Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

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 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. Despite this increase in lifespan, individuals with Down syndrome 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. 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.

Down syndrome is associated with an increased prevalence of autism and epilepsy. About 75% of individuals experience cognitive decline in a syndrome that resembles Alzheimer’s disease but has its onset a decade or two earlier than typical Alzheimer’s disease. Individuals with Down syndrome 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 Down syndrome 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. Understanding this unique combination of risk and resiliencies will inform medical advances for individuals with Down syndrome, and for individuals who do not have Down syndrome but share these co-occurring conditions.

This NOFO is one of several trans-NIH research initiatives created in response to Fiscal Year 2018, 2019, 2020, 2021, 2022, and 2023 Omnibus Appropriations Reports, which encourage NIH to expand its current efforts on Down syndrome and common co-occurring conditions also seen in the general population, while increasing the number of Down syndrome investigators and enhancing the diversity of study populations and researchers. Together, the initiatives are called the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Information about projects that were funded in prior years, as well as the NIH INCLUDE Down Syndrome Research Plan, are available on the INCLUDE Project website at https://www.nih.gov/include-project/. The INCLUDE Project has three components:

• Component 1: Targeted high risk - high reward basic science studies in areas highly relevant to Down syndrome
• Component 2: Assembly of a large cohort of individuals with Down syndrome 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 Down syndrome

Purpose

This Notice of Funding Opportunity (NOFO) invites applicants to participate in a new INCLUDE Project Down Syndrome Cohort Development Program (DS-CDP) as Cohort Research Sites (DS-CRS). The purpose of this program is to recruit participants with DS across the lifespan; collect biospecimens; assemble phenotypic data, images, and omics for deep phenotyping; and make the data readily available to the scientific community. Research sites will participate in all aspects of planning and conducting a common protocol, as well as interpretation and translation of results. The DS-CRS will work in concert with the Down Syndrome Clinical Cohort Coordinating Center (DS-4C; RFA-OD-24-005 ) which will provide overall management, coordination and oversight for the DS-CDP. A related NOFO (RFA-OD-24-004 ) will support a Federated Biobanking Resource (DS-Biorepository) to store and distribute biospecimens collected under the auspices of the DS-CDP.

Scope

This NOFO addresses Component 2 of the INCLUDE Project. Specifically, it is designed to support the Down Syndrome Cohort Development Program (DS-CDP) with the goal to improve our understanding of the natural history of Down syndrome and the relationship of demographic factors (e.g., race, ethnicity, gender, geographic location) to outcomes; help address critical and co-occurring health conditions for individuals with Down syndrome; and expand our understanding of the safety, dosing and efficacy of therapeutics across the lifespan. We encourage projects that will recruit participants across the lifespan, including infants, toddlers, adolescents, young adults, and adults with DS, as well as projects focused on the transition periods of development, although a focus on a particular age range from a DS-CRS applicant is acceptable. This new prospective cohort of people with DS will undergo a comprehensive deep phenotyping and biosample acquisition protocol ( common protocol ) at the Cohort Research Sites (DS-CRS), developed in conjunction with the DS-4C and DS-Biorepository during the first year of the awards. Collection of demographic, clinical, laboratory, biospecimen and imaging data from people with DS will be combined with further bioprofiling (e.g., genomics, proteomics, metabolomics) to enable discovery and validation of new biologic targets. Ultimately, data from such a cohort will help identify genomic and social determinants of risk and resilience, at both the individual and societal levels.

We encourage applicant institutions to partner with resource-limited institutions (RLIs), as defined below, and institutions in states eligible under the Institutional Development Award (IDeA) program (https://www.nigms.nih.gov/Research/DRCB/IDeA/Pages/default.aspx) . For purposes of this NOFO, an RLI is defined as a domestic institution located in the United States and its territories which:

1. has received less than $25 million dollars per year (total costs) from NIH Research Project Grants (RPGs) in each of the preceding two fiscal years, calculated using NIH RePORTER ; and/or

2. has a documented historical and current mission to educate students from any of the populations that have been identified as underrepresented in biomedical research as defined by the National Science Foundation (NSF), see http://www.nsf.gov/statistics/wmpd/ (i.e., African Americans or Blacks, Hispanic or Latino Americans, American Indians, Alaska Natives, Native Hawaiians, U.S. Pacific Islanders, and persons with disabilities) or (a) has a documented historical record of recruiting, training and/or educating, and graduating underrepresented students as defined by NSF (see above), which has resulted in increasing the institution's contribution to the national pool of graduates from underrepresented backgrounds who pursue biomedical research careers, and (b) for institutions that deliver health care services, and has a documented record of providing clinical services to medically underserved communities. Such institutions could include Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), or Tribally Controlled Colleges and Universities (TCCU).

