It is critical that applicants follow the Research (R) 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

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress. Common Fund initiatives are short term, stimulatory investments, and for the UDN, the Common Fund is providing funds through FY22.

Nature of the Research Opportunity

The purpose of this funding opportunity announcement (FOA) is to provide 8-10 Clinical Sites for participants seen through the Undiagnosed Diseases Network (UDN).

Background

Undiagnosed diseases are considered to be disorders with long-standing symptoms or signs that have not been diagnosed despite extensive clinical investigation. Undiagnosed diseases include 1) rare, previously described diseases, afflicting less than 200,000 individuals in the United States, that are often not recognized because they are so infrequent; 2) yet-to-be-described disorders, previously unknown to medicine also presumed to be rare; and 3) rare variants of more common diseases. Rare and yet-to-be described disorders are difficult problems for patients, their families, and their physicians. Patients and their family members will be referred to as participants in this FOA.

The goals of the UDN are to (1) improve the level of diagnosis and care for patients with undiagnosed diseases through the use of common protocols designed by a large community of investigators; (2) facilitate research into the etiology of undiagnosed diseases, by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures; and (3) promote an integrated and collaborative community across multiple Clinical Sites and among laboratory and clinical investigators prepared to investigate the pathophysiology, cell biologic, and molecular mechanisms underpinning these difficult to diagnose diseases. Phase I (FY13-FY17) of the Undiagnosed Diseases Network (UDN) extended the success of the NIH Intramural Undiagnosed Diseases Program (UDP) to a network of UDN sites across the United States (https://commonfund.nih.gov/Diseases/index). Phase I included seven Clinical Sites including the intramural NIH UDP, a Coordinating Center, and five Core Laboratories (Central Biorepository, Metabolomics Core, Model Organisms Screening Center, and two Sequencing Cores). There was also additional support provided for gene function research studies to complement the UDN. After a year of developing network-wide protocols, a single IRB, and an innovative Data Sharing and Use Agreement that allows for sharing of identifiable patient information with all members of the UDN, the UDN Gateway (https://undiagnosed.hms.harvard.edu/about/) started accepting applications in September 2015. Extensive information on the current network, including the UDN Manual of Operations, and publications to date is available to the scientific community (https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/, https://commonfund.nih.gov/publications?pid=32). In addition, case information has been deposited for matchmaking in PhenomeCentral (a part of Matchmaker Exchange) and will be available for request in dbGaP.

Continuation of the UDN into Phase II

In October of 2015 a Request for Information solicited input regarding potential strategies for undiagnosed diseases research and the clinical and laboratory evaluation of undiagnosed patients (https://grants.nih.gov/grants/guide/notice-files/NOT-RM-16-001.html). The replies and progress to date were discussed at the March 2016 Workshop on Future Directions for Undiagnosed Diseases Research: The UDN and Beyond (https://www.genome.gov/27564304/future-directions-for-undiagnosed-diseases-research-the-udn-and-beyond/).

Outside experts supported the continuation of the UDN into a Phase II. To address these recommendations, Phase II of the UDN aims to form a sustainable national resource to diagnose both rare and new diseases and enhance collaboration among laboratory and clinical researchers. In Phase II the Coordinating Center is expected to develop plans for sustainability once Common Fund support ends in FY22, substantiated by clear institutional commitments.

Scientific Knowledge to be Achieved

The applicant(s) funded by this FOA will join the NIH Undiagnosed Diseases Network, consisting of future grantees from the related FOAs (RFA-RM-17-018 - Coordinating Center for the Undiagnosed Diseases Network (UDN) Phase II (U01), RM-17-017 - Model Organism Screening Center for the Undiagnosed Diseases Network (UDN) Phase II (U54), RFA-RM-17-016 - "Sequencing Core(s) for the Undiagnosed Diseases Network (UDN) Phase II (U01), and RFA-RM-17-015 Metabolomics for the Undiagnosed Diseases Network (UDN) Phase II (U01) ), together with the ongoing Intramural NIH UDP and NIH program staff. This funding opportunity is designed to provide Clinical Sites to the UDN. The Network will increase the availability of diagnostic services, foster opportunities for collaboration between laboratory and clinical investigators, provide resulting data and protocols to the broader community, and assess development of a sustainable national resource after Common Fund support ends in FY22. These efforts will lead to new knowledge regarding the biochemistry, physiology, and mechanisms of these diseases and improve diagnostic and management options for affected individuals and their relatives and may lead to new strategies to improve their clinical care.

