It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

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

FTD represents a clinically, genetically and pathologically diverse group of neurodegenerative disorders or syndromes resulting from atrophy in frontal and/or anterior temporal lobes. This atrophy manifests as changes in behavior, social conduct, language or speech and in some syndromes, motor deficits commonly associated with parkinsonism or motor neuron disease. FTD is a common cause of young onset dementia, often affecting individuals below the age of 65 years. Based on anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or related disorders are: (1) behavioral variant of FTD, (2) semantic variant primary progressive aphasia, (3) nonfluent agrammatic variant primary progressive aphasia, (4) corticobasal syndrome, (5) progressive supranuclear palsy, and (6) FTD associated with motor neuron disease.

Approximately, one third of FTD cases have a familial basis, with mutations in the progranulin (PGRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes representing the major genetic causes. The complexity of the FTD disease spectrum is in part manifest in the clinical symptoms that are associated with the major mutations. For instance, mutations in the genes that encode MAPT and PGRN can manifest as symmetrical parkinsonism, including the phenotypes of Richardson syndrome and corticobasal syndrome (CBS). Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations.

Although FTD genome wide association studies have enabled the identification of a number of risk factors for FTD, whole genome sequencing now enables a full survey of the genome and the ability to accurately localize genetic variants associated with disease risk and modifiers of clinical presentation, disease onset and disease pathology. The combination of transcriptomics, epigenomics and proteomic analysis of brain tissue from autopsy confirmed cases, and peripheral biosamples from clinically identified FTD cases, provide datasets that can complement genetic variant discoveries derived from whole genome sequencing and lead to the identification of targets and pathways for a tailored FTD drug development approach.

In 2016, NINDS organized a conference on Alzheimer's Disease Related Dementias (ADRDs) which focused on frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), vascular cognitive impairment or dementia (VCI/VaD), mixed diseases including the associated diagnostic challenges of multiple etiology dementias (MED), and issues related to health disparities. The conference complemented the National Institute on Aging’s Alzheimer’s Disease Research Summit 2015: Path to Treatment and Prevention. Both conferences responded to the National Alzheimer’s Project Act that was signed into law in January 2011. The objective of the ADRD conference was to contribute to the efforts directed at preventing and effectively treating Alzheimer’s disease, including Alzheimer’s disease-related dementias, by 2025. The Alzheimer’s Disease-Related Dementias steering committee solicited input from internationally recognized experts to develop prioritized recommendations to guide scientific research in the next 5 to 10 years. The top ranked clinical science recommendation from the ADRD FTD working group was directed at accelerating discovery, replication and functional validation of new familial FTD genes, genetic risk factors and disease modifiers. It was recommended that the cohorts include family-based and case/control cohorts. Family-based cohorts should also include those with FTD and ALS clinical phenotypes. Support for improved bioinformatics platforms for phenotype and genetic data storage and analysis was strongly encouraged.

The purpose of this FOA is to support the genetic discovery, replication and validation of disease causing mutations, risk variants and genetic modifiers which contribute to the pathophysiology, proteinopathies and clinical heterogeneity representative of the neurological syndromes that are classified under the broad spectrum of Frontotemporal Degeneration (FTD). The grant mechanism used to support the FTD Sequencing Consortium is a cooperative agreement (UG3/UH3) mechanism with two phases. The UG3 phase of the FTD Sequencing Consortium FOA will support: 1) genetic variant identification studies using whole genome sequencing; 2) genetic variant replication studies using whole genome sequencing; and 3) genome sequencing analysis that incorporates the development and use of analytical pipelines that address the clinical and pathological heterogeneity of FTD, as well as, if applicable, analytical approaches that parallel or complement pipelines currently applied to large scale genome sequencing studies being utilized in the Alzheimer’s Disease Sequencing Project and the Parkinson’s Disease Genome Sequencing Consortium. Genetic discovery efforts should focus on cohorts comprised of autopsy confirmed FTD cases and family-based cohorts. Replication studies can include additional autopsy confirmed FTD cases, family based cohorts or clinical cases that have extensive clinical assessments, imaging and biosamples available. The UH3 phase of the FTD Sequencing Consortium FOA will support additional replication studies using whole genome sequencing and functional validation studies using multi-omic approaches, human cell-based assays and in vivo studies in existing FTD model systems.