Research examples include, but are not limited to:

• Enroll a specified number subjects annually with emphasis on inclusion of a particular population underrepresented in clinical research .
• Conduct comprehensive clinical phenotyping for the age range proposed for study using the minimal common dataset (MCDS) developed by the INCLUDE Data Coordinating Center (DCC; includedcc.org).
• Follow trajectories of health and disease across the lifespan with in-person evaluations approximately annually (for young participants) or every 2-4 years for older participants.
• Develop cohorts of people with DS across the lifespan and perform deep phenotyping and natural history studies to understand the development of co-occurring conditions such as prevalence of cardiovascular conditions, neurological and psychological conditions, and/or gastrointestinal conditions, etc.
• Track the neurodevelopmental trajectories of individuals with DS.
• Elucidate the reasons for disparate rates of risk, resilience, morbidity and mortality across racial and ethnic groups and in underserv ed communities.

Program Organization and Governance

Cohort Research Sites (DS-CRS)

DS-CRS will serve as performance sites for cohort recruitment and the common protocol. Research sites are responsible for recruiting participants from diverse populations, assuring good clinical practice, supporting remote monitoring, and participating in a cooperative and interactive manner with one another, the DS-4C, and the NIH. Research Sites will be responsible for the planning and collection of high-quality data, images, and biospecimens for multi-omics analyses and their transfer to the DS-4C and DS-Repository for curation and analysis.

The DS-CRS shall propose to develop a diverse cohort of people with DS across the lifespan that includes variability in geographic, racial, gender, and socioeconomic status and is representative of the population demographics of DS in the US to address epidemiological, clinical, and demographic questions. The applicants should propose aims that will lead to improved understanding of incidence and prevalence of DS, case fatality, morbidity, functional impairment and geographic, racial, gender, and social determinants of health and disease in individuals with DS. The DS-CRS should engage with participants with DS and their caregivers to include experiences and knowledge that will have meaningful contribution towards understanding the natural history of DS. Involvement of a Community Advisory Board (CAB) and other community partners during the planning phase is strongly encouraged. The DS-CRS can thus use the CAB for meaningful community engagement strategies emphasizing outreach to populations that are underrepresented in biomedical research. This will maximize benefits from participation by enhancing the relevance of research findings to these populations , creating space for community input throughout the project period, potentially increasing trust in the research proposed, and ensuring that research findings are translated and disseminated, as appropriate, to participant communities. Each DS-CRS application is encouraged to include at least 3 partner institutions, with a maximum of 6 institutions in total, and is encouraged to include at least one partner that is a resource-limited institution (RLI), defined above, or an institution within an IDeA-eligible state to help promote enrollment of diverse individuals with DS.

Applicants are requested to propose a deep phenotyping protocol for the age range of persons with DS proposed for study that could be a starting point for development of the common protocol. Suitable functions of each DS-CRS should be proposed to include, but are not limited to, subject consenting and enrollment, demographics and clinical data, imaging data collection, biospecimen collection for biomarker and omics studies, and others. The final common protocol, clinical and data collection aspects, and skills training activities will be developed by the awarded sites, the DS-4C, and the DS-Biorepository over the first year of the project and submitted for DS-CDP Steering Committee approval. In response to this NOFO, applicants should highlight their specific areas of strength and their unique contributions to the DS-CDP, including their interest and ability to function as a recruitment site. It is highly recommended that each DS-CRS propose both a protocol for phenotyping the age range proposed for study as well as a strong project management plan to oversee and track its activities.

