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; 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.

Required Application Instructions

It is critical that applicants follow the 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.

The purpose of this Funding Opportunity Announcement (FOA) is to establish a Model Organisms Screening Center 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 patients enrolled at the UDN clinical sites. To assist in the diagnosis of UDN patients, applications responsive to this FOA will propose to establish a screening platform involving Drosophila and zebrafish, plus other small animal models or cell-based assays as appropriate to evaluate the pathogenicity and preliminary function of candidate gene variants in the context of the respective UDN patient's disease phenotype.

Rare and yet-to-be-described disorders are a difficult problem for patients, their families and their physicians. The NIH Office of Rare Diseases Research notes that about 6% of patients seeking their assistance have an undiagnosed disease. For those who were ultimately diagnosed, as many as 15% had persistent symptoms without diagnosis for at least 5 years, a difficult and costly delay for the patient, family (including other afflicted family members and caregivers), and physicians who struggle to identify and treat these disorders. This diagnostic odyssey is usually expensive with repeated, sequential diagnostic efforts involving a series of physicians pursuing similar, often duplicative, imaging (with increased radiation exposure and other risks) and biomarker investigations.

In addition, these patients present compelling research questions since clarification of the underlying genetics, biochemistry and physiology of these disorders will lead to a better understanding of their disease processes and those of related disorders. Advances in genetics and genomics have made it possible to understand the causes of and potential targets for treatment of some of these diseases. Furthermore, as the cost of genotyping and sequencing continues to fall and the accuracy of these methods increases, these approaches become more attractive as potentially standard means by which to diagnose these disorders.

The NIH Undiagnosed Diseases Program (NIH-UDP) began in May 2008 in hopes of catalyzing research into unknown disease mechanisms and facilitating their diagnoses. From modest initial recruitment numbers, the NIH-UDP has over a six-year period received nearly 10,000 inquiries, reviewed more than 3,000 applications, and admitted 750 patients to the NIH Clinical Center for comprehensive weeklong evaluations. As these data reveal, even without a systematic approach to advertising the program, there is a substantial unmet demand for these capabilities. This need has led to the recent creation of a Network involving seven UDN Clinical Sites including the NIH-UDP that will be able to address more inquiries, and potentially be more accessible to patients throughout the country.

The applicant(s) funded by this FOA will join the NIH Undiagnosed Diseases Network, consisting of the grantees from the related FOAs (RFA-RM-12-020, Coordinating Center for an Undiagnosed Diseases Network , RFA-RM-13-004, "Clinical Sites for an Undiagnosed Diseases Network", and RFA-RM-13-018, "DNA Sequencing Core for an Undiagnosed Diseases Network"), together with the ongoing NIH-UDP Clinical Site and NIH program staff. The Network strives to increase the availability of diagnostic services, expand the geographic distribution of patient access sites, foster opportunities for collaboration between laboratory and clinical investigators, and provide resulting data and protocols to the broader community. These efforts will lead to new knowledge regarding the biochemistry, physiology, and mechanisms of these diseases and improve diagnostic and management options for patients afflicted with them.

As part of the diagnostic workup of patients enrolled at the UDN clinical sites (CS), the designated DNA Sequencing Core(s) will conduct whole exome or whole genome sequencing on UDN patients and their family members. From the DNA sequencing and subsequent bioinformatics analysis, it is anticipated that approximately 200 gene variants each year will require additional analyses in small animal models (including Drosophila and zebrafish at a minimum) or cell-based assays to determine whether the variant is disease-causing in the context of the respective UDN disease phenotype. This funding opportunity is designed to provide centralized Model Organisms Screening services to the Network and assist in the diagnosis of UDN patients network-wide by rapidly validating the pathogenicity of UDN putative disease-causing variants in model organisms.

Of the new diseases discovered so far by the NIH-UDP, over half involve neurological dysfunction or developmental delay; the remaining clinical phenotypes span metabolic, skeletal and inflammatory diseases, among others. The types of mutations that have been identified by the NIH-UDP 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). A list of diseases diagnosed by the NIH-UDP and the associated gene variants linked to these diseases can be found at http://www.genome.gov/27551936. The most competitive applications in response to this FOA will propose a suite of gene targeting or editing strategies (e.g., knock-in using gene editing technologies in addition to knock-down approaches), models and phenotypic/expression assays that can accommodate the diversity of patient mutations and clinical phenotypes likely to be encountered by the Network.

