It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) 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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Down syndrome is the most common genetic cause of intellectual disability, the most common autosomal trisomy, and one of the most visible and universally recognized genetic syndromes. Each year there are approximately 5300 babies born in the United States with Down syndrome. Within the past 25 years, the average lifespan for a person with Down syndrome has doubled, from 30 to 60 years. Despite this increase in lifespan, individuals with Down syndrome and their families face significant and changing health challenges with age. 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.

As the most common genetic cause of intellectual disability, 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 FOA is one of several trans-NIH research initiatives created in response to Fiscal Year 2018 and 2019 Omnibus Appropriations Reports that encourage NIH to expand its current efforts on Down syndrome and common co-occurring conditions also seen in the general population while increasing the pipeline of Down syndrome investigators. This initiative is known as the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE), and a description of the research plan and its three components is available (https://www.nih.gov/include-project). The three components are:

• Component 1: targeted high risk - high reward basic science studies
• Component 2: development of a cohort to perform deep phenotyping and study co-existing conditions
• Component 3: inclusive clinical trials research for co-occurring conditions in individuals with Down syndrome

This research initiative expands many of the research objectives and opportunities previously highlighted in the 2014 Down Syndrome Directions: NIH Research Plan on Down Syndrome. More recent discoveries have enhanced our understanding of chromosome segregation and chromosome silencing, identified certain proteins and neurotropic factors involved in brain development using mouse models, and uncovered the role of interferons in immune dysregulation, each of which has the potential to lead to development of novel therapies for individuals with Down syndrome, as well as broader applications. People with Down syndrome are often excluded from clinical research, such as trials of potentially beneficial drugs and therapeutics that are used to treat the same condition in the general population. There is great value in connecting people with Down syndrome to therapies that could improve their overall health and quality of life. And there is great interest in the Down syndrome community in participating in clinical research, based on experience from NICHD’s DS-Connect : The Down Syndrome Registry , an online survey tool that connects individuals with Down syndrome and their families to research opportunities. A comprehensive clinical cohort study with deep phenotyping and exploration of pan-omics will permit identification of biomarkers and outcomes for the co-occurring conditions in Down syndrome. Coupled with development of a clinical trials readiness program, and informed by basic science discoveries, this combination of resources could have a great impact on addressing health disparities that exist for people with Down syndrome and could also lead to the development of therapies to improve outcomes for those with and without the condition. For a list of projects funded in FY2018 and 2019, see https://www.nih.gov/include-project/funding. This FOA addresses Component 2 of the INCLUDE Project: development of a cohort to perform deep phenotyping and study co-existing conditions.

The Data Coordinating Center (DCC) awardee funded by this FOA will have three broad responsibilities: 1) assembling a Data Portal Core charged with integrating and sharing INCLUDE Project data through a web-based Data Portal, 2) serving as a Data Management Core (DMC), and 3) developing and managing an Administrative and Outreach Core (AOC) for the entire DCC. The Data Portal will serve as the primary entry point to INCLUDE Project data and will provide tools to facilitate access and analyses by the broader research community. The DMC will coordinate the collection of data from researchers and data generators, and aggregate and harmonize these data to be shared through the Data Portal. The AOC will coordinate administrative logistics as well as education on use of the Data Portal, and work closely with the Steering Committee (see below under Cooperative Agreement Terms and Conditions of Award for a description of the steering committee) on overall implementation of the program goals.

Sharing of resources and effective communication of outputs of appropriate interest to broader communities are a high priority of the INCLUDE Project and are strongly encouraged for applications submitted in response to this FOA. To address new challenges, NIH has articulated specific priorities and encourages rapid and open sharing of scientific efforts in development and dissemination of innovative data analytics approaches (see Goal 3 of the NIH Strategic Plan For Data Science).

The activities of the DCC address areas of computer science, informatics and biobanking, but also require effective communication with the clinical or experimentally-oriented user communities to achieve its goals. This requires that the DCC have personnel with sufficient knowledge to serve as liaisons and translators among experimentalists, clinicians, and bioinformaticians. The DCC is therefore expected to be composed of teams with expertise sufficient to allow them to function in this way. It is also expected that the team identified in the application will have demonstrated expertise in existing Down syndrome data that can be utilized to investigate future Down syndrome datasets to be generated under INCLUDE and other FOAs. Additionally, in an effort to integrate tools and functions amenable to appropriate statistical analyses into the Data Portal, the DCC should include data science expertise within their team. The team should also have experience with phenotype ontology and harmonization, as well as experience in coordinating biospecimens and linking to a biospecimen repository(ies). In general, INCLUDE intends to prioritize the generation and collection of data from cohorts that are approved for broad data sharing and use, but recognizes that cohort data may involve a variety of data use limitations.

