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 Omnibus Appropriations Reports, which encouraged the NIH to expand its current efforts on Down syndrome (DS) and common co-occurring conditions also seen in the general population while increasing the pipeline of DS investigators. 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 DS 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 DS 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, DS is associated with an increased prevalence of autism and epilepsy. About 75% of individuals with DS 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 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. However, people with DS infrequently develop solid tumors such as breast or prostate cancer. Despite multiple risk factors for coronary artery disease and high rates of obesity, sleep apnea, and type 1 diabetes, people with DS rarely develop atherosclerosis or have myocardial infarctions. Understanding this unique combination of risk and resiliencies will inform medical advances for individuals with DS and for individuals who do not have DS but who share these co-occurring conditions.

Research Objectives

This Notice of Special Interest (NOSI) announces NIH support for the professional development of early career scientists aiming to establish a career in DS-related research. By providing these scientists with career development research experiences , resources, and mentorship, the NIH intends to foster a pipeline of investigators in DS and other intellectual disabilities who will lead future research to improve the understanding of the biology of DS and support development of new treatments for health conditions experienced by those with DS. Sharing of resources and effective communication of outputs of appropriate interest to the broader communities are a high priority of the INCLUDE Project. Applicants responding to this NOSI are strongly encouraged to describe plans for rapid sharing of data and results as well as innovative data analytics approaches(see Goal 3, NIH Strategic Plan For Data Science).

The NIH is issuing this NOSI to expand the community of investigators conducting research related to DS by encouraging CTSAs to recruit scientists and physicians early in their research careers to develop research projects related to co-occurring conditions associated with DS. This NOSI will support additional scholar slots to those KL2 grants currently approved under the CTSA Program. Sharing of resources and effective communication of outputs to the broader communities are a high priority of the INCLUDE Project. Applicants responding to this NOSI are strongly encouraged to describe plans for rapid sharing of data and results as well as innovative data analytics approaches (see Goal 3, NIH Strategic Plan For Data Science).

A list of Funding Priorities by Institute and Center is available on the INCLUDE website. Applications in response to this NOSI should be aligned with the overall INCLUDE Project Research Plan, which consists of three components:

• Component 1: Targeted, high risk-high reward, basic science studies in areas highly relevant to Down syndrome
• Component 2: Cohort Study to connect existing resources and expand to inclusion of individuals with Down syndrome
• Component 3: Inclusive clinical trials research for co-occurring conditions in individuals with Down syndrome

Projects that propose to recruit subjects with DS 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. An NIH resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing.

For further information on INCLUDE priorities, resource sharing expectations, and participating NIH Institutes and Centers, see Frequently Asked Questions.

Application and Submission Information: Applications in response to this NOSI must be submitted to PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) or its subsequent reissued equivalent. All instructions in the SF424 (R&R) Application Guide and PA-18-591 must be followed, with the following additions:

• For funding consideration, applicants must include NOT-OD-20-022 in the Agency Routing Identifier field (box 4b) of the SF424 R&R form. Applications without this information in box 4b will not be considered for this initiative.
• The supplement must comply with all of the parent FOA requirements for the KL2 program.
• Requests may be for a minimum of two years and a maximum of four years of consecutive funding for each scholar, consisting of 12-month appointments (depending on the eligibility of the parent award).
• Scholar appointment(s) must be able to be fulfilled with the active parent project period.
• Only existing awardees of KL2 active awards are eligible to apply.
• The process for Streamlined Submissions using the eRA Commons cannot be used for PA-18-591
• 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 NOT-OD-20-022 in order to facilitate efficient processing of the request.
• Applicant organizations may submit more than one application to this NOSI. Each application should include only one named candidate for the supplement. Use unique project titles for each application to ensure our systems treat each application as a distinct submission.
• Application budgets must reflect the actual needs of the proposed project.

Instructions for Electronic Application Submission through Grants.gov: Use the Apply button(s) in Part I of the PA-18-591 program announcement to access the application forms package posted at Grants.gov.

When presented with more than one form package, use the form package with Competition ID "FORMS-E-ADMINSUPP-K12-KL2-KM1-D43".

