NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 establish a Model Organisms Screening Center (MOSC) to evaluate the putative pathogenicity and function of gene variants identified through the NIH Undiagnosed Diseases Network (UDN). The Network expects to identify approximately 200 gene variants of unknown (or minimally characterized) function each year from affected individuals enrolled at the UDN clinical sites. To assist in the diagnosis of UDN participants, applications responsive to this FOA will propose to establish a strategy for screening and analyzing the most informative variants in research organisms. The analysis platform is expected to utilize cutting-edge bioinformatics tools and resources to assist in the initial screening of candidate variants for analysis by the MOSC and have the capacity to analyze selected variants in Drosophila and zebrafish at a minimum, plus other small animal models or cell-based assays as appropriate to evaluate the preliminary pathogenicity and function of candidate gene variants in the context of the respective UDN participant's disease phenotype.

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 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 central 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 a 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 Model Organisms Screening 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 the future grantees from the related FOAs (RFA-RM-17-019 - "Clinical Sites for the Undiagnosed Diseases Network (UDN) Phase II (U01)," RFA-RM-17-018 - Coordinating Center for the Undiagnosed Diseases Network (UDN) Phase II (U01), RFA-RM-17-015 Metabolomics Core for the Undiagnosed Diseases Network Phase II U01, and RFA-RM-17-16 - Sequencing Core(s) 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 a Model Organisms Screening Center 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.

As part of the diagnostic workup of participants enrolled at the UDN Clinical Sites, the designated DNA Sequencing Core(s) will conduct whole exome or whole genome sequencing on UDN participants, typically the proband and biological parents. After initial bioinformatics analysis and prioritization by the UDN Clinical Sites, it is anticipated that approximately 200 human gene sequence variants per year will be submitted to the MOSC for additional screening and analysis in order to assess the likelihood that the variant is disease-causing in the context of the UDN participant’s disease phenotype. The MOSC analysis pipeline is expected to involve innovative, cutting-edge bioinformatics approaches to assist further in the screening and identification of promising variants from those submitted to the MOSC, followed by analyses of selected variants in small research organisms or other proposed assays. At a minimum, the MOSC should have the capacity to analyze variants in Drosophila and zebrafish, but the analysis platform may include other small animal models or cell-based assays as needed. This funding opportunity is designed to provide centralized MOSC services to the Network and assist in the diagnosis of UDN participants network-wide by rapidly and preliminarily evaluating the pathogenicity of UDN putative disease-causing variants in research organisms.

Of the new or rare diseases discovered so far by the UDN, approximately 40% involve neurological dysfunction or developmental delay; the remaining clinical phenotypes span dysmorphic, metabolic, skeletal and inflammatory diseases, among others. The types of mutations that have been identified by the UDN are varied (including missense, nonsense, frameshift, truncations and other structural variants) and involve multiple forms of inheritance (e.g., recessive, de novo dominant, X-linked); see: https://commonfund.nih.gov/publications?pid=32. The most competitive applications in response to this FOA will propose a suite of strategies and bioinformatics approaches for screening and selecting the most informative variant(s) for analysis in research organisms, cutting-edge gene targeting or editing strategies, and models and phenotypic/expression assays that can accommodate the diversity of participant mutations and clinical phenotypes likely to be encountered by the Network.

The MOSC is intended to serve as the initial screen for identifying potential candidate disease-causing variants and providing a preliminary analysis of their pathogenicity in the context of the respective UDN disease phenotypes. Although not expected to provide definitive functional or pathogenic characterization of variants, the MOSC may conduct more comprehensive characterization of a subset of the most promising variants in collaboration with the other UDN Sites/Cores and with the approval of the Steering Committee. For example, additional funds may be available through the UDN Coordinating Center to support collaborations among UDN Sites/Cores/Centers for such gene function studies (see below). Data and analyses from the MOSC are expected to be submitted to the Coordinating Center according to agreed upon timelines.

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. Using advanced bioinformatics tools and model organisms, establish a strategy for selecting and analyzing the most informative variants for screening in research organisms. In order to meet overall UDN objectives, the Steering Committee will provide oversight in the selection of variants for analysis in model organisms, which may involve genes of unknown significance, variants of unknown significance in known causative genes or potential cases of phenotypic expansion.