Data Portal Core (DPC)

The selected awardee will provide a common web-based interface to enable access to aggregated and harmonized INCLUDE project datasets alongside analytical tools, as well as with links to relevant partners. The DPC will work with an NIH-designated data repository, as necessary, to facilitate access to large-scale datasets, including genomic datasets; however the DPC is not charged with storage and distribution of all these datasets. The goal of the Data Portal is to make these data readily findable and accessible to users with various levels of expertise. To that end, the design of the features and tools are to reflect statistical rigor and valid methods and approaches relevant to the Down syndrome field, serving a wide range of experts from developmental biologists to clinicians to bioinformaticians.

While innovative approaches to serve the Down syndrome research community are warranted, applications that propose to use or integrate with existing data platforms, tools, and workspaces to promote interoperability and cross-initiative data sharing and analysis, wherever possible, are strongly encouraged. It is anticipated that the Data Portal will be based on open source software and will be developed through an iterative process based on user feedback. The Data Portal is envisioned as a single point-of-entry, web-based platform for community access to the INCLUDE genomic, phenotypic and other -omics data. Applicants are encouraged to use or integrate with existing data portals, platforms, and workspaces to promote interoperability and cross-initiative data sharing and analysis, wherever possible. The Data Portal should also have the capacity to grow and adapt with the INCLUDE Program. It is expected that the Data Portal will link to, interact, and incorporate with other relevant data portals, to the extent possible. In fact, the Data Portal Core may represent a modification of an existing data portal serving a similar function for a different research community; respondents are encouraged to leverage existing resources rather than building a brand new system. Data resources created by the DPC should follow FAIR principles, that is, to make data findable, accessible, interoperable and reusable.

Data Management Core (DMC)

The DMC will collect, process, harmonize, and facilitate the sharing of genomic, phenotypic and other -omics data generated from Down syndrome cohorts by working closely with an NIH-designated data repository. To that end, it will be necessary to have a detailed understanding of diverse data types and the ability to manage quality control of the data. Integration of data from Down syndrome studies are of top priority; however, the DMC may seek to collect or link to data from other sources with the intention of creating a comprehensive Down syndrome catalog, prioritizing datasets that are approved for broad sharing and use. In conjunction with activities led by NIH, the DMC will work with investigators to define standard data elements and establish a minimal common dataset in order to harmonize existing phenotypic data and organize the collection of prospective cohort data which may require external collaboration, subcontracts, or separate funding mechanisms. The data included in the Down syndrome program are expected to increase as the number of participating cohorts increases, and the DMC will need to be able to adapt to handle different types of data. The DCC will not be expected to fund the sequencing and other -omics data acquisition related costs itself.

Another major function of the DMC will be to support a centralized Biorepository resource to coordinate a single biospecimen repository or a network of DNA, tissue specimen and cell line repositories relevant to Down syndrome research. Several existing biorepositories support Down syndrome sample collection and distribution, and the DMC is expected to provide linkages and coordination to one or more of these for the purposes of providing an integrated resource to the investigator community.

Administrative and Outreach Core (AOC)

The AOC will organize, coordinate, and oversee the administrative and outreach activities of the INCLUDE Program. Administrative activities will include facilitating meetings and communications between the DCC, NIH, and key external stakeholders, and developing procedures and policies for the operation of the DCC. Outreach activities will include establishing and maintaining a registry of investigators participating in the INCLUDE program, and educating the research community on how to use the Data Portal through user training utilizing all available methods (e.g., in person, by webinar, through YouTube videos). Equally important will be engaging users for their feedback in order to improve the functionality of the Data Portal and the overall DCC.

Pre-Application Webinar

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/funding.

Frequently Asked Questions

Questions and answers related to this FOA will 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.

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)

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)
• 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 Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• 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.
• o 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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.

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

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. 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 NOT-OD-11-101).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.