Objectives of this Research Program

The goals of the UDN are to:

1. improve the level of diagnosis and care for patients with undiagnosed diseases through the use of common protocols designed by a large community of investigators;

2. facilitate research into the etiology of undiagnosed diseases by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures; and,

3. promote an integrated and collaborative community across multiple Clinical Sites and among laboratory and clinical investigators prepared to investigate the pathophysiology, cell biologic, and molecular mechanisms underpinning these difficult to diagnose diseases.

The objectives of this program are to:

1. recruit, select, evaluate, and follow participants with disorders in any clinical specialty, adult and pediatric;

2. provide a comprehensive clinical evaluation in an expeditious manner; that is, completed within one week of initiation or a time-efficient alternative that minimizes burden on participants; and,

3. establish and maintain clinical evaluations at a rate of 30 affected UDN participants per year.

This program seeks to provide improved patient access to state-of-the-art diagnostic methods, by expanding the available expertise and facilities serving patients with these unusual disorders and to accelerate discovery and innovation in diagnosing and managing disease in these patients. In addition to the clinical infrastructure, gene function studies will be supported through a variety of funding mechanisms to elucidate the biologic mechanisms of identified genetic variants in disease causation, leading to potential pathways to improved treatments. Such funding mechanisms may include subsequent supplements to the Clinical Sites supported by this FOA to foster collaboration among laboratory and clinical investigators.

UDN investigators will share lessons learned to date in approaches to inquiries, evaluation of medical records, and detailed assessment of phenotype, environment, and genotype in participants selected for diagnostic investigations. To facilitate sharing this knowledge, the UDN Manual of Operations describing the Phase I UDN protocols is available to the scientific community at https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/. Clinical Sites will also be encouraged to share experiences they have from outside the UDN.

It is hoped that sharing these lessons will facilitate the development of Phase II of the UDN and that new directions and best practices will be developed for use by all. The Coordinating Center and Clinical Sites are anticipated to bring new ideas and alternative approaches to refine and improve upon UDN Phase I practices and adapt them for long-term sustainability.

Although every undiagnosed patient is unique and requires some individualized investigations, certain core components are expected to be relevant to all participants in the UDN. All Clinical Sites, including the NIH UDP, will be expected to utilize common investigative and data collection protocols to facilitate sharing of data to enhance the scientific and diagnostic value of the resulting information. The UDN Core(s) will similarly be expected to adopt network-wide data standards, where appropriate, and make them accessible to the community as agreed upon by the UDN Steering Committee. All sites are expected to creatively contribute to efforts to assess the UDN and identify and disseminate effective elements of the diagnostic strategy towards clinical practice. Additionally, all UDN sites are expected to develop sustainable data sharing plans that can be maintained as NIH Common Fund support ramps down.

Sustainability of the UDN

In Phase II, the UDN aims to determine the components necessary to make the UDN a sustainable national resource. All UDN Sites should propose in their applications, and to the UDN Steering Committee if awarded, new ideas and alternative approaches to refine and improve upon UDN Phase I practices (the UDN Manual of Operations describing the Phase I UDN protocols is available to the scientific community at https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/) and adapt them for long-term sustainability. Applicants are expected to be able to adapt to the unique needs and unexpected circumstances that may arise as the UDN evolves towards sustainability and NIH Common Fund support ramps down to end in FY22.

