address Specific Down Syndrome Research Objectives

Notice Number: NOT-OD-18-194

Key Dates
Release Date: June 20, 2018

Related Announcements
NOT-OD-18-203
NOT-OD-18-204
PA-18-591
NOT-OD-18-195

Issued by
National Institutes of Health (NIH)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Heart, Lung, and Blood Institute (NHLBI)
National Human Genome Research Institute (NHGRI)
National Institute on Aging (NIA)
National Institute of Allergy and Infectious Diseases (NIAID)
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 General Medical Sciences (NIGMS)
National Institute of Mental Health (NIMH)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Nursing Research (NINR)
National Institute on Minority Health and Health Disparities (NIMHD)
National Center for Complementary and Integrative Health (NCCIH)
National Center for Advancing Translational Sciences (NCATS)

Purpose

The purpose of this Notice is to solicit administrative supplement applications to existing awards that are currently NOT focused on Down syndrome research in order to accelerate scientific progress to meet new NIH Down syndrome research objectives, as described below. Please see NOT-OD-18-195 for a companion notice for applications that are currently focused on Down syndrome.

Down syndrome 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 5300 babies born in the United States with Down syndrome. Within the past 25 years, the average lifespan for a person with Down syndrome has doubled, from 30 to 60 years. While all people with Down syndrome 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.

This notice initiates a new trans-NIH program to support research on commonly co-occurring conditions in individuals with Down syndrome that are also seen in the general population, such as Alzheimer’s disease/dementia, autism, cataracts, celiac disease, congenital heart disease, immune system dysregulation, and diabetes. This is known as the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Information learned by studying people with Down syndrome will also help us learn about these conditions in people without Down syndrome. Likewise, common complications of aging, such as coronary heart disease and solid cancers, are rarely seen in individuals with Down syndrome; this warrants additional study.

This new research initiative expands many of the research objectives and opportunities previously highlighted in the 2014 Down Syndrome Directions: NIH Research Plan on Down Syndrome. More recent discoveries have enhanced our understanding of chromosome segregation and chromosome silencing, identified certain proteins and neurotropic factors involved in brain development using mouse models, and uncovered the role of interferons in immune dysregulation, each of which have the potential to lead to development of novel therapies for individuals with Down syndrome, as well as broader applications. People with Down syndrome are often excluded from clinical research, such as trials of potentially beneficial drugs and therapeutics that are used to treat the same condition in the general population. There is great value in connecting people with Down syndrome to therapies that could improve their overall health and quality of life. And there is great interest in the Down syndrome community in participating in clinical research, based on experience from NICHD’s DS-Connect : The Down Syndrome Registry, (https://DSConnect.nih.gov ), an online survey tool that introduces individuals with Down syndrome and their families to research opportunities. Opportunities to engage the Down syndrome community in research are also facilitated by the members of the Down Syndrome Consortium, a public-private partnership involving NIH Institutes and Centers, advocacy groups, private foundations and professional organizations, and self-advocates and families, all sharing a passion for promoting research that will benefit people with Down syndrome.

A comprehensive clinical cohort study with deep phenotyping and exploration of pan- omics will permit identification of biomarkers and outcomes for the co-occurring conditions in Down syndrome. Coupled with development of a clinical trials readiness program, and informed by basic science discoveries, this combination of resources could have a great impact on addressing health disparities that exist for people with Down syndrome and could also lead to the development of therapies to improve outcomes for those with and without the condition.

Supplement applications will be considered eligible for funding if they address one or more of the following components related to the INCLUDE Project research objectives:

Component 1: Targeted, high risk-high reward, basic science studies in areas highly relevant to Down syndrome: For basic science studies, supplements should target areas of science of highest impact and that are likely to translate into new therapeutic approaches to Down syndrome, even if the parent award is not focused on Down syndrome. Topics of emphasis may include: chromosome silencing, immune system dysregulation, epigenetic/metabolomic/transcriptomic profiling in model organisms/iPSCs/brain organoids, development of novel model systems, and development of a molecular atlas for cardiac and other specimens. Supplements could also support projects that will inform the other two components, namely a cohort study and a clinical trials network.