After initial bioinformatics analysis and prioritization by the UDN, the Network is expected to assign to the Model Organisms Screening Center approximately 200 human gene sequence variants per year for further evaluation in model organisms; the Model Organisms Screening Center will evaluate the putative pathogenicity of these variants in the context of the respective UDN disease phenotypes and provide additional preliminary functional characterization for a subset of the variants. Data and analyses from the Model Organisms Screening Center are expected to be submitted to the UDN Coordinating Center (CC) according to agreed upon timelines to assist in the diagnosis of new diseases. In addition, validated gene variants (for example, those deemed pathogenic by the Model Organisms Screening Center) may be candidates for future in-depth functional studies (e.g., in mouse models) supported through the Undiagnosed Diseases Gene Function Research R21 Program (e.g., RFA-RM-14-005).

The objectives of this program are to:

1. 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 the pathogenicity and preliminary function of putative disease-causing gene variants identified through the UDN.

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

3. In the appropriate models, establish a primary screening platform with the capacity to analyze approximately 200 UDN gene variants per year for preliminary validation of pathogenicity in the context of the respective UDN patient's disease phenotype.

4. Establish secondary assays (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 and/or requiring further functional characterization and validation to judge pathogenicity.

5. After an initial ramp-up period, provide results to the Network as rapidly as possible, generally within six-to-twelve months of receiving the gene variant assignment, depending on the species analyzed and depth of analysis required for the variant.

6. Recommend to the Network validated gene variants for addition to the 'Gene Function Collaboration Candidate List' located on the UDN website (http://www.genome.gov/27551936); variants on this list are candidates for future in-depth studies (e.g., in mouse models) supported by UDN Gene Function initiatives (http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-14-005.html).

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/validated technologies, approaches and models suitable for the throughput and turnaround time described above. Although mouse models are not specifically excluded from this FOA, the additional costs, lower throughput and longer expected turnaround times associated with most mouse genetic studies may be prohibitive for this program and will need to be justified in the application (e.g., for secondary analysis of a subset of gene variants); also, support for mouse studies may be duplicative with other ongoing UDN funding initiatives (e.g., Undiagnosed Diseases Gene Function Research R21 Program: RFA-RM-14-005) or with the NIH Knockout Mouse Project (KOMP).

All CS (including the NIH-UDP clinical site) will be expected to utilize common investigative and data collection protocols to the degree possible in order to facilitate pooling of data to enhance the scientific and diagnostic value of the resulting information. The UDN Model Organisms Screening Center will similarly be expected to adopt network-wide data standards, where appropriate, and submit all data to the CC for compilation in a Network-wide dataset to be distributed periodically to all CS (including the NIH-UDP) as agreed upon by the Network Steering Committee.

Utilizing the U54 Specialized Center-Cooperative Agreement grant mechanism, the Model Organisms Screening Center will consist of one central Leadership/Implementation Project, an Administrative Core and will require 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 respective 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 expertise and support to assist the leadership team in developing the screening and 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 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 (e.g., c. elegans, xenopus) or cell-based assays (e.g., yeast, mammalian cells, human fibroblasts, etc.). Additional Cores should be justified based on scientific need and reasonably supported within the allowable budget.

The award funded under this FOA will be a cooperative agreement (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award). Close interactions amongst the awardee and NIH will be required to develop this complex Network. Shortly after award, the Model Organisms Screening Center PD(s)/PI(s) and key personnel will meet with CC, CS, and Sequencing Core PD(s)/PI(s), along with NIH program staff to plan approaches, identify barriers, and propose solutions for creating and maintaining the centralized Model Organisms Screening Center service for the UDN.