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:

Huiqing Li, PhD
Telephone: 301-435-0554
Fax: 301-480-2858
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core (Use for Administrative and Outreach Core)	12
Core (Use for Data Portal Core and for Data Management Core)	12

Additional page limits 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 a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative and Outreach Core: required; maximum of 1
• Data Portal Core: required; maximum of 1
• Data Management Core: required; maximum of 1

When preparing your application, use Component Type Overall .

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

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. Indicate prior experience in developing data resources, experience in coordinating data flow in a multi-component research project, and managing administrative logistics and outreach activities.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: Concisely address the overall goals of the DCC and how the work proposed supports the overall objectives of the INCLUDE Program and the specific objectives of the INCLUDE component 2: development of a cohort to perform deep phenotyping and study co-existing conditions.

Research Strategy:

Provide a general overview including considerations that will lead to successful development and coordination of the proposed DCC.

Describe the overall design and structure of the Data Coordinating Center including its management structure, integration of components, and any possible subcontracts. Include an organizational chart of the associated tasks and milestones, identify the types of staff associated with each task, and describe their respective roles and responsibilities.

Describe plans for moving beyond simply a collection of unrelated core services to creating a well-integrated, synergic and cohesive research resource.

Describe plans for coordination and integration between the DCC Cores (AOC, DPC and DMC) and the INCLUDE Component 2 goal (development of a cohort to perform deep phenotyping and study co-existing conditions) to achieve a cohesive research resource for the investigator community.

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, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Resource Sharing Plans for all components should be addressed here under the Overall Component. Plans to share open source software, including source code, use cases, and system design documentation, in appropriate repositories, should be specified.

Applicants are encouraged to describe their approaches to ensure that the data and analytical resources supported through this FOA will conform to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles. Activities that should be discussed in this regard include, but are not limited to, alignment of data and metadata standards, indexing of data and other digital resources, and uses of computing platforms that enable better data access and interoperability. Applicants should describe their planned approach for enabling various levels of access to data such as de-identified phenotypic datasets as well as controlled access individual-level sequence datasets through the portal. Describe the timelines for which data from other INCLUDE projects and data generators will be processed, harmonized, and subsequently shared with the broader research community.

NIH intends to maximize the availability of publications and the sharing of underlying data and biospecimens for INCLUDE-supported projects, while abiding with informed consent language and protecting the identity of participants. While INCLUDE intends to prioritize the generation and collection of data from cohorts that are approved for broad data sharing and use, the DCC may be tasked with handling data that involves a variety of data use limitations. It is expected that the results of INCLUDE-funded research will be shared with the wider scientific community in a timely manner.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

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

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

When preparing your application, use Component Type Admin Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Briefly address the Specific Aims for the Administrative and Outreach Core and how they will be accomplished.

Research Strategy: Discuss how the activities listed below will be accomplished, staffed, and managed in support of the DCC. Describe how the proposed plans will leverage the experience described in the Biographical Sketch(es). Propose and justify any other coordination activities that would be useful to the INCLUDE Project, but are not listed explicitly elsewhere in this FOA.

Describe plans for the following administrative activities including, but not limited to:

• Coordination of functions of the DPC and DMC to meet the objectives of the overall INCLUDE DCC.
• Coordination of general communications between the DCC and the Steering Committee which consists of the DCC PD/PI and Core Directors, and NIH program staff. This may include leading regular updates with the INCLUDE NIH staff such as monthly conference calls (especially in the early phases of developing the Center) and/or monthly reports on progress toward meeting milestones.
• Coordination of yearly face-to-face meetings for the Steering Committee and Component 2 investigators.
• Hosting an annual External Advisory Committee (EAC) meeting to evaluate the progress of the program and to provide advice to the NIH and the Steering Committee about scientific direction; EAC membership will be determined by NIH.
• Documenting discussions, decisions and actions discussed during meetings and conference calls, and following up with relevant stakeholders when necessary.
• Archiving and tracking all materials relevant to the development of the INCLUDE DCC.
• Development and implementation of standard operating procedures and policies for the operation of the DCC and making SOPs readily available to the public.
• Compiling formal progress reports or other reports as directed by the Project Scientist.