Clinical Cohort Coordinating Center (DS-4C)

The DS-4C will consist of four Cores: Administrative, Outreach, Cohort, and Data Management Cores. The DS-4C Cohort Core has the primary responsibility to coordinate development and implementation of the common cohort development protocol. DS-CRS will work cooperatively with the Cohort Core during protocol development and throughout the program. DS-CRS awardees will work with the Data Management Core to integrate demographic and clinical data collected at the DS-CRS through the use of electronic health records and deposit into a central data resource maintained by the INCLUDE Project Data Coordinating Center. The DS-4C Administrative Core will oversee capitation to the DS-CRS for recruitment and costs of implementing the common protocol; establish contracts for core services, such as imaging analysis and biospecimen acquisition, sequencing, and other omics costs; and provide program management, meeting coordination and other administrative services. The Outreach Core will work with each of the DS-CRSs to coordinate among site CABs to improve inclusion and diversity of the cohort.

Oversight of DS-CDP

The DS-CDP Steering Committee (SC) will provide oversight and direction for the entire program and will consist of Principal Investigators from the DS-4C and from each DS-CRS, NIH Project Scientists and Program Officials, and academic researchers involved in the project. The SC will meet shortly after funding to begin protocol development, establish plans for implementation of the common protocol, establish scientific goals and set cohort-wide milestones, and develop and implement a Steering Committee charter.

NIH will provide overall support for DS cohort development. The NIH Program Officer and the NICHD Office of Grants Management are responsible for the federal stewardship of the award (management, financial and administrative oversight). The NIH Project Scientists will be involved substantially with the awardees as partners on level with DS-CRS PIs, as consistent with the Cooperative Agreement mechanism.

Independent Program Consultants (PCs), appointed by the NIH and funded through the DS-4C, will review the progress of the program annually and as needed to provide advice to the NIH about scientific direction.

An Observational Study Monitoring Board (OSMB), also to be appointed by the NIH and funded through the DS-4C, will monitor patient safety and data integrity and review the performance of each study involving human subjects. The OSMB will also review proposed ancillary studies for issues of participant burden. As a part of its monitoring responsibility, the OSMB will submit recommendations to the NIH regarding the conduct and continuation of each protocol.

Data Sharing

The NIH Policy for Data Management and Sharing (Policy) expects researchers to maximize the sharing of scientific data and make data accessible as soon as possible: no later than the time of an associated publication or the end of the award period, whichever comes first. Additionally, rapid data sharing is a critical component of INCLUDE’s goal to accelerate discovery of etiology and biologic pathways underlying co-occurring conditions of Down syndrome. NIH requires all applications submitted in response to this NOFO to include a Data Management and Sharing Plan (Plan) outlining how scientific data and any accompanying metadata will be managed and shared. It is expected that all de-identified human data coordinated and generated by this project will be submitted to the INCLUDE Data Hub (portal.includedcc.org) in coordination with the INCLUDE Data Coordinating Center (DCC). The INCLUDE Data Hub is a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions. The Data Management and Sharing Plan will be considered by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program as well as the NIH Policy for Data Management and Sharing.

Milestones

Projects proposed by the research sites in response to this NOFO must be driven by well-defined proposed milestones. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Applications are expected to provide clear descriptions of overall project deliverables, timelines, and milestones and how they align with the goals of the study. NIH may negotiate changes to the study deliverables, timelines, and milestones as well as the process for their reprioritization prior to award. Continued funding of the research site(s) will be dependent upon meeting milestones for the project, and it is expected that the study will be completed within the project period. The research team may be asked to reprioritize and adjust activities, timelines, and milestones on a periodic basis based on feedback from the Observational Study Monitoring Board (OSMB), and/or the NIH staff.

Notice of NIH's Interest in Diversity

Every facet of the United States scientific research enterprise from basic laboratory research to clinical and translational research to policy formation requires superior intellect, creativity and a wide range of skill sets and viewpoints. NIH’s ability to help ensure that the nation remains a global leader in scientific discovery and innovation is dependent upon a pool of highly talented scientists from diverse backgrounds who will help to further NIH's mission. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral and social sciences. See NOT-OD-20-031 and Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities NOT-OD-22-019 for details.