The UDN governance will rest with the Network Steering Committee (SC) in collaboration with NIH program officials, with advice from an External Scientific Panel (ESP), and subject to oversight by a UDN Working Group of the NIH Common Fund. The SC may establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific Network functions such as patient recruitment, patient selection and assignment to specific CS, clinical evaluation, final diagnosis, and access to Core Laboratories (including the Model Organisms Screening Center), as needed.

The SC composed of PDs/PIs from all sites (including the Model Organisms Screening Center, DNA Sequencing Core(s), CS, CC and the NIH-UDP) and the NIH Project Scientist(s) will be responsible for the scientific direction of the Network. The SC will meet quarterly during the first year and three times per year or as needed subsequently. Approximately 3-4 persons including the PD(s)/PI(s) from the awarded Model Organisms Screening Center should plan to attend SC meetings with associated travel costs included in the proposed budget.

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

The ESP will be named by NIH program officials and will be responsible for monitoring Network activities and making recommendations to the UDN Working Group and NIH regarding processes and substantive issues that arise during Network operations.

The Network SC will be tasked with developing an equitable process for prioritizing access to the Model Organisms Screening Center resources, whether at the NIH-UDP, CS, or their contractors or collaborators, to be reviewed and approved by the Network’s ESP and the NIH Working Group. This process will likely involve a subcommittee or working group to define priorities for access, formats for requests, and expectations for turnaround and follow-up as needed.

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; 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 Models Organisms Screening Center in meeting UDN goals, program priorities, and the availability of funds.

Data from the UDN are expected to be handled so as to increase the value of the significant public investment in the creation and operation of the Network. Consistent with achieving the goals of the program, NIH expects that the project datasets (phenotypic, environmental, covariate, process, and other relevant data) and associated genotyping/sequencing data from the Network will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. Information such as sequencing data is expected to be made available through an open access section of a database such as dbGaP, other public web sites, and publication in the scientific literature. The UDN SC will also develop and implement network-wide approaches for data deposition.

Resources generated by the Model Organisms Screening Center (e.g., animal models, targeting constructs, etc.) are also expected to be widely shared with the Network and the broader scientific community for research. The UDN SC will develop and implement network-wide approaches for resource deposition and use including submission to national repositories as appropriate.

Applicants should plan to participate with the CC in preparing yearly reports for the Network leadership, the ESP, and the NIH UDN Working Group. The yearly report for FY17 will include a more detailed report that an external group will use to make recommendations on the continuation or shut-down of the UDN effort.

This review group will also be asked to make recommendations for orderly close-out of this project either in FY18/FY19 if the mid-year review determines that close-out is warranted, or for issuing a renewal FOA to continue the project through final closeout in FY22.

The Network can be envisioned as beginning with a phase of network design prior to the award of the UDN Model Organisms Screening Center. Once the UDN Model Organisms Screening Center is awarded, subsequent phases involving the Core will include: 1) start-up; 2) full network operation; and 3) mid-course review. Should the mid-course review be successful, a repeat solicitation for Network continuation and eventual close-out will be released; if unsuccessful, modest close-out. funding may be provided.

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:

• Hispanic-serving Institutions

• Historically Black Colleges and Universities (HBCUs)

• Tribally Controlled Colleges and Universities (TCCUs)

• Alaska Native and Native Hawaiian Serving Institutions

• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)

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

For-Profit Organizations

• Small Businesses

• For-Profit Organizations (Other than Small Businesses)

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, including the NIH intramural program

• 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 not 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 the Models Organisms Screening Core may be submitted by individuals located at the same institution as an applicant for the CC submitted under FOA RFA-RM-12-020, a CS submitted under RFA-RM-13-004, or another Core Laboratory under FOA RFA-RM-13-018 However, applicants may not be the PD/PI of applications awarded through RFA-RM-12-020, RFA-RM-13-004, or RFA-RM-13-018. Applicants may be the PD/PI of an Undiagnosed Diseases Gene Function Research R21 (RM-13-003 and RM-14-005).

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;

• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or

• Of an application with a changed grant activity code.

