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). 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 Metabolomics Core to evaluate patients metabolic changes to aid the NIH Undiagnosed Diseases Network (UDN) in reaching final patient diagnoses. The Network expects to identify 150-250 clinical cases per year from patients enrolled at the UDN Clinical Sites (CSs) that require more intensive study than the routine panel of metabolomics assays. The Network does not need laboratory services that can provide routine clinical metabolite analyses, such as urinary organic acids, blood carnitine profiles, quantitative amino acids, electrolytes, and lactate concentrations. Applications responsive to this FOA will propose a metabolomics consultative and research service that provides the UDN with comprehensive and complementary analytical tools, analyses, technologies and the expertise to identify and quantitate non-traditional metabolites found to be important in clinical studies of these rare and undiagnosed diseases. The complementary metabolic procedures developed with the funds from this FOA are expected to aid in developing a diagnosis for UDN patients, contribute to the joint UDN investigation of rare and under-described diseases, and benefit the study of pathogenicity of candidate gene variants.

Rare and yet-to-be-described disorders are difficult problems for patients, their families, and their physicians. The NIH Office of Rare Diseases Research notes that about 6% of patients seeking its 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.

In addition, these patients present compelling research questions since clarification of the underlying genetics, biochemistry, and physiology of their disorders will lead to a better understanding of their disease processes and those of related disorders. Advances in genetics, genomics and clinical metabolomics have made it possible to better understand the causes of and potential targets for treatment of some of these diseases.

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 CSs 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 awardees 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", RFA-RM-13-018, "DNA Sequencing Core for an Undiagnosed Diseases Network" and RFA-RM-14-016, "UDN Model Organism Screening Core"), together with the ongoing NIH-UDP CS and NIH program staff. This funding opportunity is designed to be part of several funded core laboratories to provide a high level of expertise in specialized technical areas in support of the UDN. These core laboratories will be comprised of a Sequencing Core, Model Organisms Screening Core and the Metabolomics Core. The Network will 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 the 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 CSs, clinicians will require metabolic profiles to develop or confirm a patient diagnosis. Approaches that have proven helpful in the search to better understand these rare diseases include assays that measure changes in metabolite composition and concentrations from human and animal samples. Although metabolomics approaches have proven useful in clinical diagnoses and gene function studies, limitations in currently routine clinical sample preparation, speed of measurement, time for analysis, availability of standards, methods of quality assurance/quality control (QA/QC) and limitations in the number of measureable metabolites reduce the usefulness of the technology to contribute to precise patient diagnoses. In contrast to routine and established metabolic panels ordered in the clinic (such as urinary organic acids, plasma amino acids, blood carnitine profiles, electrolytes, and lactate concentrations), this funding opportunity seeks to expand the application of metabolomics through innovative and advanced assay methods to enable detection and quantitation of non-traditional metabolites that are likely abnormal products of rare and under-described diseases. These metabolic data will be combined with other UDN information to aid in patient diagnosis and improve understanding of the underlying pathology of rare diseases.

The application of metabolomics to investigate chemical changes in difficult-to-diagnose patients should have several potential benefits to science and most importantly to patients. The application should produce new methods and data on monitoring novel metabolites. The potential for discovery is considerable, including the identification of new inborn errors of metabolism, new analytes to speed diagnoses and new regulatory factors for metabolic genes. These studies will provide an opportunity to evaluate the use of metabolomics as a clinical diagnostic tool especially in diseases expressing similar phenotypic traits. Study results will also provide better insights into the use of metabolomics in the evaluation of putative pathogenicity of human gene variation. Disease-associated gene variants 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).