2. Establish a model organism screening pipeline to include Drosophila and zebrafish at a minimum, and involving other small animal models or cell-based assays as appropriate, for rapidly and efficiently evaluating, preliminarily, the pathogenicity and possible function of putative disease-causing gene variants identified through the UDN.

3. Implement state-of-art, proven, and validated gene targeting or editing strategies to evaluate UDN gene variants in the appropriate model organisms as described above.

4. Using advanced bioinformatics approaches and/or small animal and cell-based models, establish a primary screening platform with the capacity to analyze at least 200 UDN gene variants per year for preliminary evaluation of pathogenicity in the context of the respective UDN participant's disease phenotype.

5. Establish assays in research organisms or cell-based models (e.g., expression analysis, cellular or organ-level phenotype, protein function, etc.) to conduct a more comprehensive functional and phenotypic analysis of a subset of the gene variants, e.g., those variants identified as potentially disease-causing from the primary screen or requiring further functional characterization and validation to judge the preliminary pathogenicity. Note: the MOSC is intended to serve as the initial screen for identifying and prioritizing potential disease-causing variants and, as such, is not expected to provide definitive functional or pathogenic characterization of variants, except when approved by the Steering Committee and in collaboration with the other UDN Sites/Cores.

6. Provide results to the Network as rapidly as possible, optimally within six-to-twelve months of receiving the gene variant assignment, depending on the species analyzed and depth of analysis for the variant, as approved by the Steering Committee.

7. Participate in an integrated and collaborative research community across multiple clinical sites and core laboratories to investigate the pathophysiology of these new and rare diseases and share this understanding to identify improved options for optimal patient management.

This FOA is not meant to support the development or optimization of new technologies, assays or model systems; instead, responsive applications will propose to establish a screening pipeline involving state-of-the-art, proven, and validated technologies, approaches and models suitable for the throughput and turnaround time described above.

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 and MOSC services, 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 include subcontracts to investigators supported by the Coordinating Center 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 patients and families 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/. The MOSC and other UDN 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 MOSC and other UDN 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 patients. All Clinical Sites, including the NIH UDP, will be expected to utilize common investigative and data collection protocols in order to facilitate sharing of data to enhance the scientific and diagnostic value of the resulting information. The UDN MOSC and other Core(s) will similarly be expected to adopt network-wide data standards, where appropriate, and make it accessible to the community as agreed upon by the Network 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 MOSC as NIH Common Fund support ramps down. 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.

Overall Organization of Center Components

Utilizing the U54 Specialized Center-Cooperative Agreement grant mechanism, the MOSC will consist of one central Leadership/Implementation Project, an Administrative Core and at least two Resource Cores as described below:

1. A central Leadership/Implementation Project involving a team of investigators with the knowledge and expertise to evaluate putative disease-causing gene variants within the context of the specific UDN disease phenotype. The Project will be responsible for developing and implementing a rapid, efficient and tailored screening pipeline and analysis plan for evaluating specific gene variants in the most relevant and informative model system(s). The Project, at a minimum, should include the following elements: 1) a leadership team that will interact with the UDN to gain knowledge about the specific gene variant and respective clinical information, and develop a tailored screening and analysis plan for the variant using available Core models and resources; and 2) bioinformatics resources and expertise to assist the leadership team in the nomination and prioritization of variants for analysis in research organisms and in developing the tailored analysis plan for specific gene variants.

2. A Center Director [Program Director/Principal Investigator (PD/PI)] responsible for scientific and administrative oversight of the Center. The PD/PI must devote at least 1.2 person months (10% of full-time professional effort) to this Program.

3. An Administrative Core that will coordinate and manage activities and resources between the UDN, NIH program staff, the MOSC Leadership/Implementation Project and Resource Cores.

4. At least two Resource Cores to include gene targeting/editing and phenotypic analysis in Drosophila and zebrafish models respectively; additional Cores may be proposed as needed for primary screening or secondary analysis of specific gene variants in other small animal models or cell-based assays. Additional Cores should be capable of meeting the throughput and turnaround expectations of the FOA (as outlined above) and should be justified based on scientific need and reasonably supported within the allowable budget.