Applicants can access the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

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 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 A. Mamounas, Ph.D.
National Institute of Neurological Disorders & Stroke
Telephone: 301-496-5745
Email: [email protected]

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed with the following exceptions or additional requirements:

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

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 - one Project is allowed

• Resource Cores - required, at least two, including analysis in Drosophila and zebrafish models at a minimum

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.

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

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.

Research & Related Senior/Key Person Profile (Overall)

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.

Budget (Overall)

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.

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.

PHS 398 Research Plan (Overall)

Specific Aims: List each aim for the UDN Model Organisms Screening Center and how it supports the overall objectives of this research program.

Research Strategy: The Center overview should describe the Center organization, expertise and the overall vision and leadership plan for the proposed Model Organisms Screening Center including how the Center 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:

• Present an overview (and/or 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 the pathogenicity of UDN gene variants in the context of respective UDN disease phenotypes.

• Justify the need for model(s) in addition to Drosophila and zebrafish, and discuss how the model(s) will contribute to the overall objectives of the Center; if relevant, applicants may also explain why a particular model was not proposed (e.g., mouse), for example based on cost, throughput/turnaround time, informative value, etc. (not applicable to Drosophila and zebrafish models which are required elements of the Center).

• Describe the bioinformatics infrastructure and approaches proposed to assist the leadership team in developing a tailored screening and analysis plan for specific variants.

• Discuss 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/validation; describe the process, including Center bioinformatics support and collaborations with the UDN, for tailoring the analysis of specific gene variants based on knowledge of the UDN patient’s mutation (e.g., mode of inheritance) and disease phenotype, and/or orthologs in the model organism. Discuss how data from previous publications (e.g., expression, functional studies of orthologs) will be incorporated into the plan.

• Discuss how results and outcomes from functional assays will be interpreted and the criteria for determining whether gene variants are disease-causing in the context of the respective UDN disease phenotype.

• Provide a timeline and preliminary set of milestones for: 1) ramping up to full productivity after award; and 2) achieving FOA expectations of throughput (screening and analysis of approximately 200 gene variants per year) and turnaround time (approximately 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 and/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.

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.

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.

SF424 (R&R) Cover (Administrative 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 (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative 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) (Administrative 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 (Administrative 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.

• 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 (Administrative Core)

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.

PHS 398 Research Plan (Administrative Core)

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 central 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 Leadership/Implementation Project and the Resource Cores.

Describe the leadership team and how components of the Center, including key personnel, will interact within the Center itself and with the broader UDN and NIH program staff.

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.

Describe how the Administrative Core will manage and coordinate communication, day-to-day activities, collaborations, and resource and data sharing both within the Center (including Resource Cores) and with the UDN and NIH program staff.

Describe plans to communicate results to the UDN and indicate who will be the primary point of contact.

Letters of Support: Institutional commitments made to the UDN Model Organisms Screening Center should be clearly documented.

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

Planned Enrollment Report (Administrative Core)

Not Applicable

PHS 398 Cumulative 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:

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

• 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.

• 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 model organisms.

• 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 Model Organisms Screening Center.

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 Model Organisms Screening Center.

Research Strategy: The Model Organisms Screening Center 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 will require analysis in all model systems available to the project (e.g., in both Drosophila and zebrafish). 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 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. 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/turnaround expectations of the program. Note: this FOA is not meant to support the development or optimization of new technologies, assays or model systems.

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 expertise and support to assist the leadership team in developing the screening and 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 overall design and explain the rationale for the proposed analysis pipeline including the primary screening platform(s), secondary assays when appropriate, and the animal or cell-based models that will be used to investigate the pathogenicity and function of specific gene variants in the context of the respective UDN patient’s phenotype.

• Describe and explain the rationale for the gene targeting or editing strategies (e.g., morpholino 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/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).

• 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/if the new technology is sufficiently developed and validated for introduction to the Model Organisms Screening Center.

• Provide preliminary 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 Model Organisms Screening Center 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 (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.

• 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.

Planned Enrollment Report (Leadership/ Implementation Project)

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

PHS 398 Cumulative Inclusion Enrollment Report (Leadership/ Implementation Project

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

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. Additional Cores may be proposed as needed for primary screening or secondary analysis of specific gene variants in other small animal models (e.g., c. elegans, xenopus) or cell-based assays (e.g., yeast, mammalian cells, human fibroblasts, 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.