Of the new diseases explored 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 and the diverse organ systems involved indicate that study of these diseases will require special metabolomics techniques to measure non-standard metabolites and possible development of new analytical methods. A list of gene variants found in UDN patients by the NIH-UDP can be found at http://www.genome.gov/27551936. The most competitive applications in response to this FOA will need to address a number of important challenges:

1. Establish a Metabolomics Core capable of collaborative consultation with UDN investigators and the conduct of an optimal metabolomics approach to individual patients, especially with novel analytical methods to examine changes in non-traditional metabolites from a broad range of sample sources. Examples of patients with undiagnosed diseases that might be referred for expert opinion and recommendations for further metabolic evaluations:

• A 21-year-old college sophomore has had unexplained 3-day episodes of abdominal pain with nausea and sometimes vomiting for 13 years, about 3 times a year, with no clear association with diet, activity, season, or day of the week. Her father remembers he had similar troubles as a teenager, but none since age 18 years. Her younger brother had two such episodes, one so severe at age 12, that appendectomy was done (pathology report was normal). Work up for porphyrias was negative, but one urinary organic acid analysis, just after an episode in the proband, showed a non-specific peak, that was absent a month later.
• A 7 year-old boy seemed to have an excess of ear infections and for the past year, occasional frontal headaches easily relieved with acetaminophen. He had occasional bone pain in the legs (causing only trouble getting to sleep); radiographs showed some periosteal thickening. Calcium was slightly high, but alkaline phosphatase was normal; serum alanine aminotransferase activity was elevated on two occasions. Amino acid chromatography and urinary organic acids patterns were normal.

2. Identify rare, abnormal and novel metabolites as defined by a patient’s disease. The project plan for the Metabolomics Core is not expected to develop new technology but should propose cutting edge, innovative approaches that will allow identification and measurement of these novel metabolites.

3. Participate in co-interpretation of metabolomics data alongside other data, in particular genomics data, to help identify candidate causal mutations and critical metabolites.

4. Apply state-of-the-art metabolomics technology and instrumentation for analyzing 150-250 clinical cases per year in support of an integrated Network approach to improve patient diagnostic and management options. Each clinical case may require the testing of multiple samples from patient and additional testing of relatives as determined by the Metabolomics Core.

5. Participate in an integrated and collaborative research community across multiple UDN Clinical Sites (CSs) and core laboratories with laboratory and clinical investigators as they investigate the pathophysiology of these unknown and rare diseases and share this understanding to improve patient diagnosis and management.

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

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 augment this complex Network. Shortly after the award, the Core Laboratory’s Program Director(s)/Principal Investigator(s) (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 incorporating the Metabolomics Core into the UDN.

The UDN governance rests with the Network Steering Committee (SC) in collaboration with NIH program officials, with input from an External Scientific Panel, 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 Metabolomics Core), as needed.

The PD(s)/PI(s) of the Metabolomics Core will join the UDN SC, composed of PDs/PIs from all sites (including the Core Laboratories, CSs, CC) and the NIH Project Scientist(s), which will be responsible for the scientific direction of the Network. The SC will meet three times per year or as needed.

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 materials to the wider scientific community.

An External Scientific Panel (ESP) will be named by NIH program officials and will be responsible for monitoring Network activities 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 Metabolomics Core; this process will 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., expected annual throughput, rapid development of new assays,) milestones will be developed with applicant(s) prior to award. Milestones are goals that are quantifiable for measuring success, and include associated annual or semi-annual quantitative criteria. Prior to funding an application, NIH program staff will contact the applicant to establish a final set of milestones based on the information and preliminary milestones provided in the application (see Section IV); milestones will include: 1) time required for ramping up to full productivity after award; 2) meeting FOA expectations of throughput (up to 250 patient cases per year); 3) sample analysis turnaround time (approximately 2-4 weeks); 4) development times for bringing new assays on line for patient sample monitoring 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 Metabolomics Core 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, metabolic, environmental, covariate, process, and other relevant data) and associated genotyping and 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 new analytical methods and metabolic data are expected to be made available through an open access section of a database (such as the Human Metabolome Database (HMDB) or the Scripps Metabolite and Tandem MS Database (METLIN)), other public web sites, and publication in the scientific literature. The UDN Steering Committee will also develop and implement network-wide approaches for data deposition.

Resources generated by the Metabolomics Core (e.g., instrumentation, special standards, 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 External Scientific Panel, 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 external group will also be asked to make recommendations for orderly close-out of this program either in FY18/FY19 if the mid-course review determines that close-out is warranted, or for issuing a renewal FOA to continue the project through final closeout in FY22.