To support the best science, the INCLUDE project encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

• Transdisciplinary research projects and collaborations among neuroscientists and researchers from fields such as biochemistry, bioengineering, computational biology, molecular biology, health services, pharmacology, computer and data sciences, bioinformatics as well as bioethics
• Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based ).
• Individual applications and partnerships that enhance geographic and regional heterogeneity.
• Investigators and teams composed of researchers at different career stages.
• Participation of individuals from diverse backgrounds, including groups historically underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Project-based opportunities to enhance the research environment to benefit early- and mid-career investigators.

For the purposes of this NOFO, diverse refers to diversity of the scientific workforce supporting these cohort research sites as well as diversity of participants taking part in the Cohort Development Program.

Plan for Enhancing Diverse Perspectives (PEDP)

• This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV).
• Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Pre-Application Webinar and Frequently Asked Questions

A Pre-Application Webinar for all interested prospective applicants will be hosted by INCLUDE Program staff. Webinar date and other details will be posted on the INCLUDE website: https://www.nih.gov/include-project/. Frequently Asked Questions (FAQs) will also be posted and updated on the INCLUDE website: https://www.nih.gov/include-project/frequently-asked-questions.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

The PD/PI(s) are strongly encouraged to devote a minimum of 2.4 calendar months effort for the PD/PI or a minimum of 2.4 person months combined effort for all multi-PDs/PIs.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Sujata Bardhan, PhD
Telephone: 301-435-0471
Email: sujata.bardhan@nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed. The additional instructions apply:

Facilities and Other Resources: Include the following information.

Applications from institutions that have a Clinical and Translational Science Award (CTSA) funded by NIH should identify the resources that could be available to support the proposed CRS, commenting particularly on aspects that will enhance the ability to conduct clinical research efficiently, including data science and recruitment resources. In such a case, a description of the CTSA and how the applicant proposes interacting with it should be included. Given the fiscal limitations and costs of clinical research, applications with additional research support for clinical studies provided by other mechanisms are of special interest.

Institution descriptions should include information about the clinics and medical facilities in which individuals with DS are cared for, including a description of the numbers of patients that would be expected to be eligible for participating in DS-CDP.

Plan for Enhancing Diverse Perspectives

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review.

Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically under-represented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For the purposes of this NOFO, diverse refers to diversity of the scientific workforce supporting these cohort research sites as well as diversity of participants taking part in the Cohort Development Program.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed. The additional instructions apply:

DS-CRS budgets should reflect support for personnel and infrastructure costs of the center. Budget must include support for at least 9 person-months effort for the clinical study coordinator; 6 person months effort for the local outreach coordinator; a minimum of 2.4 calendar months effort for the PD/PI or a minimum of 2.4 person months combined effort for all multi-PDs/PIs; and other investigators and staff as required. Travel costs for a Steering Committee meeting and an investigators meeting each year in Bethesda, MD should be included for 2-3 members of the DS-CRS, including at least one PD/PI and the coordinator.

Line 8 should be identified as Accrual Costs, and the estimated costs of screening, recruiting, and enrolling subjects entered under Funds Requested ($) in this line.

As part of the budget justification section, applications must support the Accrual Costs by indicating an estimated average per-subject cost for recruitment and enrollment applied to the total target expected to be screened, and indicate the total enrollment the applicant expects to contribute to the overall DS-CDP cohort. The actual costs of phenotyping subjects, obtaining, processing, and storage of DNA specimens do not need to be included, as they will be covered by the DS-4C Administrative Core through a capitated cost model. The costs for omics evaluations will be supported through separate awards and will not be included in the DS-4C budget proposal.

Additional budget pages for each DS-CRS partner site for critical personnel should be included under subaward costs. As for the main site, each partner site requires support for at least 9 person-months effort for the clinical study coordinator; 6 person months effort for the local outreach coordinator; a minimum of 2.4 calendar months effort for the PD/PI or a minimum of 2.4 person months combined effort for all multi-PDs/PIs; and other investigators and staff as required.

PEDP implementation costs

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy
  Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Applicants should list the overall Specific Aims of the proposed DS-CRS within the DS-CDP.