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 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 Network 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, participant selection, and assignment to specific Clinical Sites, clinical evaluation, final diagnosis, network assessment, dissemination, and access to Core Laboratories as needed. The Steering Committee will provide oversight and approval of variants selected for analysis by the MOSC, particularly those that require more comprehensive characterization in research organisms.

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 Network. 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.

Institutions applying to be a UDN MOSC may also apply to be another UDN Clinical Site, Coordinating Center or Core (e.g., Metabolomics or Sequencing Core). The UDN Steering Committee will develop 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 Common Fund UDN Working Group. This process will likely involve the Model Organisms Working Group or a subcommittee or other 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 (i.e., an expected yearly throughput and turnaround time to analyze gene variants as described above), milestones will be negotiated with applicant(s) prior to award. Milestones are goals that are quantifiable for measuring success, and include annual or semi-annual quantitative criteria associated with them. 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 the: 1) ramp-up time to reach full productivity in a newly funded program; and 2) yearly throughput and turnaround time for analyzing gene variants after ramp-up. After review and approval by the NIH 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 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 MOSC 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. Through the UDN’s Coordinating Center, the NIH expects that its datasets (phenotypic, environmental, covariates, and other relevant data) and associated data from the Cores will be widely shared with the scientific community for research, while carefully observing standards of participant 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, presented at national meetings, 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 also develop and implement network-wide guidelines for data deposition.

Resource Sharing under this Initiative

Resources generated by the MOSC including all research organisms developed under this award are also expected to be widely shared with the Network and the broader scientific community for research as appropriate considering participant 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 Informationfor 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 MOSC 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), Clinical Sites submitted under RFA-RM-17-019 - Clinical Sites for the Undiagnosed Diseases Network (UDN) Phase II (U01), or one of the other Core Laboratory FOAs (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 MOSC 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).

A button to access the online ASSIST system 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.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

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:

Laura Mamounas
National Institute of Neurological Disorders and Stroke /NIH
Telephone: 301-496-5745
Email: [email protected]

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	6
Admin Core	6
Project (Use for Leadership/Implementation Project)	12
Core (use for Resource Cores)	6 for each Core

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 Core: required
• Leadership/Implementation Project - required, minimum and maximum one
• Resource Cores - required, minimum two, maximum five

When preparing your application in ASSIST, 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.

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 MOSC, 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

Provide an overview of the plan for sustainability to include:

• Sustainability of the core functions of the MOSC after NIH Common Fund support ends in FY22.
• Proposing, in collaboration with UDN investigators, protocols and operating guidelines that will define common and sustainable approaches to participant selection, data collection, laboratory investigation, and ultimate diagnosis.
• Plans to maintain, improve, and make sustainable the UDN Manual of Operations (https://undiagnosed.hms.harvard.edu/udn-manual-of-operations/).

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 Network 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 the MOSC are sought to assess, refine, and enhance the sustainability of the UDN model. 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 NIH. Applicants should discuss alternatives, defend the approaches they favor, and describe their willingness to implement approaches agreed upon by the Network as a whole to move towards a sustainable UDN after Common Fund support ends in FY22.

The Responsibilities of the MOSC 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 Network 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 to define a mode of operation that best matches the capabilities of the selected sites, within broad guidelines of parity, openness, cost-effectiveness, timeliness, and optimal patient care, as defined by the Steering Committee, the NIH, and its advisors.

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.

Describe the experience of the PD(s)/PI(s) in managing complex, multi-site (if relevant) projects involving teams of scientists.

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. The Center Director is the overall PD/PI. The sum of the PD/PI's effort to the components of the Program must be at least 1.2 person months.

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: List each aim for the UDN MOSC and how it supports the overall objectives of this research program.