Once the UDN Metabolomics Core is awarded, the 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 FOA 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 Metabolomics 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 FOAs RFA-RM-013-018 and RFA-RM-14-016, but an individual may not be the PD/PI of an award from RFA-RM-12-020, RFA-RM-13-004, RFA-RM-013-018, or RFA-RM-14-016 and a Metabolomics Core award.

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 must download 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.

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. 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:

Carson R. Loomis, Ph.D.
National Center for Advancing Translational Sciences \
Telephone: 301-827-7970
Email: [email protected]

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

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

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

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

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

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

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

Approximately 2-3 persons including the PD(s)/PI(s) should plan to attend SC meetings with associated travel costs included in the proposed budget.

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

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

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

Specific Aims: List each aim for the UDN Metabolomics Core and how it supports the Objectives of this Research Program.

Research Strategy: In this FOA, as in all FOAs related to the UDN, applicants are encouraged to creatively address the scientific and operational problems needed for the Network to be a success. Within the framework of this FOA, there are a variety of approaches to Network function that may ultimately be adopted by the Steering Committee and NIH.

In order for reviewers and NIH to evaluate the merit of the application, the application should discuss the services to be offered by the Metabolomics Core, explain plans for the Core, defend the approaches favored, and describe the willingness to implement protocols agreed upon by the Network as a whole. A major challenge for the core will be the need to provide detection and quantitation of uncommon and novel metabolites in patient samples. Samples submitted to the Core by the Clinical Sites will come from patients with disorders in any clinical specialty; rare and undiagnosed conditions may cluster in certain disciplines such as neurology; rheumatology; gastroenterology; psychiatry; or vascular, metabolic, environmental or infectious diseases. Describe how the Core will try to successfully address these challenges and provide a core with diverse areas of expertise. The project plan for the Metabolomics Core should propose cutting edge, innovative approaches that will allow identification and measurement of abnormal and novel metabolites. The Core should not plan to provide routine metabolomics analyses that the UDN can obtain from commercial services and the Core should not plan to commit more than 20% effort in the development of new approaches to measure unusual metabolites. Specific points that will need to be mentioned are:

1) Provide an overview of the proposed Metabolomics Core with overall scientific objectives, relevant background and significance. Define the proposed Core’s capabilities relative to the current state-of-the-art of the metabolomics field. Describe the types of biological samples the Core will be able to test (e.g., blood, sputum, CSF). Describe the types of metabolomics analyses the Core would be able to provide (e.g., lipidomics, glycomics, neurotransmitters).

2) Provide a timeline and preliminary set of milestones for:

-Ramping up to full productivity after award,

-Meeting FOA expectations of throughput (analysis of approximately 250 biological samples per year),

-Turnaround time (approximately 2-4 weeks after samples are sent to Core).

3) Describe approaches that will increase the efficiency and cost-effectiveness of the analysis pipeline and/or reduce the turnaround time.

4) Contributing to an integrated and collaborative Network is an essential task for PD(s)/PI(s) from all Network Centers and Cores of the UDN. Describe how the Core will work with the other components of the Network. The following aspects should be considered when describing the concept of a UDN Metabolomics Core:

• Applicants should describe prior experience in working as part of a research network or other collaborative activities to meet individual and group goals, including examples of prior collaborative efforts.
• Most patient diagnoses will be a result of the joint effort of the Network of Centers and Cores. The applicant should describe plans to work with the CS, CC and the other technology cores to optimize data collection and analysis strategies.
• Describe ways that the core can facilitate public access to the UDN metabolomics data through the CC and organizations such as the National Center for Biotechnology Information (NCBI).

5) Describe how the PD(s)/PI(s) will provide the following details in the development of their Metabolomics Core:

• Describe how the Core will be able to identify, measure and interpret the complex, time-related concentration, activity and flux of select metabolites important in the investigation of disease pathology.
• Applicants should describe plans for how their Cores will track biological samples, genetic and analytic data for each patient.
• Samples submitted to the Core by the Clinical Sites will come from patients with disorders in any clinical specialty; rare and undiagnosed conditions may cluster in certain disciplines such as neurology; rheumatology; gastroenterology; psychiatry; or vascular, metabolic, environmental or infectious diseases. Applicants should describe specific strengths and experience their laboratory/laboratories or institutions may apply to disease-specific clinical areas. The applicant should also describe their ability to investigate disorders outside their specific areas of expertise such as, but not limited to, plans for establishing collaborations with other laboratories as needed.