Prepare applications using the SF424 (R&R) forms associated with the chosen package. Please note that some forms marked optional in the application package are required for submission of applications for this announcement. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate required and optional forms, with the following additional guidance:

Program Plan: (may not exceed 12 pages)

• Background: Include a summary or abstract of the funded parent award project. Provide rationale for the proposed supplement program and its alignment with the main goals of the INCLUDE Project (to accelerate the development of new therapies, while simultaneously bringing promising agents already in development to individuals with DS as quickly as possible).
• Research Program Plan: The proposed plan should align with the missions of the INCLUDE Project and the NCATS CTSA Program. Describe how the proposed project will contribute to the scholar's career goals and path to independence. Present a timeline for career development activities and potential publications and grant applications for future support.
• Career Development Plan: Describe key activities of the candidate scholar during the supplement, included mentored team science activities, didactic coursework (including formal degree programs if appropriate), and other activities. Describe how the proposed career development activities experiences will enhance the candidate's clinical and translational science skills and prepare them for an independent research career.
• Mentoring Faculty: Provide information about the program faculty who will be involved in the supplement activities, including the complementary expertise and experiences, active research and other scholarly activities in which the faculty are engaged, as well as experience mentoring individuals at the proposed career stages. If any co-mentor is not located at the sponsoring institution, describe the frequency and type of communication that will be used to engage the scholar
• Vertebrate Animals: Complete this section if the scholar will design and conduct their own independent vertebrate animal research. Approval by the Institutional Animal Care and Use Committee (IACUC) at the grantee institution is required prior to award.

Letters of Support: Attach appropriate letters from all individuals confirming their roles in the proposed supplement program. Include a signed letter, on institutional letterhead, that describes the applicant institution’s commitment to the planned proposed research project. The letter should provide assurance that the candidate scholar will be able to devote a minimum of 9 person-months (75 percent of full-time professional effort) to the supplement project. The letter should confirm that the scholar will be supported by the KL2 if the supplement is funded. The letter should also identify the laboratories, centers, and other specialized institutional facilities that will be made available to the scholar for the research project.

Project/Performance Site Location form: Include the primary site where the proposed supplement activities will be performed. If a portion of the proposed supplement activities will be performed at any other site(s), identify the locations in the fields provided.

Senior/Key Person form:

• List the PD/PI as the first person (regardless of their role on the supplement activities).
• List Senior/Key Personnel who will be serving as members of the scholar's mentoring team.
• List the scholar proposed to be added through this supplement. Scholars for this supplement support must have an eRA Commons account, and the scholar's Commons Username must be entered in the Credential field.
• Biographical sketch Senior/Key Personnel: Include a biographical sketch of the KL2 PD/PI(s) and of each of the individuals who will compose the scholar's mentoring team. The personal statement of each individual who will serve on the scholar's mentoring team should include a description of his/her specific role in mentoring the scholar, how the mentoring will occur (e.g., frequency and mode), and how the scholar's progress will be monitored during the supplement award period.
• Biographical sketch Scholar: The personal statement of the scholar's biographical sketch should include a description of his/her research objectives and career goals, and why their experience and qualifications make them particularly well-suited to receive an INCLUDE / NCATS CTSA Program KL2 supplement award. Relevant factors include previous training and research accomplishments in complementary and integrative health research and any source(s) of current funding.

Budget forms: Using the R&R budget form, only include funds requested for the additional supplement activities.

R&R Other Project Information form, Facilities and Other Resources attachment:Describe how the scientific environment in which the career development activities will be done contributes to the probability of the scholar's success (e.g., institutional support, physical resources, and intellectual rapport). For CTSA Program hub Training Resources, describe the training resources that are available to the scholar.

PHS Human Subjects and Clinical Trials Information form:Complete this section if the scholar will design and conduct their own independent human subjects research. Approval by the human subjects Institutional Review Board (IRB) at the grantee institution is required prior to award. Adherence to the NIH policy for including women and minorities in clinical studies must also be ensured, if additional human subjects involvement is planned for the supplement component.