Research Strategy: The Center overview should describe the MOSC organization, expertise and the overall vision and leadership plan including how the MOSC will communicate and collaborate across the Project and Resource Cores and with the UDN and NIH program staff to achieve Center and network objectives. The specific items to be addressed in this section include but are not limited to the following:

• Provide a brief overview of the strategy, including bioinformatics approaches, for nominating and analyzing the most informative variants for screening by the MOSC, which may involve genes of unknown significance, variants of unknown significance in known causative genes or potential cases of phenotypic expansion; describe the process for communicating and interacting with the Clinical Sites to gain information about the variant in the context of the UDN participant’s clinical phenotype.
• Present a brief overview (may include a diagram) of the design and framework of the screening and analysis pipeline, including a concise description of the gene targeting strategies, models and functional assays proposed to investigate preliminarily the pathogenicity of UDN gene variants in the context of specific phenotypes of UDN participants.
• Briefly justify the need for any model(s) proposed in addition to Drosophila and zebrafish, and discuss how the model(s) will contribute to the overall objectives of the Center (additional details may be included in the Leadership/Implementation Project or Resource Core sections).
• Provide an overview of the leadership plan for analyzing gene variants, including the rationale for assigning specific gene variants to specific Resource Core(s) for primary screening and, when appropriate, secondary analysis or validation; describe the process, including Center bioinformatics support and communication/collaborations with the UDN Clinical Sites, for tailoring the analysis of specific gene variants based on knowledge of the UDN participant’s mutation (e.g., mode of inheritance) and disease phenotype, or presence of an ortholog in the research organism. Discuss how data from previous publications (e.g., expression, functional studies of orthologs) will be incorporated into the plan.

Bioinformatics Plan

Provide an overview of the 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 to assist the MOSC leadership team in developing a tailored screening and analysis plan for specific variants.
• Innovative new bioinformatics approaches or resources available to assist the UDN in evaluating and selecting variants of unknown significance for further analysis by the MOSC and/or other UDN sites/cores.
• 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.

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.

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.

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

When preparing your application in ASSIST, 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 Admin 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.
• Address the following elements in the relevant Biographical Sketches: Describe the experience of the Admin Core Lead in managing complex, multi-site (if relevant) projects involving teams of scientists.
• Describe the previous experience, if any, of the Admin Core Lead in managing or participating in large-scale screening projects involving the rapid evaluation of gene variants in model organisms.

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: List each aim for the Administrative Core and how it supports the overall objectives of this research program.

Research Strategy: Describe the overall plans to coordinate and manage activities and resources between the UDN, NIH program staff, the MOSC Leadership/Implementation Project and Resource Cores. The specific items to be addressed in this section include but are not limited to the following:

• Provide an overview of the Center organization including coordination and interactions between the MOSC Leadership/Implementation Project and the Resource Cores.
  
  
• Describe how the Administrative Core will manage and coordinate communication, day-to-day activities, collaborations, and resource and data sharing both within the MOSC (including Resource Cores) and with the UDN and NIH program staff.
  
  
• Describe the leadership team and how components of the MOSC, including key personnel, will interact within the MOSC itself and with the broader UDN and NIH program staff. For example: describe the process of communicating with the Steering Committee the nomination of variants for analysis by the MOSC (note: the Steering Committee will provide oversight in the selection and prioritization of variants for analysis); describe how outcome and results will be communicated to the UDN Clinical Sites and Coordination Center, and indicate who will be the primary point of contact.
  
  
• Describe how decisions (e.g., assignment of gene variants to the Resource Cores) will be made by the leadership team (e.g., by consensus; by one individual or small group of individuals and, if so, by whom?) and carried out.
  
  
• Describe mechanisms to ensure internal quality control of ongoing research activities across the Center.
• 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 MOSC:
• Describe prior experience in working as part of a research network or other large-scale collaborative activities to meet individual and group goals, including examples of such prior work.
  
  
• Applicants should describe their team experience with a single IRB (or central IRB as referred to in Phase I of the UDN). The Network 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.
  
  
• State willingness to adhere to Network-wide policies and procedures for the key MOSC functions described in this FOA as well as network-defined timelines for MOSC functions. Applicants should also describe plans for, and willingness to abide by, Memoranda of Understanding and other sharing agreements potentially needed for data and sample sharing within the Network.
  
  
• Describe plans to work with the Coordinating Center to optimize data collection 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.
• Describe plans for collaborating with other UDN sites and NIH program officials to design or improve network operations and implement protocols. This may include updating the UDN Manual of Operations, and contributing to a Network-wide bioinformatics and analysis pipeline.