Sustainability plans proposed should be relevant to maintaining the critical functions of the UDN Site applied for. In addition, applicants may propose approaches to network assessment, sustainability, and function that may ultimately be adopted by the Steering Committee and UDN. Applicants are expected to implement approaches agreed upon by the UDN as a whole to move towards a sustainable UDN after Common Fund support ends in FY22.

Program Formation and Governance

The awards funded under this FOA will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award). Close interactions among the awardees and NIH will be required to maintain this complex network. Shortly after the awards, representatives of all UDN sites and NIH program staff will meet to plan approaches, identify barriers, and propose strategies for maintaining the UDN.

The UDN governance will rest with the UDN Steering Committee in collaboration with NIH program officials, with advice from Program Consultants providing critical scientific and managerial insights, and subject to oversight by the UDN Working Group of the NIH Common Fund. The Steering Committee may establish subcommittees, working groups, etc., to facilitate development, implementation, and monitoring of specific network functions such as participant recruitment, selection, and assignment to specific Clinical Site, clinical evaluation, final diagnosis, network assessment, dissemination, and access to Core Laboratories as needed.

A Steering Committee composed of PD(s)/PI(s) from all Clinical Sites, Coordinating Center, Core laboratories and the NIH Project Scientist(s) will be responsible for the scientific direction of the UDN. The Steering Committee will meet quarterly during the first year and three times per year or as needed subsequently for 1-2 day meetings.

The UDN Steering Committee will be the operational group through which the NIH Common Fund UDN Working Group interacts with the UDN. It will also ensure dissemination of program data such as sequence data and other materials to the wider scientific community.

Program Consultants will be named by NIH program officials and will be responsible for monitoring UDN activities and making ongoing recommendations to the NIH Common Fund UDN Working Group regarding processes and substantive issues that arise during network operations.

Core Laboratories for Metabolomics, Model Organisms Screening, and Sequencing are also being solicited for Phase II of the UDN (RM-17-017 - Model Organism Screening Center for the Undiagnosed Diseases Network (UDN) Phase II (U54), RFA-RM-17-016 - "Sequencing Core(s) for the Undiagnosed Diseases Network (UDN) Phase II (U01), and RFA-RM-17-015 Metabolomics for the Undiagnosed Diseases Network (UDN) Phase II (U01), ). To facilitate data sharing and pooled analyses, Core Laboratories will provide these services network-wide. Depending on capabilities at the individual Clinical Site, additional testing (beyond those services provided by the UDN Core Laboratories) could also be conducted locally according to agreed-upon standards, with resulting data submitted for network-wide analyses and deposition. Institutions applying to be UDN Clinical Sites may also apply to be Core Laboratories. The UDN Steering Committee will be tasked with developing an equitable process for prioritizing access to the UDN Cores; this process will be reviewed and approved by the UDN’s Program Consultants and the NIH Common Fund UDN Working Group. This process will likely involve a subcommittee or working group to define priorities for access, formats for requests, and expectations for turnaround and follow-up as needed.

Development of Milestones before Award

Because this FOA includes specific achievable goals milestones will be developed with applicant(s) prior to award. Milestones are goals that are quantifiable for measuring success, and include associated annual or semi-annual quantitative criteria. Prior to funding an application, NIH program staff will contact the applicant to establish a final set of milestones based on the information and preliminary milestones provided in the application (see Section IV). Milestones will include: 1) time required for ramping up to full productivity after award for new Clinical Sites, and 2) meeting FOA expectations of throughput (at least 30 previously undiagnosed cases evaluated per year) for all Clinical Sites. After review and approval by the NIH Common Fund UDN Working Group, the final set of approved milestones will be specified in the Notice of Grant Award.

Progress towards achieving the final set of milestones will be evaluated by NIH program staff and the NIH Common Fund UDN Working Group on an annual or semi-annual basis. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, the project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall progress of the Clinical Site in meeting UDN goals, program priorities, and the availability of funds.