Describe plans for the following outreach activities including, but not limited to:

• Development and implementation of an outreach plan to promote the Data Portal to the Down syndrome research community as well as the broader Down syndrome stakeholder community.
• Establishment and maintenance of a registry of investigators participating in the INCLUDE Project's activities.
• Facilitation of communication between investigators who wish to recruit using DS-Connect : The Down Syndrome Registry and the registry coordinators at NIH to ensure maximal recruitment of subjects into the registry.
• Creating in-person events and workshops with current or potential users of the Data Portal to provide hands-on tutorials on how to best use the Data Portal and soliciting feedback on the usability of and desired features for the Portal.
• Development of online tutorials and how-to guides to be integrated into the Data Portal.

Providing guidance in the appropriate use of the resource for the breadth of the user community envisioned for the INCLUDE DCC.

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, with the following modification:

Do not include a Resource Sharing Plan for this Component. Any resources to be developed under this

component should be included with the Resource Sharing Plan for the Overall Component.

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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

When preparing your application, use Component Type Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Briefly address the Specific Aims for the Data Portal Core and how they will be

accomplished.

Research Strategy: Describe how existing data sharing infrastructure will be utilized to fulfill the web-based data portal requirement of the INCLUDE DCC or alternatively, how a new portal would be designed, launched, maintained, and continuously improved. Provide a detailed timeline of activities with a particular focus on early design and launch milestones to measure progress. Specify metrics to evaluate usage and usability of the data through the Data Portal.

The plans to utilize or develop a Data Portal must include, but are not limited to:

• Web-based Data Portal Interface: Describe the plans for the design and implementation of a web-based Data Portal to make INCLUDE data accessible to the research community. Include a description of how the proposed Data Portal will catalog, display, make searchable, enable summary statistics and basic analyses of all INCLUDE data and facilitate access to associated individual level -omics data which may be stored and/or distributed through other mechanisms or data resources, such as dbGaP. Propose solutions for linking to controlled access data per NIH policies, to be finalized in discussions with NIH. The environment should have the ability to become interoperable with the NIH Data Ecosystem in the future.
• Integration of diverse datasets: Describe plans for facilitating access to and integration of diverse datasets (gene function, expression, other -omics data, phenotypic data, etc.) to allow those with unique perspectives on human disease to perform data mining and complex data analyses. Describe how the Data Portal will integrate datasets that may include, but are not limited to:
• Data generated under currently funded INCLUDE projects (see: https://www.nih.gov/include-project/funding)
• De-identified datasets extracted from INCLUDE-funded clinical trials
• Clinical trial and clinical study data and electronic health record (EHR) data using Fast Healthcare Interoperability Resources (FHIR) standards
• Existing Down syndrome cohorts in dbGaP/SRA, and other data repositories
• Other external repositories or datasets that may exist in the research or clinical community. Some files may exist in outside domestic and international repositories; the data portal team will be tasked with identifying, cataloging, and creating links to outside datasets, while conforming to the various data sharing policies of the outside repositories.
• Data Storage: Describe plans for hosting data, including summary data, in the portal to facilitate search capability and access to datasets that may reside in other data resources. Outline proposed actions for establishing partnerships with other data resources, per the guidance of INCLUDE staff, to build avenues of data exchange, where appropriate.
• Data Analysis: Describe plans for integrating or developing infrastructure and tools that will enable:
• Viewing, manipulating, and exporting summary analysis of multiple datasets at the same time.
• Identification of cohorts through a "free text" search that accepts a broad range of search terms encompassing standard ontology as well as other common vocabulary relevant to gene variant, proteomic, metabolomic, and phenotypic data.
• User-defined queries to identify cases and/or samples sets, based on variants, other -omics, and phenotypes.