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

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 submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• All applicants should name a responsible individual as contact for data 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.

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

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). 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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness 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.

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 the 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.

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? Will the Core’s conceptual design and overall operating plan provide the required strategy and resources to advance the field of metabolomics as an important technique in the diagnoses of human diseases?

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 PD(s)/PI(s) and research team have the required experience and expertise in metabolomics to significantly contribute to the primary goals of the UDN? Are the PD(s)/PI(s) and research team capable of improving assays and modifying methods to enable analyses of non-routine metabolites identified by the UDN? Do the PD(s)/PI(s) and research team have the necessary expertise in biochemistry, genetics, bioinformatics and experience in metabolomics studies to successfully undertake 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: As new technologies become available, is the research team poised to recognize when they are sufficiently developed and validated to be added to the UDN resources? Does the research plan include the modification of assays to successfully isolate and quantitate novel metabolites? Are the bioinformatics approaches innovative and likely to provide the best utilization of the metabolomics data?

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?

Additionally for this FOA: Does the project plan propose cutting edge, innovative approaches capable of identifying rare, abnormal and novel metabolites? Will the Core's conceptual design and overall operating plan effectively investigate the underlying pathogenicity of the UDN’s rare and yet to-be-described diseases? Will the Core’s design and operating plan provide ample opportunity to investigate the function of metabolomics in the context of the respective UDN disease phenotype?

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

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

Additionally for this FOA: Are the resources, equipment and infrastructure available and in place (or readily obtainable) to allow quick ramp-up and output from the Metabolomics Core? Are the bioinformatics infrastructure/capabilities and computational resources in place (or readily obtainable) and adequate to support the project?

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 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.

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

Not Applicable

Not Applicable

Not Applicable

As applicable for the 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.

Not Applicable

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

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

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

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Center for Advancing Translational Sciences Advisory 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.

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 network-wide Steering Committee (SC) and working groups as needed.
• Refining and implementing the resulting consensus framework at their sites and Network-wide, in collaboration with the CC and NIH-UDP.
• Providing protocols, reports and data in a timely fashion as agreed upon by the SC.
• Submitting all data from UDN patients as soon as they are collected to the CC for cleaning, quality control, and 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 dbGaP or other suitable database.
• 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 SC for the UDN.
• Abiding by common definitions, protocols, procedures, as chosen by majority vote of the SC.
• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the SC.
• Submitting periodic progress reports in a standard format, as agreed upon by the SC and NIH Working Group.
• Attending and participating in SC 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 SC 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 awardee 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 Council of the National Center for Advancing Translational Sciences.
• Serving on subcommittees of the SC, 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.

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 develop the UDN. The awardee and the Project Scientist(s) will meet in person with the UDN SC 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 SC will serve as the main scientific body of the UDN. The SC will be responsible for coordinating the activities being conducted. The Steering Committee membership will include the PD(s)/PI(s) of the DNA Sequencing Core, PD(s)/PI(s) of each CS and the CC award, PD/PI of Metabolomics Core, other staff as needed (ex-officio) and the NIH Project Scientist(s). The SC may add additional members, and other government staff may attend the SC meetings as desired. Each CS (including the NIH-UDP), the CC, the Metabolomics Core, and the DNA Sequencing Cores will each have one vote and the NIH Program Scientist(s) will have one vote.

The SC may establish working groups as needed to address particular issues, which will include representatives from the UDN 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 Core Laboratories Awardees agree 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 SC.
• 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 SC 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 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.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Carson R. Loomis, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-7970
Email: [email protected]

David J. Eckstein, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-496-0141
Email: [email protected]

Arnold Revzin, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1153
Email: [email protected]

Leslie Le, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0856
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.