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 Model Organisms Screening Center service.

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; describe how the model will be obtained or created including methods for generating/breeding and maintaining/housing the model unless standard; describe and justify the expected time required for analysis of gene variants in the model.

• Provide more experimental details and methods if needed of the proposed gene targeting/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.

• 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.

• For animal models or cell-based assays proposed in addition to Drosophila and zebrafish, justify its 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: http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf) 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 patient’s clinical presentation.

• Provide preliminary 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/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.

Planned Enrollment Report (Resource Core)

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

PHS 398 Cumulative Inclusion Enrollment Report (Resource Core)

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

Part I. Overview Information contains information about Key Dates. 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.

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.

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.

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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above. The intramural project should be added as a separate component to the parent application.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

Significance

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

Will this project make a significant contribution to the overall goals and objectives of the Undiagnosed Diseases Network (UDN) and assist in the diagnosis of patients 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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 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 model 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?

Innovation

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 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?

Approach

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

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

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?

Is the analysis plan (including bioinformatics support) 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 patient mutations and clinical phenotypes likely to be encountered by the UDN?

Is the time proposed for ramping up to full productivity reasonable? After ramp-up, will the project likely achieve the required throughput (screening and analysis of approximately 200 gene variants per year) and turnaround time expectations (approximately 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?

Environment

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

Are the resources, equipment and infrastructure available and in place (or readily obtainable) to allow quick ramp-up and 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 patient 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 Network. 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 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 Network?

• After ramp-up, 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.

Center as an Integrated Effort and Interaction with the UDN

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 Network? 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?

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

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.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• 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.

• Likelihood that the proposed project will contribute to the overall objectives of the UDN.

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.

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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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.

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 study-wide Steering Committee and working groups as needed.

• Refining and implementing the resulting consensus framework at their sites and Network-wide, in collaboration with the UDN CC, CS, Sequencing Core(s) and NIH-UDP.

• Providing protocols, reports and data in a timely fashion as agreed upon by the Steering Committee.

• Submitting all data from gene variant studies in model organisms to the CC for compilation in a Network-wide dataset to be distributed periodically to all CS (including the NIH-UDP), as agreed upon by the Network Steering Committee, and deposited in public repositories as appropriate.

• Preparing abstracts, presentations and publications and collaborating Network-wide in making the public aware of the program.

• 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 patients and clinicians.

• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Steering Committee for the UDN.

• Abiding by common definitions, protocols, procedures, as chosen by majority vote of the Steering Committee.

• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the Steering Committee.

• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and NIH Working Group.

• Attending and participating in Steering Committee meetings and accepting and implementing decisions by the NIH Working Group, as appropriate.

• 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.

NIH staff has 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 Steering Committee members in addressing issues that arise with UDN planning, operation and 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 resource.

• Reporting periodically on Network progress to the NIH 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 Working Group staff may assist the awardee as designated by the Program Official.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop the UDN. The awardee and the Project Scientist(s) will meet in person with the program Steering Committee on a quarterly schedule during the first year of Network operation 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 (SC) 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 the PD(s)/PI(s) of the DNA Sequencing Core, PD(s)/PI(s) of the Model Organisms Screening Center, PDs/PIs of each CS including the NIH-UDP and the CC award, 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 CS (including the NIH-UDP), the CC, and the Core Laboratories 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 SC will have the overall responsibility of assessing and prioritizing the progress of the various working groups and other needed subcommittees.

The Model Organisms Screening Center Awardee agrees to work collaboratively to:

• Provide for secure, accurate and timely data submission.

• Participate in presenting and publishing new processes and substantive findings.

• Participate in the governance of the UDN as a member of the Steering Committee.

• Interact with other relevant 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 Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
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Laura A. Mamounas, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]

Anastasia L. Wise, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-443-0585
Email: [email protected]

Peer Review Contact(s)

Joseph Rudolph, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-408-9098
Email: [email protected]

Tijuana Decoster, MPA
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 Parts 74 and 92.