• Gene-specific or gene-set-specific queries, returning all data across defined project data sets.
• Queries based on metadata or phenotypic characteristics, returning all data across defined project data sets.
• Creating synthetic cohorts by allowing users to specify phenotypes or custom range of data values which will be applied across multiple studies in the DCC.
• Grouping and exploring queries by consent group or Data Use Limitations. Specifically, when assembling a cohort, filtering out datasets or individuals that cannot be accessed for further analysis.
• Other summary-level queries.
• Easy access to existing data analysis tools for researchers to use.
• Access to analytic tools that were developed through other INCLUDE FOAs.
• Data Display: Describe plans to develop or adapt existing open source or commercially available software utilities to provide online tools for phenotype and -omics data visualization. Outline plans for providing intuitive and easy-to-understand display of data and query results.
• Describe planned approach for creating a dynamic and cross-referenced index of dataset files relevant to the INCLUDE Project and providing links to access information about the data sources.
• Provide a summary of plans to develop partnerships and links to relevant programs designated by INCLUDE staff. Potential partnerships include, but are not limited to, NCBI, ClinGen, the NIH Common Fund’s Gabriella Miller Kids First Pediatric Research Program, NHLBI's TOPMed program, the Pediatric Cardiac Genomics Consortium Data Hub, DS-Connect : The Down Syndrome Registry, FaceBase, the Rare Disease Clinical Research Network Portal, NICHD’s Newborn Screening Translational Research Network, NIA’s Alzheimer’s Therapeutic Research Institute and National Alzheimer’s Coordinating Center, Matchmaker Exchange, and the Monarch Initiative.
• Describe plans for creating a system for users to contact cohort recruiting sites for collaboration and collection or sharing of further data, such as more detailed phenotype information. This may involve linking to a PI registry or integrating existing registry systems.
• Outline the plans for creating or leveraging a system for biospecimen request, review, approval, and distribution through partner biorepository(ies).
• Explain how new findings, i.e. new annotations or minimal common data elements, will be incorporated into INCLUDE or other Down syndrome datasets shared through the Data Portal.
• Describe plans for working with potential users to refine use cases; design, test, and improve the usability of the interface; and solicit and incorporate ongoing feedback. For example, it is anticipated that users will range from developmental biologists to bioinformaticians. Therefore, describe several anticipated use cases by different types of users and how the design and implementation of the Data Portal will enable data analysis. Outline how the Data Portal user interface will be adaptable for future improvements or new data types that might be suggested by the NIH staff as well as the external user community so that the Data Portal may be improved and refined throughout the project period.
• Describe plans for development of web-based tutorials for users, including interactive help pages and FAQs
• Explain plans for devising and maintaining a system for collecting metrics on portal usage and functionality, including a user login/registration system, to inform future decisions about changes and modifications needed for website improvements.
• Describe how "help desk" functionality for handling questions related to data access, data deposition, etc. will be provided.
• Describe plans for facilitation of recruitment through the DS-Connect registry and how users will be effectively directed to the professional portal of the registry website.
• Outline plans for working with DS-Connect registry developers and NIH staff to develop a referral code model to facilitate participant-level linkages between disparate datasets, including DCC data, biorepository specimens, and DS-Connect registry data via unique identifiers in a de-identified manner.
• Describe plans for the web portal to support all major platforms with consideration of the development of mobile apps and the necessary flexibility to respond to the changing needs of the scientific community in a timely manner.
• Outline how federation features will be incorporated into the Data Portal and integrated with the authentication and authorization services necessary to ensure user compliance with data access policies associated with each data set.
• Describe planned approach to ensure that the data and analytical resources supported through this FOA will conform to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles. Activities that should be discussed include, but are not limited to, alignment of data and metadata standards, indexing of data and other digital resources, and uses of computing platforms that enable better data access and interoperability.