Component 2: Molecular snapshot of Down syndrome through a cohort study: The goal is to add a Down syndrome cohort to an existing cohort focused on a condition that commonly co-occurs in Down syndrome, with data collected in a shared database using common data elements and building on the DS-Connect patient registry. Supplements could add comprehensive molecular (i.e. pan- omics) analyses or support existing infrastructure for sample and neuroimaging collection in the Down syndrome population.

Component 3: Inclusive clinical research for individuals with Down syndrome: Supplement requests could leverage existing clinical trials infrastructure to add a new Down syndrome cohort to an existing trial, to start building in Down syndrome-specific modules for a future study, or to test drugs or therapies for co-occurring conditions in the Down syndrome population. Of particular interest are ongoing clinical trials testing therapies for common conditions such as asthma or sleep apnea that occur in people with and without Down syndrome.

We encourage projects that:

Are within the scope of the active parent award
Are not currently focused on Down syndrome but could add a Down syndrome cohort, module, or model system of great relevance to Down syndrome
Propose to address one of the components listed under the Down syndrome research objectives
Are likely to stimulate additional activity leading to progress on Down syndrome
Address a priority for the IC that issued the parent award (if applicable--see below)

Investigators should submit applications as responses to the parent active administrative supplement PA, Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) : https://grants.nih.gov/grants/guide/pa-files/PA-18-591.html

Supplements to existing clinical trials are allowed, but addition of a new clinical trial that was not a part of the parent award is not allowed. Supplement requests addressing components 2 or 3 should encourage participants with Down syndrome or their caregivers to register in DS-Connect : The Down Syndrome Registry (https://DSConnect.nih.gov).

If the parent award is focused on Down syndrome, see NOT-OD-18-195

Before submitting a supplement request, principal investigators are strongly encouraged to contact their program officer or the program contact at the Institute, Center or Office supporting the parent award to discuss whether the proposed supplement is within the scope of the INCLUDE Project and the priorities of the IC supporting the parent award or with any questions.

Award Project Period

To be eligible, the parent award must receive funds in FY18 (Oct. 1, 2017-Sept. 30, 2018) and not be in an extension period. The request is for one year of funding, but the research proposed in the supplement must be accomplished within 1-2 years. The earliest anticipated start date is August 1, 2018.

Budget

Supplement budget requests cannot exceed $500,000 in direct costs exclusive of Facilities and Administrative costs on sub-contracts, or 50% of the direct costs of the current parent award, whichever is less. Requests must reflect the actual needs of the proposed project. Requests may be for one year of support only. Modular and categorical budgets are permitted.

Eligible Individuals (Program Director/Principal Investigator)

Individual(s) must hold an active grant or cooperative agreement. For supplements to parent awards that include multiple PDs/PIs, the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award.

Submitting an Application

For additional information, see the parent program announcement to Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) PA-18-591.

As part of the application investigators should submit a no more than one-page abstract of the proposed research that shows the relevance to the INCLUDE project and articulates the component(s) and any IC-specific priorities that the supplement is addressing. Applicants should begin the supplement application abstract by stating: This application is being submitted to PA-18-591 in accordance with NOT-OD-18-194."

Page Limits: NIH will consider supplements with a Research Strategy of no more than 6 pages, in addition to the abstract.

Supplements should be submitted electronically if allowed by parent mechanism. In addition, applicants are strongly encouraged to notify the program contact at the institute that is supporting the parent award (see list below) that an application has been submitted in response to this FOA in order to facilitate efficient processing of the request.

Requests must be received by 5:00 PM Pacific Daylight Time (P.D.T.) on July 23, 2018 for funding in FY 2018.

Institute, Center (IC) and Office-specific Instructions

National Cancer Institute (NCI): NCI priorities include the following:

Evaluation of the genetic, epigenetic, and epidemiologic factors associated with trisomy 21 that lead to greatly increased risk of childhood leukemias and that lead to the distinctive biological and clinical behavior of these leukemias.
Evaluation of the genetic, epigenetic, and epidemiologic factors associated with trisomy 21 that lead to reduced risk for selected childhood and adult solid tumors.
Characterization of the biological and clinical factors that drive the development of transient abnormal myelopoiesis (TAM) and its progression to acute myeloid leukemia (AML) in children with trisomy 21.
Mining and/or generation of -omics datasets of clinically annotated specimens of Down syndrome acute lymphoblastic leukemia (ALL) and AML.
Translational research associated with completed/ongoing clinical trials to identify prognostic factors (e.g., minimal residual disease) that can be used to reliably guide treatment for children with leukemia associated with Down syndrome.