Data Sharing under this Initiative

Data from the UDN are expected to be managed to increase the value of the significant public investment in the creation and operation of the Network. Consistent with achieving the goals of the program, NIH expects that the project datasets (phenotypic, environmental, covariates, and other relevant data) and associated data from the UDN Cores will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/). Information is expected to be deposited in database repositories, such as dbGaP, and published in the scientific literature with plans for outreach beyond database repositories welcomed. Plans for data sharing are also expected to be sustainable and maintained as NIH Common Fund support ramps down. The UDN Steering Committee will additionally develop and implement network-wide guidelines for data deposition.

Resource Sharing under this Initiative

Resources generated by the Clinical Sites are also expected to be widely shared within the UDN and with the broader scientific community for research as appropriate considering patient confidentiality. The UDN Steering Committee will develop and implement network-wide approaches for resource deposition and use including submission to national repositories as appropriate.

Interim and Final Reports

Applicants are expected to participate with the Coordinating Center in preparing yearly reports for the UDN leadership, Program Consultants, and the NIH Common Fund UDN Working Group. All UDN Phase II awards will be for four years (FY18-FY21), with FY22 close-out funding determined based on performance and needs of the UDN. The yearly report for FY20 will include a more detailed report which will be used to assess close-out of the UDN effort in FY22. NIH support for some critical functions in FY22 and beyond will also be assessed in FY20. Additionally, a workshop will be held in FY20 including outside experts to determine the infrastructure necessary to transition the UDN to a sustainable national resource and make recommendations for final close-out of this project in FY22.

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 in response to 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 not 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) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

Applications for a Clinical Site grant may be submitted by individuals located at the same institution as an applicant for the Coordinating Center submitted under RFA-RM-17-018 - Coordinating Center for the Undiagnosed Diseases Network (UDN) Phase II (U01) , or any of the Core Laboratory FOAs (RM-17-017 - Model Organism Screening Center for the Undiagnosed Diseases Network (UDN) Phase II (U54), RFA-RM-17-016 - "Sequencing Core(s) for the Undiagnosed Diseases Network (UDN) Phase II (U01), and RFA-RM-17-015 Metabolomics for the Undiagnosed Diseases Network (UDN) Phase II (U01) ), but an individual may not be the PD/PI of another UDN application and a Clinical Site application.

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).

Buttons to access the online ASSIST system or to download application forms are 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 Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Anastasia L. Wise, PhD
National Human Genome Research Institute
Telephone: 301-480-3517
Email: anastasia.wise@nih.gov

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 FOA.

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

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

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

Facilities and Other Resources:

Applicants should describe the relevant institutional environments which would facilitate the effective implementation of the proposed program. Applicants should also describe existing or planned resources that would be available to the Clinical Site, such as clinical and laboratory facilities, participating and affiliated institutions and units, geographic distribution of space and personnel, and consultative and statistical resources.

Other Attachments: Please include the following information as an "Other Attachment."

Sustainability Plan

Propose a plan for sustainability to include:

• Sustainability of the model proposed and maintaining recruitment of 30 affected UDN participants per year.
• Assessment of sustainability as NIH Common Fund funding ramps down.

In this FOA, as in all FOAs related to the UDN, applicants are encouraged to creatively engage the scientific and operational problems that need to be addressed for the UDN to be a sustainable success. NIH recognizes that the approach to diagnosis and investigation developed by the UDN in Phase I is only one model, albeit a successful one. New ideas and alternative approaches proposed by all Clinical Sites are sought to refine and enhance the care of patients and the science generated from careful study of their cases. Within the framework of this FOA, there are a variety of approaches to network assessment, sustainability, and function that may ultimately be adopted by the Steering Committee and UDN. Applicants should discuss alternatives, defend the approaches they favor, and describe their willingness to implement approaches agreed upon by the UDN as a whole to move towards a sustainable UDN after Common Fund support ends in FY22.

The Responsibilities of the UDN Clinical Sites are described in Section VI.2, Administrative and National Policy Requirements. Applicants should indicate their willingness to cooperate with other awardees in the development and design of research approaches, procedures, policies and strategies to be applied to this program. Applicants should also describe their ability to adapt to unique needs and unexpected circumstances that may arise as the UDN evolves towards sustainability and NIH Common Fund support ramps down to end in FY22.