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, with the following modification:

Do not include a Resource Sharing Plan for this Component. Any resources to be developed under this

component should be included with the Resource Sharing Plan for the Overall Component.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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

When preparing your application, use Component Type Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Briefly address the Specific Aims for the DMC and how they will be accomplished.

Research Strategy: Discuss how data management tasks will be accomplished, staffed, and managed. Use or integration with existing data management systems and biorepositories is strongly encouraged, wherever possible. Describe how the proposed plans in this section will leverage experience described in the Research & Related Senior/Key Person Profile.

Describe plans for accomplishing the activities of the DMC including, but not limited to:

• Coordination of the submission of existing data from multiple INCLUDE projects and future data generators to the DCC and/or relevant repositories, including possible sequence and other -omics data generated through other mechanisms.
• Facilitation of the necessary NIH procedures, as needed, for example dbGaP procedures for genetics studies.
• Management of quality control for data from all INCLUDE cohorts and other related cohorts that will be incorporated into the DCC and Data Portal.
• Processing and harmonizing diverse data types to facilitate analyses across disparate datasets. Include a description of plans for storing data, when necessary, to support the data processing and harmonization, as well as analysis, to generate summary results that will be shared through the Data Portal.
• Development and implementation of a plan for phenotype harmonization that might include:
• Working with PIs to obtain and clarify/understand source phenotype data
• Working with NIH-convened INCLUDE activities to create standard trait definitions, common data elements, and minimum common data elements
• Documenting standard operating procedures
• Creating a web-based phenotype inventory
• Leveraging existing efforts where relevant
• Coordination of the collection of new datasets and biospecimens according to these standards and common data elements (as described in prior bullet).
• Development and implementation of a plan to receive and annotate the results of secondary analyses of INCLUDE data.
• Activities to support an integrated biorepository resource to coordinate a single biospecimen repository or a network of biospecimen repositories relevant to Down syndrome research, housing samples such as DNA/RNA, plasma/serum, cell lines, and all kinds of tissues. Several biorepositories exist that support Down syndrome sample collection and distribution. Explain how linkages and coordination to one or more of these resources will be leveraged to provide an integrated resource to the investigator community. The biorepository services may include:
• Possible Down syndrome repositories for partnership could include, but are not limited to: NIA-funded National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Human Trisome Project, Coriell, NIH NeuroBioBank, and the NIA Alzheimer’s Disease Research Centers.
• Documentation of the processing and quality control of biospecimens held by the repository(ies), to ensure high-quality materials are available for subsequent analysis.
• Ensuring that biorepository facilities comply with safety and biohazard containment guidelines and regulations, as well as applicable federal, state, and local laws for handling biosamples and current best practices.
• Protection of research participant confidentiality.
• Providing security and back-up systems for the repository access functions.
• Creation or leveraging a high quality, robust, flexible, and secure information system for biospecimen request, review, approval, and distribution, including rapid retrieval of metadata associated with the samples, through partner biorepository(ies).
• Working closely with the DCC to use unique identifiers for linking the biospecimens with the metadata associated with the samples located at the DCC.
• Carrying out all the work in a high-quality manner, with rigorous quality control (QC) and quality assurance (QA) programs as well as establishing a succession plan.

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, with the following modification:

Do not include a Resource Sharing Plan for this Component. Any resources to be developed under this

component should be included with the Resource Sharing Plan for the Overall Component.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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

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.

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) using ASSIST or other electronic submission systems. 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 Policy on Late Application Submission.

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.

This initiative is not subject to intergovernmental review.

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.

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

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). 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.

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.

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 Data Coordinating Center (DCC) 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 DCC 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 Center that by its nature is not innovative may be essential to advance a field.

Does the proposed Center address the needs of the research resource that it will coordinate? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research resource?

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing Down syndrome research? Do the investigators demonstrate significant experience with coordinating collaborative basic or clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, plans for conflict resolution, and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA: Are the broad areas of expertise necessary for development of the overall DCC represented? Do the investigators have experience in developing and managing data resources and coordinating data flow in a multi-component research project?

Does the application propose novel organizational concepts or management strategies in coordinating the research resource the Center will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts or management strategies proposed?

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research resource the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the resource, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the resource is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the resource? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

Specific to this FOA: How strong are the plans for the DCC to build on existing resources to address the specific needs of the Down syndrome research community; alternatively, how strong are the plans for new resources to be developed to address these needs and flexibly meet the future needs of building a Down syndrome cohort?

How likely is it that the proposed DCC will function as a true Center rather than a collection of unrelated core services with the sum of the parts being greater than the individual components?

To what extent do the coordination and integration between the Cores (AOC, DPC and DMC) and the INCLUDE Component 2 investigator community reflect a cohesive research resource?

How strong are the plans for data sharing and consistent with achieving the goal of broad data sharing within the INCLUDE program? Is there a plan for the data and other results of INCLUDE-funded research to be shared with the wider scientific community through the Data Portal in a timely manner, consistent with FAIR principles?

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research resource it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Reviewers will provide only one overall adjectival rating for the Administrative and Outreach Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• How strong and how appropriate is the experience of the Administrative Core Lead for overseeing the administrative and outreach activities of the Core?
• Are the other Core personnel appropriate? To what extent is the investigative team experienced in working with the Down syndrome patient and research community?
• Is the management plan sufficient and commensurate with the complexity of the overall DCC?
• To what extent will the services provided by the Core enable the other components to achieve their goals?
• Are the Core's plans for outreach and community training to enhance the use and utility of the INCLUDE Data Portal sufficient and to what extent are the plans likely to be successful?
• Is the Administrative Core leveraging existing resources to support its mission?