National Eye Institute (NEI):
The NEI is interested in supplementing existing grants that have the potential to further the understanding of ocular pathologies frequently seen in Down syndrome (manifestations that include, but are not limited to, cataract, amblyopia, strabismus and refractive errors). Applications examining the regulation or dysregulation of eye development in Down syndrome are also encouraged. Interested applicants are advised to contact the NEI program officer prior to submitting the supplement application.

National Heart, Lung, and Blood Institute (NHLBI): NHLBI priorities include the following:

Incorporation of individuals with Down syndrome into existing disease cohorts and clinical trials directed toward sleep apnea, congenital heart disease, pediatric pulmonary hypertension, and adult cardiovascular disease. This could include collection of tissue or blood specimens and -omics data generation and analysis (genomics, transcriptomics, metabolomics, etc.), imaging, computational modeling, or expansion of a clinical trial to include a number of Down syndrome cases necessary to provide sufficient statistical power for stratification. Studies are encouraged to leverage the DS-Connect registry to identify potential participants.
Mining and/or generation of -omics datasets of heart, lung, blood, and sleep disorders for functions of genes on chromosome 21 or downstream of genes on chromosome 21.

Characterization in animal models of the morphological events occurring in early heart development that give rise to the specific forms of congenital heart disease that are the primary cause of death during the first year of life for infants born with Down syndrome.
Characterization of differentiation of disease-related tissue types in induced pluripotent stem cells derived from cells from individuals with Down syndrome and compared to euploid iPSC cells.
Identification of potential risk and resilience factors that make individuals with Down syndrome susceptible to transient or persistent blood disorders and congenital heart disease but protected from adult cardiovascular disease.

National Human Genome Research Institute (NHGRI): NHGRI is interested in the following:

Ethical, legal and social implications (ELSI) related to preimplantation and prenatal screening and testing for trisomy 21.
Research into how Down syndrome is understood by individuals, families, and specific subgroups within society.

National Institute on Aging (NIA): NIA is interested in the following:

Epidemiologic, genomic, and mechanistic research studies aiming to understand the molecular mechanism underlying the interplay between aging and neurodegeneration in Down syndrome.
Mechanisms of resilience in Down syndrome individuals who remain free of dementia in the face of Alzheimer's pathology.
Understanding all aspects of brain aging in individuals with Down syndrome.
Identification of sensitive neuropsychological measures of cognitive decline, and imaging, blood-based, and genetic biomarkers associated with transition from normal aging to mild cognitive impairment to clinical dementia in adults with Down syndrome.
Of particular interest are studies that will generate and make available high quality 'omics data that can be used for downstream systems biology and other predictive modeling efforts.

National Institute of Allergy and Infectious Diseases (NIAID):
Addition of research focused on immune system dysregulation in Down syndrome; its molecular basis, impact on health, including infections and autoimmunity, and intervention strategies.

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

Basic science studies focused on chromosome silencing; white matter and brain development; gene therapy or prenatal therapy in animal models that can include a component of significant relevance to Down syndrome; studies of rodent models to understand cognition, behavior, and other aspects of the phenotype across different stages of development; development of novel tools for understanding the basic biology of Down syndrome, such as well-characterized induced pluripotent cell lines, cell and tissue repositories, new murine and other rodent models that can better replicate the chromosome regions syntenic to human chromosome 21 as well as reproduce the complex neurobehavioral and other phenotypic features of Down syndrome, and mechanisms to link to current model organism databases and resources.
Supplements that will increase the pool of individuals with Down syndrome for cohort studies, deep phenotyping, biospecimen collection, 'omics studies, and ultimately, clinical trials, such as through enhancements to recruitment, phenotyping services, and biobanks and supplements to perform pan-'omics approaches in readily available cohorts; supplements that will recruit individuals from IDeA states with limited NIH funding to ensure representation from rural and underserved areas; approaches that capture the priorities of parents and individuals with Down syndrome; supplements that facilitate linkages between pan-'omics data sets, patient-reported outcomes, electronic medical records, and DS-Connect to facilitate data sharing, data mining, and secondary uses; development and validation of sensitive, robust, and reproducible outcome measures for complex phenotypes such as cognition and behavior using tools such as the NIH ToolBox; studies to expand and extend the available biomarkers for studies of regression, aging, and dementia in adolescents and adults with Down syndrome; and studies of risk and resilience for co-occurring conditions in Down syndrome.
Studies to add a Down syndrome component to an existing pharmacologic clinical trial for a condition common in Down syndrome but for which dosage and efficacy have not been established in this population; supplements to existing clinical trial networks to establish the infrastructure necessary for clinical trials in those with Down syndrome, including efforts to link to existing datasets and add participants to DS-Connect ; studies to develop new therapeutics and interventions for people with Down syndrome; supplements that explore the ethical, legal, and social implications of research on populations with reduced decisional capacity and optimal methods for obtaining informed consent in those with Down syndrome.