Applicants should describe how they will work with the other members of the UDN Steering Committee (SC) to define a mode of operation that best matches the capabilities of the selected sites, within broad guidelines of parity, openness, cost-effectiveness, and timeliness as defined by the Steering Committee, the NIH, and its Consultants.

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

The PD(s)/PI(s) should be well-established in clinical research and at least one must devote at least 2.4 person months (20% of full-time professional effort) to this Program.

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

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

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

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

Specific Aims

List each aim for the Clinical Site and how it supports the Objectives of this Research Program as described in Section I. Funding Opportunity Description.

Research Strategy

Describe how the PD(s)/PI(s) will carry out the following responsibilities in the continuation or implementation of this Clinical Site:

• Although Clinical Sites are expected to be able to recruit, select, evaluate, and follow participants with disorders in any clinical specialty, rare and undiagnosed conditions may cluster in certain disciplines such as (but not limited to) cardiology; gastroenterology; neurology; pediatrics; psychiatry; rheumatology; or metabolic, environmental or infectious diseases. Applicants should describe unique strengths such as systems- or disease-specific clinical expertise available at their site, their willingness and approach for making such expertise available network-wide, and their ability to investigate and diagnose disorders outside their specific areas of expertise. UDN Clinical Sites may have a clinical focus area of expertise, but must be able to recruit, select, evaluate, and follow participants with disorders in any clinical specialty, adult or pediatric. Applicants should also describe potential organizational or structural barriers to the creation of a UDN Clinical Site and their plans to mitigate these problems.
• Clinical services for UDN participants may be billed to insurance when indicated; however, Clinical Sites must also plan for participants who are uninsured or under-insured and should include these costs in their budgets.
• UDN Clinical Sites should budget for UDN participant travel costs including travel, room, and board for affected UDN participants along with one additional family member or caregiver. Based on current UDN Phase I costs, an average cost of $2000 per affected UDN participant for travel, room, and board (including the affected UDN participant and one additional family member or caregiver) is estimated. This does not include hospital bed charges. UDN Clinical Sites should also minimize travel costs when possible by taking advantage of local programs, such as subsidized housing, when available.

Integration and collaboration are essential tasks for all UDN investigators who are chosen to participate in Phase II. The following recommendations should be considered when describing the concept of a UDN Clinical Site:

• Applicants should describe prior experience of the team as a whole in working as part of a research network or other collaborative activities to meet individual and group goals, including examples of prior collaborative efforts and/or participation in networks or consortia.
• Applicants should describe how they will collaborate with each other, other UDN sites, and program officials to design UDN operations and implement protocols. This includes reviewing and modifying draft protocols and operating guidelines developed for handling participant inquiries, reviewing prior diagnostic efforts, accepting participants for and conducting detailed evaluation, collecting and submitting data, discussing results with affected participants, their families, and their clinicians, and conducting follow-up and program assessment.
• Applicants should describe plans for identifying and solving operational problems involving recruitment, data collection, quality assurance and refinement of protocols and the UDN Manual of Operations. Applicants should suggest plans that will assist in developing collaborations between clinical and laboratory scientists both within and outside the UDN.
• Applicants should also describe their experience of the team as a whole with a single IRB (or central IRB as referred to in Phase I of the UDN). The UDN will use a single IRB at the NIH to accelerate IRB approval of network-wide protocols. Applicants and their institutions should indicate their willingness to participate in a network that uses a single IRB.

Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project.