The UG3 phase will support discovery projects and replication studies using whole genome sequencing. Discovery projects should include autopsy confirmed cases and/or family cohorts only. Study considerations for the UG3 phase include, but are not limited to:

• Sequencing of FTD family cohorts with small pedigrees (4 to 6 individuals in 1st and 2nd generations) should include all individuals.
• Sequencing of FTD family cohorts with large pedigrees should include a rationale for analysis of a subset of individuals from the pedigree
• Sequencing of autopsy confirmed cases preference will be given to autopsy cases that have both fixed and frozen tissue available for analysis. If autopsy cases do not include a pathological assessment for all known FTD proteinopathies, then the study should include an assessment of the pathology.
• Sequencing of clinical cases for replication clinical cases may be used in replication studies if extensive clinical phenotypes, imaging and biosamples are available
• All DNA samples to be sequenced should have an accompanying phenotypic data set that includes, but is not limited to demographics (gender, ethnicity), age of symptom onset, diagnosis. For autopsy cases disease duration should also be known.
• All DNA samples to be sequenced must have a global unique identifier (GUID) or pseudoGUID generated using the PDBP GUID server.
• Inclusion of statistical justification for the sample size of discovery and replication cohorts proposed.
• Inclusion of existing control cohorts, where the whole genome sequencing coverage and quality control are aligned with FTD genetic case data.
• Documentation that patient consents for all DNA samples to be sequenced allow for broad data sharing, as appropriate and consistent with achieving the goals of the program.
• Utilization of a cloud-based data storage and analysis platform that supports data sharing across the FTD Genetics Consortium, as appropriate and consistent with achieving the goals of the program
• Deposition of whole genome data with the NIH database for genotype and phenotype data (dbGaP) by the end of the UG3 phase, as appropriate and consistent with achieving the goals of the program.

The UH3 phase will support replication studies using whole genome sequencing approaches and functional validation studies. Functional validation study approaches for the UH3 phase include, but are not limited to:

• Transcriptomic, epigenomic and/or proteomic analysis of tissues or cells isolated from autopsy confirmed cases or controls used for whole genome sequencing.
• Human cell-based assays to determine if prioritized genetic variants identified in the UG3 phase have functional consequences on normal CNS cellular functions.
• Use of robotic microscopy, cryo electron microscopy, or cryo tomography to determine functional consequences of the genetic variants identified in the UG3 phase on CNS cell morphology.
• Use of existing in vivo FTD model systems to determine the functional consequences of genetic variants.
• Functional validation studies will use standard data form structures that are compliant with NIH standards and include meta data that fully describe the experimental design and execution.

Both the UG3 and UH3 phases of the project should be milestone-driven.

Studies not responsive under this FOA:

UG3 - Studies that include clinical cases in the discovery cohort and studies that include poorly defined clinical cases (those lacking extensive clinical phenotypes, imaging and biosample availability) in the replication cohort.

UH3 - Studies that include development of new in vivo FTD models.

Grants funded under this FOA will function as a consortium to develop shared strategies for: 1) FTD pathological confirmation of autopsy cases; 2) a shared FTD classification and review of clinical cases to be used in replication studies; 3) a shared whole genome sequencing platform; 4) a shared cloud-based data storage and analytical platform; 5) a shared file format for pedigree data; 6) the development of a memorandum of understanding (MOU) that defines the responsibilities of consortium membership and the analysis plans of the consortium; 6) the development of analytical pipelines that address the clinical and pathological heterogeneity of FTD; and 7) application, where applicable, of analysis pipelines currently being applied to large scale sequencing projects in Alzheimer’s Disease and Parkinson s Disease.

The overall outcome of the FTD Sequencing Consortium will be a coordinated large scale sequencing effort for FTD spectrum disorders, where sequencing and data analysis approaches allow for broad data sharing both within and outside the consortium and with other relevant disease-based sequencing efforts. An external liaison committee will be identified by the consortium investigators and NIH representatives. The external liaison committee will be charged with providing expert knowledge support for functional variant analysis strategies to be applied in the UH3 phase. A face to face meeting will be held within sixty days of receipt of the notice of grant award to define the FTD Sequencing Consortium strategies. Monthly teleconferences will be held with NIH staff to review progress and address any roadblocks or delays being experienced that would impact the successful transition to the UH3 phase. A second face to face meeting with NIH staff and the external liaison committee will be held three to four months prior to the UH3 transition.

An Applicant Informational Webinar will be scheduled to provide an overview of the FOA, key requirements, and the function of the FTD Sequencing Consortium. The webinar is open to all prospective applicants. Participation in the webinar is not a prerequisite for applying, and is not required for a successful application. Information about how to participate in the webinar will be posted at http://www.ninds.nih.gov. Potential applicants are encouraged to submit their questions or comments to [email protected] prior to the meeting. Afterwards, the webinar slides and a summary of the questions and answers will be posted on the same site. NIH will also post a list of Frequently Asked Questions (FAQs) and answers; this information may be updated without additional notice.