Assessment, Dissemination, Outreach, and Training

• Describe plans for collaborations on assessments, dissemination, outreach and training including:
• 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 and clinicians.
• Training activities at the MOSC to disseminate the UDN model.
• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Steering Committee for the UDN.

Letters of Support: Institutional commitments made to the UDN Model Organisms Screening Center should be clearly documented including those sustaining the program beyond NIH Common Fund support.

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

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.

PHS Inclusion Enrollment Report (Administrative Core)

Not Applicable

When preparing your application in ASSIST, use Component Type Project.

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

SF424 (R&R) Cover (Leadership/Implementation Project)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Leadership/Implementation Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Leadership/Implementation Project)

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.

Project /Performance Site Location(s) (Leadership/Implementation Project)

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.

Research & Related Senior/Key Person Profile (Leadership/Implementation Project)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project 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.
• Address the following elements in the relevant Biographical Sketches:

o Describe the experience of the Project Lead in managing complex, multi-site (if relevant) projects involving teams of scientists.

o Describe the knowledge and expertise of the Project Lead and other senior/key personnel in the functional characterization of putative disease-causing gene variants in animal and cell-based model systems.

o Describe the previous experience, if any, of the senior/key personnel in managing or participating in large-scale screening projects involving the rapid evaluation of gene variants in research organisms.

o Describe the training and expertise of the Project Lead, and other senior/key personnel in human genetics/genomics, bioinformatics and/or clinically-related disease research specifically as relevant to the objectives of the MOSC.

Budget (Leadership/Implementation Project)

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

Include an itemized breakdown of costs per gene variant for primary screening and secondary functional analysis.

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.

PHS 398 Research Plan (Leadership/Implementation Project)

Specific Aims: List each aim for the Project and how it supports the overall objectives of the MOSC.

Research Strategy: The MOSC will include one central Leadership/Implementation Project involving a team of investigators with the knowledge and expertise to evaluate putative disease-causing variants within the context of the respective UDN disease phenotype and develop a tailored screening and analysis plan for each variant. It is not expected that each gene variant submitted to the MOSC will require analysis in all model systems available to the project (e.g., in both Drosophila and zebrafish), or will even require wet-lab work in all cases. Instead, the Project will be responsible for developing and implementing a rapid, efficient, cost-effective and tailored screening pipeline and analysis plan for evaluating specific gene variants using the most effective approaches (including bioinformatics) and in the most relevant and informative model system(s) and assays. Nevertheless, a subset of gene variants may require additional analysis in other model systems or in secondary assays, depending on the direction and approval of the Steering Committee. Therefore, a thoughtful and well-developed plan for evaluating and implementing analysis of specific gene variants will be essential to the success of the project. Competitive applications will propose to use the most powerful and state-of-the-art technologies available in the field; however, at the same time, the technologies, approaches and models proposed should have a proven track-record for producing reliable, consistent and validated results within the throughput and turnaround expectations of the program. Note: this FOA is not meant to support the development or optimization of new technologies, assays or model systems nor for definitive evaluation and validation of all variants.

The Leadership/Implementation Project, at a minimum, should include the following elements: 1) a leadership team that will interact with the UDN to gain knowledge about the specific gene variant and associated clinical information, and develop a tailored screening and analysis plan for the variant using available Core models and resources; and 2) bioinformatics resources and expertise to assist the leadership team in the nomination and prioritization of variants for analysis in research organisms and in developing the tailored analysis plan for specific gene variants. The specific items to be addressed in this section include but are not limited to the following:

Model Organisms Screening Pipeline and Analysis Plan

• Describe the strategy (including bioinformatics and/or wet-lab approaches) for screening and identifying the most informative/promising candidate variants for further analysis by the MOSC; for example, under the direction of the Steering Committee, this may involve genes of unknown significance, variants of unknown significance in known causative genes or potential cases of phenotypic expansion.
• Describe the overall design and rationale for analysis of variants in the Resource Cores including: the animal and/or cell-based models that will be used to investigate the pathogenicity and preliminary function of specific gene variants in the context of the specific UDN participant s phenotype; and, after initial screening, the number of variants per year expected to be assigned to each Resource Core for analysis.
• Describe and explain the rationale for the gene targeting or editing strategies (e.g., knockdown, CRISPR/Cas9 genome editing) proposed to evaluate the pathogenicity of gene variants in specific model organism(s) or systems; describe the advantages and disadvantages of each gene targeting and editing approach, plans to validate the results, and alternative strategies if not successful (note: applicants may provide and refer to more detailed descriptions and methodologies in the Resource Core sections of the application).
• Describe and explain the rationale for the assays proposed to evaluate the functional consequences of the gene variant on protein function (e.g., loss-of-function, gain-of-function, expression, splice change, stability, intracellular localization, etc.) and resulting phenotypes (e.g., cellular, biochemical, anatomical, physiological, behavioral) in the proposed model organisms; describe the strengths and limitations of each assay for that model, plans to validate results, and alternative strategies if not successful (note: applicants may provide and refer to more detailed descriptions and methodologies in the Resource Core sections of the application).
• Discuss how results and outcomes from functional assays will be interpreted and the criteria for identifying gene variants as promising/likely disease-causing candidates in the context of the specific UDN disease phenotype.
• Provide a timeline and preliminary set of milestones for: 1) ramping up to full productivity if a new award; and 2) achieving FOA expectations of throughput (screening and analysis of about 200 gene variants per year) and turnaround time (optimally within 6-12 months from the time the variant is assigned to the research team for analysis to submission of results to the Network) after ramp-up; describe approaches that will increase the efficiency and cost-effectiveness of the analysis pipeline or reduce the time required for analysis; explain and justify cases (e.g., models, assays, challenging gene variants) in which more analysis time may be required.
• The technology in this field is evolving rapidly; describe any new technologies on the horizon that could facilitate achieving project aims in future years, and plans for determining when and if the new technology is sufficiently developed and validated for introduction to the MOSC.
• Provide preliminary or published data, if available, that support the feasibility of the analysis pipeline, models, gene targeting strategies, assays, bioinformatics, throughput, and other approaches proposed in the application.

Letters of Support: Institutional commitments made to the UDN MOSC should be clearly documented.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome-Wide Association Studies) 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 and Resource Sharing Plan.
• All applicants should name a responsible individual as contact for data and resource sharing both within and outside the Network, and clearly identify support requested for data sharing.

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.

PHS Inclusion Enrollment Report (Leadership/ Implementation Project)

When preparing your application in ASSIST, use Component Type Core.

Applications submitted in response to this FOA require at least two Resource Cores to perform gene targeting/editing and phenotypic analysis in Drosophila and zebrafish models, respectively. Up to three additional Cores may be proposed as needed (a maximum of five Resource Cores are allowed) for primary screening or secondary analysis of specific gene variants in other small animal models (e.g., C. elegans, Xenopus, mice, etc., if throughput and turnaround expectations of the FOA can be met) or cell-based assays (e.g., yeast, mammalian cells, human fibroblasts or induced pluripotent stem cells, etc.). Additional Cores should be justified based on scientific need and should be reasonably supported within the allowable budget.

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

SF424 (R&R) Cover (Resource Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Resource Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Resource Core)

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.

Project /Performance Site Location(s) (Resource Core)

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.

Research & Related Senior/Key Person Profile (Resource Core)

• 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.
• In the Biographical Sketch of Senior/Key persons, describe the training and expertise in conducting large-scale genetics/genomics studies in the proposed animal or cell-based models.

Budget (Resource Core)

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

For each model system proposed in the Core, provide an itemized breakdown of costs per gene variant for primary screening and secondary functional analysis in that model.

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.

PHS 398 Research Plan (Resource Core)

Specific Aims: List the aims for the Resource Core and how it will support the overall objectives of the MOSC.