• Applicants should detail their team's experience and expertise (describing the synergy and expertise of the team as a whole not duplicative of the information provided in individual biosketches), proposed approaches, and potential alternatives to performing the various Clinical Site tasks summarized below. Additional tasks not detailed here but, in the applicant’s view, essential to UDN operations should be noted and potential approaches described. Applicants should articulate their plans for all aspects of participant recruitment, selection, consent, and counseling; clinical evaluation and data collection; investigation of family members, where appropriate; final diagnosis and, if feasible, recommendations for management; return of information to affected participants, their families, and their referring physicians; transfer of care to referring clinicians; participant follow-up for psychosocial, health, and other relevant outcomes; data analysis, data sharing, and publication; and complementary laboratory and gene function studies, as appropriate to make a diagnosis. Prior experience and ongoing related programs on which the Clinical Site could build but not duplicate should also be described.
• Applicants should describe the feasibility of providing a comprehensive clinical evaluation in an expeditious manner; that is, completed within one week of initiation. These evaluations are anticipated to include assessment by a complete array of consultants and require an in-patient stay and/or well coordinated multidisciplinary outpatient evaluations. Applicants should describe their ability to provide such evaluations during a single in-patient stay and provide any institutional commitment for doing so; or, if this is not feasible, explain why not and describe time-efficient alternatives that minimize burden on participants.
• Applicants should describe their willingness to adhere to network-wide policies and procedures for the key Clinical Site functions described above as well as network-defined timelines for recruitment, data collection, and accurate submission of process and tracking data and scientific variables such as phenotype, genotype, and environmental exposures data. Currently, the UDN aims for an approximately 50/50 distribution of adult and pediatric cases and no more than 50% of accepted participants having been previously seen by the Clinical Site enrolling. Applicants should also describe plans for, and willingness to abide by, Memoranda of Understanding or other sharing agreements potentially needed for data and sample sharing within the UDN.
• Applicants should describe plans to continue or create their proposed Clinical Sites and a sustainable UDN as a whole, including collaboration in central collection and distribution of inquiries across sites, sharing of chart review, potential use of special participant evaluations at specific Clinical Sites to take advantage of local expertise, and transfer of participants among Clinical Sites based upon expertise, interest and geographic proximity to the participant.
• Recognizing that the NIH Clinical Center accepts participants without regard to ability to pay, applicants should describe their approaches, for the duration of the UDN, to recruiting, investigating, diagnosing, referring for care, and following up participants who are uninsured or under-insured. In addition, they should describe plans for sustaining and continuing the UDN-supported approaches to evaluating and managing difficult-to-diagnose participants once Common Fund support ends.
• Applicants should discuss their plans to collect data on environmental exposures, genotype and phenotype and describe plans to work with the Coordinating Center to optimize data collection (such as use of standard collection tools or ontologies) and analysis strategies and facilitate public access to the UDN data through the Coordinating Center and organizations such as the National Center for Biotechnology Information (NCBI), which maintains NIH databases such as dbGaP, to optimize data analysis and public access to the data.
• Provide a timeline and preliminary set of milestones to establish and maintain clinical evaluations at a rate of 30 affected UDN participants per year by the end of year 1. Plans to meet these recruitment milestones should be described, as should plans for analyzing exome or genome, metabolomics, and model organism data. Methods for supporting this rate of clinical evaluation as NIH Common Fund funding ramps down starting in FY20 should also be described.
• Applicants should describe plans for pursuing outcome follow-up, gene function studies, and specialized technologic investigations of participants previously seen and sustaining this rate as Common Fund support ramps down. Similarly, the approaches to evaluating the UDN diagnostic approach to determine which components increase the likelihood of a diagnosis being reached should be described and changes to the current UDN Phase I model explored as appropriate (for new applicants, information on the current Phase I UDN model can be found in the UDN Manual of Operations: https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/).

Bioinformatics Plan

Propose a plan for bioinformatics analysis to include:

• Plans for how bioinformatics infrastructure, capabilities, and computational resources in place (or readily obtainable) as described in Facilities and Other Resources will be leveraged.
• Bioinformatics approaches and innovation to provide the best utilization of the data produced by the UDN including innovative approaches capable of identifying rare and novel diagnoses.
• Plans to collaborate with the UDN Coordinating Center and other UDN sites to develop and disseminate bioinformatics tools and resources within the UDN and to the scientific community to improve the UDN model.