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff at the beginning of the planning stage of their application (see Agency contacts, Section VIII).

See Section VIII. Other Information for award authorities and regulations.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government-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)

Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is that the results and accomplishments of the activities that it funds and supports should be made available to the public.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (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.

The FTD Sequencing Consortium (PD/PI) should be an established leader, with a history of successful funding and proven expertise in the stewardship of large-scale research programs. Other important factors include current research productivity, active funding (NIH R01-equivalent or greater) and the capacity for visionary leadership of an interdisciplinary team, which will be an important aspect of the UH3 phase.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Margaret Sutherland, PhD
Telephone: 301-496-5680
Fax: 301-480-1080
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.

Budget considerations for UG3 should include, but are not limited to:

• Estimated cost per whole genome sequencing (discovery and replication studies) - $1,000 per genome. Sequencing costs will be handled as a service agreement to a contract research organization (CRO) selected by the FTD Sequencing Consortium.
• Estimated cost per cloud-based storage and analysis time - $125,000 per year. Cloud computing costs will be handled as a service agreement to a CRO selected by the FTD Sequencing Consortium.
• Travel costs for PDs/PIs and 2 scientific advisory committee members to attend 2 face to face meetings in Washington, DC.

Budget consideration for UH3 should include, but are not limited to:

• Estimated cost per whole genome sequencing (replication studies) - $1,000 per genome. Sequencing costs will be handled as a service agreement to a CRO selected by the FTD Sequencing Consortium.
• Estimated cost per cloud-based storage and analysis time - $125,000 per year. Cloud computing costs will be handled as a service agreement to a CRO selected by the FTD Sequencing Consortium.
• Travel costs for PDs/PIs and 2 scientific advisory committee members to attend 1 face to face meeting per year in Washington, DC.

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:

• Provide the overall goals or hypotheses for the entire project period and identify separate Specific Aims to be accomplished in the UG3 phase and in the UH3 phase.

Research Strategy:

• Provide separate sections that describe both the UG3 and UH3 phases
• Provide information on the pedigree structure for extended family cohorts and strategies for selection of a subset of individuals from the cohorts for whole genome sequencing
• Provide a description of the hypotheses to be tested in the UH3 phase of the study
• Provide justification for the functional evaluation approaches to be used to test the hypotheses proposed in the UH3 phase.

Go/No-Go Transition Milestone for transition from the UG3 Phase to the UH3 Phase

• UG3 milestones should include a timeline for completion of DNA sequencing, DNA sequencing quality assessment and pipeline analysis including variant annotation and prioritization and data deposition with dbGaP.
• Include a clearly identified Go/No-Go transition milestone for completion of the UG3 phase at the end of Year 2 and transition to the UH3 phase for 3 years of additional funding.
• A timeline (Gantt chart) including milestones is required for all studies. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years.

Milestones and the timeline for each stage must be provided in a separate heading at the end of the Approach section for each UG3 and UH3 phases and include the following.

• UH3 milestones should incorporate the number of variants to be analyzed and timeline for functional variant analysis based on the platforms to be used for analysis and the timeline for data deposition with dbGaP.
• Provide detailed quantitative criteria by which milestone achievement will be assessed.
• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Letters of Support: Letters of agreement from collaborators (academic scientists, industry partners, non-government organizations) indicating their willingness to share DNA samples and phenotype information and the ability of the contributor (based on patient consent and institutional approval) to broadly share data derived from the DNA samples with the broader research community, as appropriate and consistent with achieving the goals of the program.

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:

• As appropriate and consistent with achieving the goals of the program, the Data Sharing Plan will be developed by the FTD Sequencing Consortium and include: 1) development of a study for the FTD Sequencing Consortium in dbGaP; 2) development of a detailed cloud-based sharing plan for consortium members; 3) development of an analysis pipeline plan for whole genome sequencing data; 4) development of a timeline for data deposition with dbGaP; and 5) development of a FTD Sequencing Consortium memorandum of understanding outlining the rules of membership and consortium data analysis plans.
• Resource Sharing Plans will be outlined based on the biological systems and assays utilized in the UH3 phase of the study, as appropriate and consistent with achieving the goals of the program.