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

Better understanding of the natural history of communication disorders (hearing, balance/vestibular, voice, speech, language, taste and smell) throughout the lifespan in Down syndrome.
Early identification and clinical management of communication disorders throughout the lifespan in individuals with Down syndrome.

National Institute of Dental and Craniofacial Research (NIDCR):

Oral health problems experienced by individuals with Down syndrome: malocclusion, increased caries, periodontal diseases and advanced pain.
Evidence-based evaluation of treatment approaches for individuals with Down syndrome: Is orthodontic treatment warranted? What are the best approaches for the treatment of sleep apnea in individuals with Down syndrome?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
NIDDK is interested in research focused on Down syndrome and obesity, urologic conditions, type 1 diabetes, autoimmune thyroid disease, and other autoimmune diseases within the purview of NIDDK.

National Institute of Environmental Health Sciences (NIEHS):
The PD/PI must propose a project that has a focus on environmental exposures within the NIEHS mission. Environmental agents which are considered of primary interest for NIEHS include: industrial chemicals or manufacturing byproducts, metals, pesticides, herbicides, air pollutants and other inhaled toxicants, particulates or fibers, fungal, and bacterial or biologically derived toxins. Investigators who propose studies with a primary focus on NIEHS mission-relevant exposures are encouraged to consider inclusion of other relevant environmental exposures (e.g., periconceptional smoking) in order to assess their role(s) as cofactors/modifiers of the risk or protection associated with the primary exposure(s). Applications that propose laboratory-based studies using only model compounds (i.e., those without potential for human exposure) must provide a clear, reasonable and specific description as to how research on the model compound will lead to a better understanding of the mechanisms involved in responses to specific environmental agents which are included in the mission responsibility of the NIEHS.

NIEHS priorities include the following:

Characterization of how environmental exposures are linked to cognitive/dementia phenotypic variations observed in individuals with Down syndrome.
Incorporation of animal models to explore how toxicity from environmental agents impact oxidative stress pathways which can exacerbate Down syndrome symptomology.
Exploration of the genetic susceptibility to environmental exposures influencing progression, onset, and/or severity of the complex clinical outcomes of individuals with Down syndrome.
Epidemiologic and mechanistic research studies aiming to understand the contribution of environmental exposures on subsequent co-morbidities and/or health factors of individuals with Down syndrome.

National Institute of General Medical Sciences (NIGMS):
As the NIGMS MIRA (Maximizing Investigators Research Award) program provides support for an investigator's overall program of research within the Institute’s mission, MIRA awardees are not eligible for this supplement program.

National Institute of Mental Health (NIMH):
NIMH supports translational research examining the neurodevelopmental underpinnings of psychopathology, as well as the onset, developmental trajectories, and outcomes of mental health conditions across the lifespan, including depression, anxiety, and psychosis. Research from a dimensional perspective is supported to identify fundamental components that span multiple disorders, such as attention, executive function or affective regulation, and may involve developing and/or validating biological markers, developing and/or validating methods or measures to assess domains of psychopathology, and testing integrative models within longitudinal frameworks to track trajectories of risk and protection. Of interest are supplements to add specific Down syndrome cohorts to develop validated measures of psychopathology for these individuals, and to elucidate the onset, course and functional outcomes, including risk and resilience, for individuals with Down syndrome who have comorbid psychopathology.