Assessment, Dissemination, Outreach, and Training

Propose a plan for assessment, dissemination, outreach, and training to include:

• Assessing and disseminating data, protocols, consent materials, and methods developed for or derived from the UDN within and outside the Network.
• Developing and implementing appropriate educational and outreach materials for participants, clinicians, and other researchers.
• Training activities to expose students, fellows, staff, and faculty to the UDN model.
• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Steering Committee for the UDN.

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.
• Applicants should also describe plans for sharing of software and analysis tools.

Letters of Support: Institutional commitments to providing a comprehensive clinical evaluation within one week of initiation, evaluating uninsured participants, and sustaining the program beyond NIH Common Fund support should be clearly documented.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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). 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.

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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 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. See Section III of this FOA for information on registration requirements.

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. 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.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Additionally, for this FOA: Will this project make a significant contribution to the overall goals and objectives of the UDN and assist in the diagnosis of participants who suffer from rare or yet to-be-described diseases? Will the Clinical Site’s conceptual design and overall operating plan provide the required strategy and resources to advance the diagnoses of rare or yet to-be-described diseases?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Additionally, for this FOA: Do the PD(s)/PI(s) and research team have the required experience and expertise in evaluation and management of difficult-to-diagnose participants and are they recognized within and outside their institutions as expert diagnosticians? Have the PD(s)/PI(s) and research team participated as a Clinical Site in any collaborative, multi-center networks and do they have a track record of working collaboratively and disseminating findings? Do the PD(s)/PI(s) have the appropriate experience in managing complex, multi-site (if relevant to the application) projects involving teams of scientists? Do the PD(s)/PI(s) and research team have experience collecting, analyzing, and publishing phenotypic and genomic data?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Additionally, for this FOA: As new technologies become available, is the research team poised to recognize when they are sufficiently developed and validated to be added to the UDN protocols? Are the bioinformatics approaches described innovative and likely to provide the best utilization of the data produced for the UDN? Will this research advance the use of genomics, related technologies and the use of common data elements and protocols in clinical management of patients with rare or as-yet-undescribed diseases?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Additionally, for this FOA: Do the project plan and bioinformatics plan propose cutting edge, innovative approaches capable of identifying rare and novel diagnoses? Will the Clinical Site’s conceptual design and overall operating plan effectively investigate the underlying pathogenicity of the UDN’s rare and yet to-be-described diseases? Will the Clinical Site’s design and operating plan provide ample opportunity for collaboration, integration, and interaction within the UDN in order to diagnose participants and investigate UDN disease phenotypes? Are plans for assessment, dissemination, outreach, and training proposed and feasible? Is a sustainability plan proposed and feasible?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additionally, for this FOA: Are the resources, equipment, and infrastructure available and in place (or readily obtainable) to allow quick ramp-up and evaluations from the Clinical Site? Are the bioinformatics infrastructure and capabilities and computational resources in place (or readily obtainable) and adequate to support the project? Are institutional resources and infrastructure being committed or leveraged? Are adequate plans for investigation and referral for care of uninsured or under-insured participants? Are there plans for sustaining the Clinical Site once Common Fund support ends, presented and substantiated by clear institutional commitments?

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 six 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 six 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 project 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 children 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

For Renewals, the committee will consider the progress made in the last funding period. For existing UDN sites, how productive have their sites been and have they demonstrated leadership and collaboration in network-wide efforts?

Not applicable

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.

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 (GDS).

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 National Advisory Council for Human Genome Research. 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.
• Inclusion of diverse and under-served populations such as disadvantaged or non-European ancestry groups.
• Inclusion of diverse practice settings such as community hospitals, primary care practices, specialty groups, and military or Veterans Administration hospitals.
• Inclusion of diverse geographic sites throughout the United States.
• Plans for caring for uninsured or underinsured participants.
• Balance of unique or specialized capabilities.
• Plans for sustainability.