Research Strategy: The specific items to be addressed in the Research Strategy include but are not limited to the following:

Resource Core Description and Methods

• Describe each animal or cell-based model proposed in the Core and how the model fits into the overall design of the screening and analysis pipeline (e.g., part of the primary screen or secondary analysis); estimate the number of gene variants to be analyzed in the model each year (note: it is not expected that each gene variant will require analysis in all model systems available to the MOSC); describe how the model will be obtained or created including methods for generating, breeding, maintaining and housing the model unless standard; describe and justify the expected time required for analysis of gene variants in the model.
• Provide additional experimental details and methods if needed of the proposed gene targeting and editing strategies for each model in the Core; discuss methods to validate the results (e.g., confirm locus specificity and absence of off-target mutagenesis), and alternative strategies if not successful at first.
• Describe in more detail, if needed, how gene variants assigned to the Core will be functionally evaluated in each model including the experimental design, methods (unless standard) and plans for replication; describe how outcomes will be validated, and alternative strategies if not successful at first.
• For each animal model or cell-based assay proposed in addition to Drosophila and zebrafish, justify their need relative to the overall objectives of the project and/or discuss how it complements the Drosophila and zebrafish models.
• Describe plans to increase the rigor and reproducibility of the outcomes (see: https://www.nih.gov/research-training/rigor-reproducibility) whenever appropriate for the model or system being studied; describe approaches, if available, for analyzing potential sex differences of gene variants in model organisms, particularly if relevant to the UDN participant s clinical presentation.
• Provide preliminary or published data, if available, that support using the model(s), gene targeting strategies, assays, and other approaches proposed in the Core (unless already presented in the Project section of the application).

Letters of Support: Provide Letters of Support, if needed, for collaborations and consultants involving models, gene targeting strategies or assays in the Resource Core.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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 and Resource Sharing Plan.

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.

PHS Inclusion Enrollment Report (Resource Core)

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 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) 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.

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 Center 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 Center 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 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 Center 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 Undiagnosed Diseases Network (UDN) and assist in the diagnosis of participants who suffer from rare or yet to-be-described diseases involving genetic mutations?

Will the knowledge gained from this project lead to a better understanding of the underlying genetics, biochemistry and/or pathophysiology of these and related disorders?

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 Center Director and 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 the background and expertise in gene targeting/editing technologies and analysis of putative disease-causing gene variants in Drosophila, zebrafish and other animal and cell-based models as proposed in the application?

Do the PD(s)/PI(s) and research team have experience in managing or participating in large-scale screening projects involving analysis of gene variants in research organisms?

Does the research team have the necessary and/or integrated expertise in genetics/genomics, bioinformatics and/or clinically-related disease research as required for this project?

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:

Does the project achieve an optimal balance in proposing state-of-art, cutting-edge technologies and approaches that are also proven, validated and reliable so as to meet the throughput and turnaround expectations of the FOA?

This FOA is not intended to support the development or optimization of new technologies, assays or models. However, as new and more powerful technologies emerge in the field, is the research team poised to recognize when these new technologies are sufficiently developed and validated for incorporation into the screening and analysis pipeline?

Are the conceptual design and framework of the screening pipeline and analysis plan creative, innovative and likely to take maximum advantage of available bioinformatics and Core resources in achieving program objectives?

Are the bioinformatics approaches innovative, state-of-the-art and likely to facilitate the development of a tailored, efficient and successful screening/analysis plan for specific variants?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? 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?

If the Center 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?

Additionally, for this FOA:

Will the MOSC’s conceptual design and overall operating plan effectively and efficiently investigate the underlying pathogenicity of the UDN’s rare and yet to-be-described diseases? Does the design and operating plan provide ample opportunity for collaboration, integration, and interaction within the UDN (e.g., communication and collaboration with the Clinical Sites, and the nomination of gene variants to the Steering Committee for approval) in order to diagnose participants and investigate UDN disease phenotypes?

Is there an overview of the strategy for screening and nominating the most informative variants for further analysis by the MOSC (may involve genes of unknown significance, variants of unknown significance in known causative genes or potential cases of phenotypic expansion)? Does the strategy for screening and identifying the most informative/promising variants for analysis provide an informed and fair approach to decisions about which gene variants to explore further in the research pipeline?

Will the screening and analysis pipeline effectively and efficiently uncover the pathogenicity and preliminary function of gene variants in the context of the respective UDN disease phenotype? Is the overall framework of the pipeline (including the proposed models and functional assays in the pipeline) well-designed and are the component parts well-integrated and complementary so as to achieve maximum productivity at minimal cost?