Research Strategy: The Research Strategy must consist of two subsections: Research Center Overview and Research Strategy. The Research Center Overview may be up to 2 pages and the entire Research Strategy section should be up to 12 pages.

A. Research Center Overview

Provide a research center overview to discuss the DS-CRS overall research goals, how the site(s) will contribute to those goals, and the strategic plan to achieve those goals. The research goals should be put into the context of the current state of knowledge of Down syndrome co-occurring conditions, application to clinical management, and current general technologic capabilities for omics evaluations. This subsection should include a statement of assurance that the applicant will (1) comply with all INCLUDE policies and procedures, including those specified in the Resource Sharing Plan instructions and (2) provide timely responses to all communications from the INCLUDE Steering Committee Chair, INCLUDE DCC, and INCLUDE Project Scientists. In addition, the Overview subsection should address the following areas:

Qualification and experience

Applications for DS-CRS must demonstrate experience and expertise in the collaborative conduct of complex deep phenotyping clinical studies and expertise working with people with DS. Describe the site’s established research program in the scientific areas of interest, appropriate expertise, the infrastructure that supports multi-center studies, the track record of successful collaborative research, and access to a sufficient number of potential participants to accomplish the DS-CRS portion of the DS-CDP protocol. Application to participate in the DS-CDP cohort should not be undertaken lightly, as participation entails a significant commitment in terms of time, organizational skills, and administrative ability. Applications should indicate willingness to attend all Steering Committee meetings, which may include conference calls at least monthly and in-person meetings at least twice a year, as well as participation in other aspects of the DS-CDP (protocol development, data analysis, publications, ancillary studies, and other committees). It is highly recommended that each DS-CRS propose both a protocol for phenotyping the age range proposed for study as well as a strong project management plan to oversee and track its activities.

Collaboration

Provide a clear and concise description of the interrelationships among the members of the proposed team, and the contribution of each member to fulfilling the objectives of the DS-CDP overall. In addition, the application should provide a plan to ensure the maintenance of close cooperation and effective communication among members of the proposed team and evidence of the capability of the applicant’s organization to participate and interact effectively in cooperative multi-center research. Applicants should provide a description of cross-disciplinary learning opportunities in clinical research and application of data science principles, if applicable, especially for junior investigators who are part of the research team. Community partners may also be an important component of a DS-CRS application.

Applications may propose to participate as a DS-CRS made up of two or more sites, such as including a resource-limited institution (RLI), defined in section I above, or an institution within an IDeA-eligible state (see section B below). For Research Centers with more than one site, plans for collaboration and interaction among institutions should be clearly documented in the application, and the responsible investigator(s) at the collaborating site(s) should be named. Centers with more than one clinical site should provide management plans that include descriptions of supervision, skills development, certification, data handling, quality assurance, cost-effective management, and communication.

Applicants must agree, if awarded, to accept the Cooperative Agreement Terms and Conditions of Award in Section VI. 2. A.

Research Team

The PD/PI or another member of the physician investigative team is expected to be readily available to respond directly to questions about DS-CDP matters on a daily basis, preferably through e-mail and this should be indicated in the application. The PDs/PIs must have a demonstrated track record of successful leadership of a multi-disciplinary team, including the ability to communicate promptly with and ensure collaboration among physicians, geneticists, nurses, and other related subspecialists. While the multiple PD/PI leadership strategy is highly encouraged, in the case of a single PD/PI, an alternate PD/PI must be designated to serve in the absence of the PD/PI.

Plans for availability of key personnel, including study coordinators and/or recruitment staff, must also be included in the application. The level of training and experience of individual staff, as well as qualifications and prior involvement in clinical research, should be described in the Personal Statement section of the Biographical sketch.

Skills Development

Applications should include a description of skills development plans for junior investigators and/or how junior investigators will be included in the research teams. Specific examples of how junior investigators have been included in past efforts and specific plans for inclusion in DS-CDP activities should be provided.

