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 Funding Opportunity Announcement (FOA) requests submission of applications for the National Institute on Aging (NIA) Late Onset of Alzheimer's Disease (LOAD) Family Based Study (FBS). Analysis of families that are multiply affected with Alzheimer's disease (AD) provides distinct advantages for characterizing the impact of genetic variants on disease risk. First, multiplex families are likely to be enriched for genetic variants associated with increased risk, providing increased statistical power to estimate the effects. Second, analysis of multiply affected families provides insight into the remaining unknown genetic influences (i.e., the "residual heritability") as well as antecedent modifying factors that interact with identified genetic variants to influence disease risk. Third, family members at risk are followed at regular intervals, facilitating prospective investigation of the effects of the genetic variants on age-at-onset as well as the modifying effects of antecedent risk and protective factors. Finally, family data can provide information regarding the influence of known variants on the rate of disease progression and the residual heritability of disease progression.

The NIA LOAD FBS began in 2003 with the collection and longitudinal follow up of large multiply affected families under individual NIA investigator awards. Funded investigators developed, refined, and circulated a procedure manual for the collection and follow up of families with AD that is still in use. In this initial phase 1,885 samples from 422 families were collected. A cooperative agreement to continue this collection was funded in 2005 to complete the collection of 1,000 new families, recruit appropriate members in existing families, and initiate and complete follow-up in all participating families. The Center for Inherited Disease Research (CIDR) genotyped the first 500 families; data were deposited into the Database of Genotypes and Phenotypes (dbGaP) for broad sharing with the genetics community. At the conclusion of the cooperative agreement, investigators had created a resource of 1,000 well-characterized families with LOAD. Sample acquisition and longitudinal follow up has continued under an R01 that was funded simultaneous with the launch (2012) of the Alzheimer’s Disease Sequencing Project (ADSP).

The ADSP Discovery Phase included the sequencing of 583 subjects from 111 multiply affected families (three or more) drawn largely from the NIA LOAD FBS. The criteria and standards employed by the NIA LOAD FBS were adopted by the ADSP. The ADSP Discovery Extension Study (2015-2016) includes whole genome sequencing (WGS) on up to 500 individuals from multiply affected families. The ADSP Follow-Up Phase (2016-2021) will heavily engage resources provided by the NIA LOAD FBS and will depend upon the longitudinal follow-up of families and the collection of additional families, in particular those from diverse populations. The characterization of additional relatives with ascertainment of antecedent risk factors, and recruitment for autopsy will benefit the field by expanding the scientific value of the NIA-LOAD FBS. Numerous investigators outside of the ADSP are also using DNA from the NIA LOAD FBS.

NIA LOAD FBS DNA samples are provided to the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University, which makes the samples and phenotypic data broadly available to the research community. Clinical data are collected in a uniform fashion as the NIA-LOAD FBS developed specific criteria for the inclusion of families with LOAD and has used standardized methods to identify affected and unaffected individuals across the NIA-funded Alzheimer's Disease Centers (ADCs).

As an essential research resource, the NIA LOAD FBS acts as the key provider of the DNA and clinical data on large multiplex families for the ADSP, the Alzheimer Disease Genetics Consortium (ADGC), the Consortium for Alzheimer's Sequence Analysis (CASA), and the network of NIA sponsored Alzheimer's Disease Centers (ADCs). Other ongoing collaborations include the NIA Cell Repository for Alzheimer's Disease (NCRAD), the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), and the National Alzheimer's Coordinating Center (NACC). The NIA LOAD FBS works closely with the NHGRI- funded Large Scale Sequencing and Analysis Centers (LSAC), the Data Base for Genotypes and Phenotypes (dbGaP), the National Human Genome Research Institute (NHGRI) and other NIH Institutes and Centers (ICs). The NIA LOAD FBS has developed working relationships with all of these entities. Future success depends on keeping the relationships together. Thus, an important aspect of the function of the NIA LOAD FBS is to continue to coordinate with NCRAD, NACC, NIAGADS and dbGaP and to provide infrastructural support in the form of DNA and clinical data for the ADGC, CASA, ADSP, and other NIA-funded genetic studies such as the ADSP Discovery Phase, the ADSP Follow-Up Phase Analysis Studies, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), and other multiple- and single-site studies that involve the collection and storage of DNA and phenotypic data for genetic research on AD.