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

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Institute of Neurological Disorders and Stroke. 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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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

For this particular announcement, note the following:

The UG3/UH3 phased innovation grant supports discovery, replication and validation of genetic factors contributing to the clinical, pathological and biological heterogeneity of neurological syndromes making up the FTD spectrum. Reviewers will assign a single impact score for the entire application, which includes the UG3 and UH3 phases, as well as a separate impact score for each of the phases (UG3 and UH3).

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

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

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

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? Has the PD/PI demonstrated leadership ability in bringing together a broad nationally or internationally based consortium to advance genetics research? Does the PD/PI have expertise in gene and genetic modifier discovery, replication and validation? Does the PD/PI demonstrate current research productivity, and the capacity for visionary leadership of an interdisciplinary team?

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?

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

Are the milestone plans for the UG3 and UH3 phase appropriate and responsive to criteria outlined in the FOA and do the milestone plans define clear go no/go decisions? Do the UG3 milestones clearly address the transition criteria for the UH3 phase? Are DNA samples readily available, so that milestones and timelines defined for the UG3 phase can be achieved?

UG3 approach:

For the UG3 phase, is the discovery cohort composed of autopsy confirmed and/or family-based FTD cases, and is the discovery cohort size sufficiently powered for statistical significance? For the UG3 phase, if a replication cohort is proposed, does the replication cohort include additional (not used in the discovery phase) autopsy confirmed, family-based or clinical FTD cases with extensive phenotypic characterization, imaging and biosample availability and is the replication cohort size sufficiently powered to achieve statistical significance? Are the cases to be included in the discovery and/or replication cohorts consented to allow for broad data sharing? Does the sequencing analysis include the use of existing control cohorts and does the sequencing quality of the genetic data from these control cohorts match the coverage and quality control proposed for the FTD case discovery and replication cohorts?

UH3 approach:

If a replication cohort is included, does the replication cohort include additional (not used in the discovery phase) autopsy confirmed, family-based or clinical FTD cases with extensive phenotypic characterization, imaging and biosample availability, and is the replication cohort size sufficiently powered to achieve statistical significance? Are the cases to be included in the replication cohort consented to allow for broad data sharing? Does the sequencing analysis include the use of existing control cohorts and does the sequencing quality of the genetic data from these control cohorts match the coverage and quality control proposed for the FTD case discovery and replication cohorts? If omic approaches are proposed for pathway and target identification, are the approaches appropriate and will data derived contribute to our understanding of FTD biology and/or pathophysiology? Are the model systems proposed for functional validation appropriate for advancing our understanding of the genetic variant influence on FTD biology and/or pathophysiology?

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?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

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

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

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

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

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

Not Applicable

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Neurological Disorders and Stroke, 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 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.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program 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 experimental approaches, designing protocols, setting project milestones and conducting experiments;
• Adhere to FTD Sequencing Consortium policies regarding data sharing and analysis, publication, and other policies that might be established during the course of this activity;
• Report to NINDS Scientific Program staff regarding timeline and milestone achievement during the course of the project, as delineated in the terms and conditions of award;
• Submit annual progress reports during the funding period, in a format as agreed upon by NINDS program staff;
• Accept and implement any other common guidelines and procedures developed for the FTD Sequencing Consortium;
• Attend in-person FTD Sequencing Consortium meetings to be held annually and organized in collaboration with NINDS program staff where PD(s)/PI(s) will present up to date findings (including unpublished results) on ongoing projects. The cost of these meetings will be covered under the current funding for this application.
• Awardees are expected to make new information and materials known to the research community not only in the annual meetings but also in a timely manner through publications, web announcements, reports to NINDS program staff, and other mechanisms.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

Publications:

• The PD(s)/PI(s) will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The PD(s)/PI(s) and Project Leaders are requested to submit manuscripts to the NIH Project Scientists within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the PD(s)/PI(s) and appropriate Project Leaders and will require appropriate acknowledgement of NINDS and FTD Sequencing Consortium support. Timely publication of major findings is required.
• NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientists will be to facilitate and not to direct the activities.

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

• NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientists will be to facilitate and not to direct the activities.
• Contribute to the adjustment of research protocols, project milestones or approaches as warranted;
• Serve as a liaison between the awardees, the NINDS Advisory Council and the larger scientific community;
• Coordinate the efforts of the awardees with others engaged in FTD research, including other awardees funded by related NIA, NINDS and NCATS programs;
• Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.
• Additionally, an NINDS program official or NINDS program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Email: [email protected]

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

Telephone: 301-710-0267

Margaret Sutherland, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]

Marilyn Miller, PhD
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Chief Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-4188
Email: [email protected]

Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Mahasin Ingram
National Institute on Aging (NIA)
Telephone: 301-402-7736
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.