B. Research Strategy

The Research Strategy subsection should discuss the approach for identifying, screening, recruiting and enrolling participants and collecting biospecimens. Justification for the number of participants expected to be processed by the DS-CRS should be provided in sufficient detail to show feasibility. If the CRS proposes to study a specific age group , racial/ethnic population , or range of cognitive abilities, this should be described. If adults are proposed for ascertainment, the protocol should include adult phenotyping components compatible with those developed by the Alzheimer Biomarkers Consortium Down Syndrome (ABC-DS) project (https://www.nia.nih.gov/research/abc-ds). Partnering with resource-limited institutions (RLIs), defined in section I above, or institutions within IDeA-eligible states, is encouraged and integration of research personnel from these partners should be described within the approach. Proposed efforts to leverage existing mobile technology, conducting remote assessments, using wearables or telemedicine approaches should be described, if applicable. Proposed multi-omics and clinical data collection should also be described, with the understanding that the actual protocol to be implemented with be coordinated with the DS-4C and other DS-CRS, and enrollment and phenotyping costs will be covered by the DS-4C using a capitated model.

Each DS-CRS application must address the following:

• Specify several hypotheses the DS-CRS team considers high priority for the DS-CDP to test as a collaborative program. The hypotheses should be related to the proposed clinical and multi-omics data collection and allow for surveillance or follow-up of participants over time.
• Describe the population to be targeted (e.g., age ranges, race/ethnicity; social determinants); process for identifying, contacting and enrolling potential participants; common protocol for phenotyping and biosample acquisition; and potential future omics data generation using the biospecimens.
• Describe the proposed study design. Provide details on the baseline phenotyping protocol proposed. Describe if the common protocol proposes to leverage existing electronic health records (EHR) systems, mobile technologies, wearable devices, remote assessments, or other telemedicine approaches.
• Describe the data analysis approach for the DS-CRS application and its proposed enrollment, a description of the study population with sample size calculations, and a description of the statistical analysis plan, recognizing that any individual DS-CRS will not be fully powered to address the entire recruited cohort.
• Propose and justify milestones and timelines that could be used to evaluate the success of the DS-CRS throughout the duration of funding. Core milestones that are of particular interest include, but are not limited to:
  • Develop study protocols for recruitment, phenotyping, and retention of participants
  • Complete and finalize protocol and informed consent documents
  • Conduct feasibility and pilot studies
  • OSMB approval by of a common protocol
  • IRB approval of final protocol and consent and/or assent
  • Initiate recruitment
  • Enroll 5% of the target participants per DS-CRS
  • Enrollment of 100% of the projected recruitment for all study participants
  • Full plan for maintaining retention of study participants
  • Completion of baseline evaluation
  • Collection of data related to relevant clinical endpoints and data transfer to DS-4C
  • Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results

Letters of Support: Include letters of institutional and departmental support for participation in the DS-CDP. Applicants are encouraged to reach out to the INCLUDE DCC (https://includedcc.org/) for a letter of support for their proposal.

If the application is from a site that has a CTSA funded by the NIH National Center for Advancing Translational Sciences, provide a letter of support from the CTSA PD/PI stating the specific CTSA resources that will be used.

Letters of support from any partner organizations that will be supporting screening, recruitment, and enrollment of subjects are encouraged.

Table of Study Population: Applicants should have access to sufficient patients to support recruitment in a variety of studies in the DS-CDP. Include a table providing annual estimates of the number of persons with DS in the catchment area along with racial/ethnic breakdown, and outpatient visits for infants, children, and adults with DS. It is acceptable for a DS-CRS to have a preponderance of available subjects within a particular age range or demographic category. An approximate breakdown of the incidence of co-occurring conditions in the potential subjects should also be included.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• It is expected that all de-identified human data coordinated and generated by this project will be submitted to the INCLUDE Data Hub (portal.includedcc.org) in coordination with the INCLUDE Data Coordinating Center (DCC). The INCLUDE Data Hub is a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review (CSR), in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

• Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Compliance with resource sharing expectations.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have primary responsibility for:

The PD(s)/PI(s) assume(s) responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research supported by the U01 award in accordance with these terms and conditions of the award. As such, the recipient PD(s)/PI(s) will be responsible for all aspects of the study and cohort, as well as any modification(s), unless otherwise provided for in these terms or by action of the cohort Steering Committee.