Does the analysis and bioinformatics plan propose cutting edge, innovative approaches capable of identifying rare and novel diagnoses? Is the analysis plan effective and tailored to the genetics and putative pathology of specific gene variants?

Are the proposed models (those in addition to Drosophila and zebrafish), gene targeting/editing strategies and functional assays optimal and well-designed for discovering pathogenic disease variants in a high-throughput screening environment?

Has the project proposed a suite of gene targeting or editing strategies (e.g., knock-in as well as knock-down approaches), phenotypic assays and approaches that can accommodate the diversity of participant mutations and clinical phenotypes likely to be encountered by the UDN?

For new awards, is the time proposed for ramping up to full productivity reasonable? Will the project likely achieve the required throughput (i.e., using a combination of bioinformatics and wet-lab approaches, screen and analyze approximately 200 gene variants per year) and turnaround time expectations (optimally within 6-12 months from the time the variant is assigned to the research team for analysis to submission of results to the Network) of the FOA? If longer turnaround times are proposed, is the timeframe reasonable and justified for the species and depth of analysis required? Are the proposed timeline and milestones robust, associated with clear, quantitative criteria for success, and realistic based on the information provided in the application?

When appropriate for the model, are the plans to increase the rigor and reproducibility of the outcomes acceptable?

Is a Sustainability plan proposed and is it feasible?

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 achieve the required output from the screening and analysis pipeline?

Are the bioinformatics infrastructure/capabilities and computational resources in place (or readily obtainable) and adequate to support the project? Are safeguards in place to protect participant personal identifiable information if relevant?

Resource Core activities should be capable of effectively and efficiently supporting research productivity and contribute to the overall objectives of the Center and UDN. In addition, reviewers should consider the review criteria below in determining the scientific merit of each Core. Each assigned reviewer will provide one score for each Research Resource Core. The scientific merit of the Research Resource Core should also be considered by reviewers in determining Overall Impact score for the Center.

Is there adequate scientific and technical merit (e.g., quality of models, gene targeting/editing approaches and functional assays proposed) to justify the Core?

For Cores that propose animal models or cell-based assays in addition to Drosophila or zebrafish, do the models contribute to the overall objectives of the Center and/or complement the Drosophila and zebrafish models? Are they essential to the mission of the Center and UDN?

After ramp-up for new awards, will the Core likely achieve the throughput and turnaround time proposed in the application?

Does the Core provide adequate leadership and scientific/technical expertise to ensure that it will meet its stated goals?

Are the staffing, allocated space, equipment, and other resources that are available to the Core sufficient to meet the anticipated demand on its services? Is the budget allocated to the Core reasonable to support the proposed activities?

Are the plans to ensure quality-control, rigor and reproducibility of research activities in the Core acceptable (e.g., validation of gene-targeting and other approaches, blinding and randomization when appropriate for the model, replication, standardization when appropriate, etc.)?

As applicable for the Administrative Core 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.

Is the leadership plan, including how decisions will be made across the Project and Resource Cores, appropriate? Are the plans for communicating and collaborating with the UDN and NIH program staff appropriate and likely to facilitate overall program objectives? Are the plans for submitting data, outcomes, and resources (when relevant) to the UDN acceptable?

Will there be coordination, communication, cohesiveness and synergy among the Project and Resource Cores as they relate to achieving the overall objectives of the Center and UDN? Are mechanisms proposed for regular communication and coordination among investigators in the Center? Are administrative structures in place for the day-to-day management of the Center, including mechanisms for internal quality control of ongoing research?

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 .

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 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 Neurological Disorders and Stroke Council. 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 Neurological Disorders and Stroke Council.
• 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 DNA 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 CC, The Metabolomics Core, the Model Organisms Screening Center, and the DNA 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 MOSC 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: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)

Telephone: 301-945-7573

Laura Mamounas
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]

James J. Li, PhD
Center for Scientific Review (CSR)
Telephone: 301-806-8065
Email: [email protected]

Tijuana Decoster, PhD,
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9531
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.