NIMH also supports studies investigating whether various mental disorders (such as schizophrenia, bipolar disorder, major depressive disorder, PTSD) increase the risks of developing dementia or excessive cognitive decline, or speed the rate of the biological aging process. Many of these studies follow aging adults prospectively, and most include protocols for neuroimaging of changes in brain structure and/or function, or for assessing molecular, cellular, neuroinflammatory, and other factors important in the biological aging process. Of interest are supplements to include persons with Down syndrome, and thereby to contribute usefully to an understanding of how Down syndrome often leads to early-onset, Alzheimer-type dementia or to accelerated biological aging.

Finally, NIMH has interest in discovery of specific genetic variants within the chromosome 21 critical region that have specific effects on comorbid diseases and mental health outcomes.

National Institute of Neurological Disorders and Stroke (NINDS): NINDS priorities include the following:

Addition of a Down syndrome component to a basic research study related to cognitive decline and Alzheimer's disease;
Understanding the role of aberrant neurotrophin signaling in the cognitive and behavioral characteristics of Down syndrome;
Development and characterization of animal models of developmental delays, cognitive, dysfunction and cognitive decline in Down syndrome;
Determine the role of white matter in individuals with Down syndrome.

National Institute of Nursing Research (NINR):
NINR priorities for research on co-occurring conditions across the lifespan of individuals with Down syndrome include health promotion, disease prevention, health disparities, caregiving, management of symptoms, self-management, genetics, epigenetics, palliative care needs and care at the end of life. Topics of special interest include integration of biological and behavioral sciences, application of new technologies to research questions, and improving the quality and effectiveness of interventions.

National Institute on Minority Health and Health Disparities (NIMHD):
NIMHD priorities include the inclusion of 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 conduct meaningful subgroup analysis.

Topics of particular interest related to individuals with Down syndrome from health disparity populations include but are not limited to the following:

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
The transition from child to adult healthcare and other service systems

National Center for Complementary and Integrative Health (NCCIH):
NCCIH priorities include the following:
Understand the use of mind and body approaches to improve cognitive function and for managing Down syndrome-associated health conditions (e.g., chronic pain, anxiety disorders, etc.)

Review process

Each IC will conduct administrative reviews of applications submitted to their IC separately. The NIH Office of the Director will make funds available for the top applications submitted for consideration for this cross-IC program.

Criteria:
1. Is the work proposed within the scope of the active award?
2. Is the work relevant to Down syndrome even though the parent award is not focused on Down syndrome research?
3. Does the work proposed address one of the components listed under the Down syndrome research objectives?
4. Does the work proposed have scientific merit?
5. Is the work likely to stimulate additional activity leading to progress on Down syndrome?
6. Does the work address a priority for the IC that issued the parent award (if applicable)?

Inquiries

Please direct all inquiries to the contact at the Institute, Center or Office supporting the parent award:

Melissa A. Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

Anna E. Mazzucco, PhD
National Institutes of Health (NIH)
Telephone: 301-451-1220
Email: [email protected]

Malcolm A. Smith, MD, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6087
Email: [email protected]

Houmam Araj, PhD
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Charlene Schramm, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-3793
Email: [email protected]

Joy T. Boyer, BA
National Human Genome Research Institute (NHGRI)
Telephone: 301-480-2247
Email: [email protected]

Laurie M. Ryan, PhD
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Frosso Voulgaropoulou, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3205
Email: [email protected]

Lana Shekim, PhD
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-496-5061
Email: [email protected]

Jason Wan, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-9898
Email: [email protected]

Ellen Leschek, PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK )
Telephone: 301-402-8291
Email: [email protected]

Jonathan A. Hollander, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 984-287-3269
Email: [email protected]

Donna Krasnewich, MD, PhD
National Institute of General Medical Sciences (NIGMS)
Telephone: 301-594-0943
Email: [email protected]

Lisa Gilotty, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-443-3825
Email: [email protected]

Robert Riddle, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]

National Institute of Nursing Research (NINR)
Rebekah S. Rasooly, PhD
Telephone: 301-827-2599
Email: [email protected]

Nathan Stinson, Jr., PhD, MD
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8704
Email: [email protected]

Robin Elizabeth Boineau, MD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-435-6286
Email: [email protected]

Erica K. Rosemond, PhD
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8927
Email: [email protected]