Specific responsibilities include:

• Defining objectives and approaches of the research
• Defining the research plan and goals
• Project design and common protocol development with the DS-4C and DS-Biorepository
• Obtaining all requisite study and protocol approvals
• Data collection and quality control
• Data monitoring
• Oversight of study activities, such as protocol development, data curation and harmonization, manuscript preparation, etc.
• Overseeing/performing other scientific activities of the research plan
• Monitoring the completion of the supported activities and taking corrective actions if needed
• Participating in the activities of the Steering Committee
• Accepting and implementing the decisions approved by the Steering Committee to the extent consistent with applicable grant regulations
• Cooperating with NIH programmatic, technical, and administrative staff
• Administratively managing the U01 award
• Developing collaborations with and making data accessible to external investigators
• Ensuring submission of reports to the OSMB, if applicable
• Participating in an annual INCLUDE Investigators' Meeting and any other meetings as recommended by NIH Program Staff
• Attend and participate in the annual meeting of the independent Program Consultants convened by the DC-4C for the DS-CDP.

The recipient will be required to provide updated descriptive and meta data to the NIH upon request, including cohort characteristics, study protocols, basic counts of study participants, enrollment progress, biospecimen availability, and study variable definitions. Recipients must also provide analytical data files (illustrative examples include: derived/calculated data variables; finalized questionnaire data; data from procedures, such as echocardiography, ECG, MRI, exercise testing, polysomnography, etc.; participant follow-up data; clinical event outcomes data) to the NIH periodically based upon a mutually agreed schedule and format and at the end of the period of this award, along with documentation necessary for their use.

Recipients will be expected to evaluate and document compliance with NCI's Best Practices for Biospecimen Resources for collection, processing, and storage of previously collected biospecimens (http://biospecimens.cancer.gov/bestpractices ). Recipients will be required to explore, with NIH staff, the feasibility of data harmonization and pooling with other cohorts and studies. Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.(http://biospecimens.cancer.gov/bestpractices)

Recipients agree to the governance of the study through a Steering Committee and to accept and implement decisions approved by the Steering Committee (see "Joint Responsibilities" section below).

Recipients are expected to make their data widely available to other investigators per NIH and NIH Data Management and Sharing Policy (https://sharing.nih.gov/data-management-and-sharing-policy). Study investigators are strongly encouraged to publish and disseminate results, tools, resources, and other products of the study, in accordance with the study protocols and governance. It is expected that all methods, analyses, software, and algorithms will be made available in a timely manner to the scientific community.(https://sharing.nih.gov/data-management-and-sharing-policy)

Support or other involvement of industry or any other third party in the study may be advantageous and appropriate. Participation by the third party; involvement of study resources; citing the name of the study or NIH support; or special access to study results, data, findings, or resources requires notification of and concurrence by NIH. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to and concurrence by NIH.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. NIH will provide overall support for DS cohort development. The NIH Program Officer and the Office of Grants Management are responsible for the federal stewardship of the award (management, financial and administrative oversight). In addition to regular award oversight, the NIH Project Scientists will be involved substantially with the recipients as partners, consistent with the Cooperative Agreement mechanism. Independent Program Consultants (PCs), appointed by the NIH and funded through the DS-4C, will review the progress of the program annually and as needed to provide advice to the NIH about scientific direction.

A designated NIH Project Scientist(s) will have the following responsibilities:

• Participate (with other Steering Committee members) in the group process of setting project priorities and making decisions on joint activities and standard practices of the INCLUDE Project and DS-CDP. The Project Scientist(s) will assist and facilitate the group process but not direct it.
• Negotiate goals and timelines with the recipients, as necessary.
• Serve as liaisons between the recipients and Program Consultants, NIH, and the larger scientific community in helping the INCLUDE Project to achieve its goals.
• Coordinate the efforts of the INCLUDE Project with others engaged in similar and related activities.
• Attend all Steering Committee meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action.
• Periodically report progress to the INCLUDE NIH Steering Committee and director of NIH.
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the recipient institutions who are to serve as Program Consultants.
• Ensuring disclosure of conflicts of interest and adherence to NIH policies
• Serve on subcommittee(s) of the INCLUDE Component 2 Working Group, as appropriate.
• Assist in promoting the availability of the data generated by the INCLUDE Project to the scientific community at large.
• Where warranted, co-author publications about the goals of this NOFO, and of results of studies funded under this NOFO.