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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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 the UDN will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), 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 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below. Awardee will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a network-wide Steering Committee and working groups as needed.
• Refining and implementing the resulting consensus framework at their UDN site and network-wide, in collaboration with the Coordinating Center and NIH UDP.
• Providing protocols, reports and data in a timely fashion as agreed upon by the Steering Committee.
• Submitting all data from UDN participants as soon as they are collected to the Coordinating Center for quality control and compilation in a network-wide dataset to be made available to all Clinical Sites (including the NIH UDP), as agreed upon by the UDN Steering Committee, and deposited in database repositories such as dbGaP.
• Preparing abstracts, presentations and publications and collaborating network-wide in making the public and professionals aware of the program.
• Assessing and disseminating data, protocols, consent materials, and methods developed for or derived from the UDN within and outside the Network.
• Developing and implementing appropriate educational materials for participants, clinicians, and other researchers.
• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the UDN Steering Committee.
• Abiding by common definitions, protocols, and procedures, as chosen by majority vote of the UDN Steering Committee.
• Accepting and complying with study policies established by NIH and with additional non-conflicting policies approved by the UDN Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and Common Fund UDN Working Group.
• Attending and participating in UDN Steering Committee meetings and accepting and implementing decisions by the Common Fund UDN Working Group, as appropriate.

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

The Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the UDN and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist(s) will participate as members of the Steering Committee and will have one vote. The Project Scientist(s) will have the following substantial involvement:

• Participating with the other UDN Steering Committee members in addressing issues that arise with UDN planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the awardees. The Project Scientist(s) will also help coordinate the efforts of the UDN with other groups conducting similar efforts.
• Attending all Steering Committee meetings as a voting member and all Working Group meetings, assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the grantee as needed to manage the logistic aspects of the UDN.
• Reporting periodically on UDN progress to the Common Fund UDN Working Group and through it to the NIH Common Fund and to the National Advisory Council of Human Genome Research Institute.
• Serving on subcommittees of the Steering Committee and Working Groups as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.
• Other NIH Common Fund UDN Working Group staff may assist the awardee as designated by the Program Official.

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. The assigned Program Official may also serve as an NIH Working Group Project Scientist(s) to assist the awardee.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage, assess, and disseminate the UDN model. The awardees and the Project Scientist(s) will meet in person with the program Steering Committee on a quarterly schedule during the first year of Phase II UDN operations and subsequently three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include PD(s)/PI(s) of each Clinical Site and the Coordinating Center award, the PD(s)/PI(s) of the Metabolomics Core, Model Organisms Screening Center, and Sequencing Core(s), other staff as needed (ex-officio) and the NIH Project Scientist(s). The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. Each Clinical Site (including the UDP), the Coordinating Center, The Metabolomics Core, the Model Organisms Screening Center, and the Sequencing Core(s) will have one vote and the NIH Program Scientist(s) together will have one vote.

The Steering Committee may establish working groups as needed to address particular issues, which will include representatives from the program and the NIH and possibly other experts. The UDN Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various working groups and other needed subcommittees.

The Clinical Site Awardee agrees to work collaboratively to:

• Assist in refining a common approach to participants with Undiagnosed Diseases.
• Participate in network-wide processes for participant selection and assignment to specific Clinical Site for evaluation.
• Provide for secure, accurate and timely data submission.
• Participate in presenting and publishing new processes and substantive findings
• Assess and disseminate the UDN model.
• Participate in the governance of the UDN as a member of the Steering Committee.
• Interact with other relevant NHGRI and NIH activities, as needed, to promote synergy and consistency among similar projects.

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 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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-945-7573

Anastasia L. Wise, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301- 480-3517
Email: anastasia.wise@nih.gov

James J. Li, PhD
NIH Center for Scientific Review (CSR)
Telephone: 301-806-8065
Email: lijames@csr.nih.gov

Lisa Oken
National Human Genome Research Institute (NHGRI)
Telephone: 301-594-5250
Email: Lisa.Oken@nih.gov

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.