Reviewers will provide only one overall adjectival rating for the Administrative and Outreach Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• To what extent does the application provide clear plans including milestones for the complex work-flow that will be required, including realistic timelines?
• Do the development plans for the Data Portal include obtaining input from potential end users and usability testing? Are all appropriate end users considered?
• To what extent has the applicant demonstrated an understanding of avenues for interfacing with other databases, such as international repositories?
• How adequate is the proposed plan regarding the ability to ensure that data, consented for different purposes, are used appropriately?
• How feasible is it that the Data Portal will be flexible and adaptable to the changing needs of the scientific community in a timely manner?
• Will the Data Portal and associated tools and features conform to FAIR principles?
• How well will the design of the Portal and associated infrastructure leverage existing resources where appropriate?

Reviewers will provide only one overall adjectival rating for the Administrative and Outreach Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• To what extent is the proposed plan clear, provide feasible and relevant work-flow milestones and include realistic timelines for facilitating deposition of Down syndrome genomic, phenotypic and other -omics data into relevant repositories as part of the INCLUDE DCC?
• How likely will the proposed plan be successful in facilitating access to the data through the Data Portal?
• How strong is the proposed framework for implementing standards and ontologies and performing phenotype harmonization that builds upon existing efforts?
• How strong are the proposed plans for supporting a centralized or networked Biorepository resource? To what extent is the strategy for coordinating multiple biorepositories feasible and effective?

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.

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the Center 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.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review, 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:

• 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.
• Will receive a written critique.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.

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.

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 grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. 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 FOA 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: Grantee 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 awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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 FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities.

Under the cooperative agreement, the NIH purpose is to support and stimulate the awardees' 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 awardees for the project as a whole, although specific responsibilities and activities may be shared among the awardees and the NIH as defined below.

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

• Accept close coordination, cooperation, and participation of the NIH staff in the aspects of scientific and technical management of the project as described below.
• Ensure that all center goals are met.
• Ensure effective interaction and coordination with project/cohort PIs and the NIH staff.
• Adhere to the NIH policies regarding intellectual property, data release and other applicable resource sharing policies that might be established during the funded period as appropriate.
• Accept and implement any procedures and guidelines developed and approved for the INCLUDE Project.
• Accept and participate in the cooperative nature of the INCLUDE Project, including:
• Attend the Steering Committee meetings, including regular conference calls, and organizing and attending the annual face-to-face INCLUDE Component 2 investigators meetings;
• Organize an annual meeting of an External Advisory Committee (EAC);
• Coordinate and collaborate within the INCLUDE Project as described above;
• Where opportunities are identified, participate in collaborations with other NIH research efforts, such as NIH-convened INCLUDE activities.

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

NIH staff will have the role of Project Scientist(s) through technical assistance, advice, and coordination. However, the role of the Project Scientist(s) will be to facilitate but not to direct the activities.

Project Scientists' responsibilities are defined as follows:

• 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. The Project Scientist(s) will assist and facilitate the group process but not direct it.
• Negotiate goals and timelines with the awardees, as necessary.
• Serve as liaisons between the awardees and External Advisory Committee (EAC), 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 awardee institutions who are to serve on the EAC.
• 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 FOA, and of results of studies funded under this FOA.

Additionally, an agency Program Official or Institute 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:

A Steering Committee will be the main governing body of the INCLUDE DCC. The Steering Committee will be composed of the overall and core PDs/PIs of the INCLUDE DCC and NIH program staff. The Steering Committee Chair will not be an NIH staff member. Each full member will have one vote except NIH Project Scientist(s), who will have one collective vote. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions. Major scientific and administrative decisions will be determined by majority vote of the Steering Committee.

The Steering Committee will:

• Establish the milestones under this FOA.
• Develop uniform procedures and policies necessary to meet the Program goals.
• Provide information to the EAC, which will be appointed by the NIH. The EAC will evaluate the progress of the INCLUDE Project’s Component 2 efforts, specifically regarding the DCC coordination of activities, and the Project s awardees, and provide advice to the NIH and Steering Committee about scientific direction.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The panel members will be a designee of the INCLUDE Steering Committee, 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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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.

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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 $25,000. 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 Appendix XII to 45 CFR Part 75, 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 Award Term and Conditions for Recipient Integrity and Performance Matters.

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: http://grants.nih.gov/support/ (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: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Melissa Parisi, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-1383
Email: [email protected]

Huiqing Li, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0554
Email: [email protected]

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

Tammi Simpson
National Heart, Lung, and Blood Institute (NHLBI
Telephone: 301-827-8051
Email: [email protected]

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.