In addition to the Project Scientist, a separate NIH Program Official will be responsible for the normal program stewardship of the cooperative agreement and will be in the Notice of Award. Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NIH staff other than the Project Scientist. The responsibility for final decision making may reside with Senior Institute management, separate organizational components, and/or oversight committees. Because it is anticipated that the Program Official will participate in activities that rise to a level of involvement (i.e., additional role as Project Scientist) that results in conflicts of interest (e.g., co-publication), other staff members such as direct line supervisor and/or other Senior NIH Program management staff may serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award. Additional NIH staff members may be designated to have substantial involvement in the study.

The NIH policy on authorship and manuscript review of NIH-sponsored extramural research protects against conflicts of interest with the Program Officer.

The NIH reserves the right to withhold funding or curtail the study in the event that any of the following occur:

• Substantial shortfall in conducting the projects including but not limited to outreach to a diverse community, data curation and data harmonization, participant data reporting or quality control
• Major breach of the protocol or substantive changes in the agreed-upon protocol, methodologies, and/or tools with which the NIH cannot concur
• Failure to develop or implement a mutually agreeable deep phenotyping protocol in a timely manner
• Human participant ethical issues that may dictate a premature end of the award
• Results that substantially diminish the scientific value of study continuation

Areas of Joint Responsibility:

A Steering Committee (SC) will be the main governing body of the INCLUDE DS-CDP. The SC voting membership shall be determined jointly by the PDs/PIs and the NIH, but shall minimally consist of the study center(s) PI(s), the NIH Project Scientist(s), the Data Coordinating Center PI(s) (if applicable), and the biorepository PI(s) (if applicable). Additional members may be added by majority vote of the SC. Meetings of the SC will ordinarily be held by teleconference, videoconference, or in-person.

The appointed voting Steering Committee members will be required to attend all Steering Committee meetings and tele/videoconferences, or to appoint a substitute that will be fully briefed on the issues at hand. Additional non-voting members to serve in an advisory capacity may be added to the Steering Committee as needed by a decision of the existing voting committee members. The Steering Committee may also form an Executive Committee (EC) and/or subcommittees as needed. The NIH Project Scientist(s) may serve on the EC and on subcommittees as deemed appropriate. The Chair of the Steering Committee will be selected from the SC voting members.

The Steering Committee will have primary responsibility for:

• Overseeing the overall organization of the study's core functions
• Providing guidance on scientific and infrastructural issues pertinent to the funded cohort study
• Providing guidance, oversight, and coordination of the activities of the cohort investigators towards cross-cohort data harmonization, if requested by the NIH
• Contributing to the development of policies and processes pertinent to the cohort infrastructure

All investigators/staff within the study will be required to accept and implement the policies approved by the Steering Committee to the extent consistent with applicable grant regulations.

Where applicable, the recipient will work with the NIH on efforts to harmonize data across NIH cohorts and studies, and explore the feasibility of using common data standards and elements.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation45 CFR Part16. 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

None; all responsibilities are divided between recipients and NIH staff as described above.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

• When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
• Awardees will provide updates at least annually on implementation of the PEDP

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

The primary point of contact for this NOFO should be:

Sujata Bardhan, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-0471
Email: sujata.bardhan@nih.gov

Huiqing Li, PhD
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-435-0554
E-mail: huiqing.li@nih.gov

Marie Mancini, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5032
E-mail: mancinim2@mail.nih.gov

Laurie Ryan, Ph.D.
NATIONAL INSTITUTE ON AGING (NIA)
Division of Neuroscience
Phone: 301.496.9350
E-mail: ryanl@mail.nih.gov

Jyoti Dayal
NHGRI - NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Phone: 301.480.2307
E-mail: jyotig@nhgri.nih.gov

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: parisima@mail.nih.gov

Katherine Malinda, Ph.D.
Center for Scientific Review (CSR)
Email: malindakm@mail.nih.gov

Fatu Kamara
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-435-7916
E-mail: fatima.kamara@nih.gov

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Philip E. Smith
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301-555-1212
E-mail: philip.smith2@nih.gov

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: margaret.young@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.