The NIA LOAD FBS should continue providing overall support for the ADSP family based studies and analysis and for investigators outside of the ADSP. The NIA LOAD FBS should have the ability to assess subjects for AD status at sites inside and outside of the United States in diverse populations; to acquire new DNA from large multiply affected families and provide these samples to NCRAD; to coordinate DNA receipt, processing, and storage; to share data related to families in keeping with appropriate informed consent; and to analyze genetic, genomic, and phenotypic data. It should devise plans for working with a range of stakeholders including government, academic scientists, industry, and data-management experts including but not exclusive to NACC; NCRAD; the Alzheimer's Disease Neuroimaging Initiative (ADNI); the Accelerating Medicines Partnership-Alzheimer's Disease (AMP) and AMP-AD Sage Bionetworks (SAGE).

It is expected in the coming five-year funding period that the NIA LOAD FBS will expand its scope to ensure that up to ~2,000 families (~8,000 subjects) are available to the AD genetics community for analysis to meet the needs of genetic/genomic research on AD with an emphasis on deep endophenotypes. The NIA LOAD FBS will act as a comprehensive resource to enhance the scientific community's ability to better understand how the Alzheimer's genome can affect risk for and protection against disease. Community outreach is an important aspect of the overall activity of the NIA LOAD FBS. Sample and data sharing, effective work flow management, and protocol standardization are expected to play a significant role in the success of these activities as an Alzheimer's community research resource to enhance rapid discovery of therapeutic approaches for AD. The rationale for continued study of multiply AD affected families should be clear. Families selected for further study should be carefully chosen and selection criteria well defined.

Under this funding opportunity announcement, in the next five years the NIA LOAD FBS should:

1). Follow-up existing families to confirm current or past diagnoses, documenting any changes in diagnoses and recruiting new family members within these families;

2). Phenotype and genotype (GWAS and/or exon chip) all new family members;

3). Recruit offspring of the proband generation for each of the existing families, and phenotype and genotype (GWAS, exon chip, or a related approach) offspring;

4). Recruit new families from other ethnic groups (3 or more affected per family) including but not exclusively African American, Afro-Caribbean, Mexican American, Central and South American, and Asian populations;

5). Create a repository of biological resources for follow-up of genetic studies in order to develop biomarkers and induced pluripotent stem (iPS) cells: peripheral blood mononuclear cells, plasma and serum, and cerebrospinal fluid (CSF);

6). Augment the repository of autopsy material for diagnostic accuracy and for follow-up of genetic variants, coordinate the deposition of samples from new individuals and their phenotype and any genotype data to NIAGADS;

7). Facilitate the disposition of DNA and other biological material to NCRAD for use by the greater scientific community;

8). Facilitate the discovery of genetic factors that may lead to the development of new therapies to prevent and treat the disease.

9). Engage in community outreach to help bring new subjects into the NIA LOAD FBS.

In summary, this FOA addresses NIA's vital need for well-coordinated acquisition and handling of DNA and related clinical data from large multiply affected AD families. The NIA is committed to facilitating the collection, storage, and sharing of DNA and related data from large multiplex AD families for research in the area of the genetics of AD. The NIA LOAD FBS is a critical facet of the NIA Alzheimer's Disease Genetics Initiative that effectively leverages the investments already made related to the etiology of AD. Applications considered for funding should effectively leverage the investments already made related to investigation of the core causes of the disease. The research resource should provide a large sample set of DNA and related phenotypic data for broad use by the research community. The research resource of families forms the core of the Family Based Study for the ADSP and is a central component of NIA funded infrastructure that supports the project to inform investigators about the genetic penetrance and heritability of the disease based on the genetic variants already discovered in families multiply affected with AD.

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
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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).

Applicants must obtain 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:

Marilyn Miller, Ph.D.
Telephone: 301-496-9350
Fax: 301-496-1494
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. It is expected that the scientific environment in which the work will be done will contribute to the probability of success of the project and of the ADSP as a whole. Institutional support, equipment and other physical resources available to the investigators should be adequate for the project proposed. Both the project itself and the ADSP should benefit from unique features of the scientific environment, subject populations, or collaborative arrangements. The research environment should have appropriate resources at the applicant Institution(s) to accomplish the research objectives of the program. It is expected that the research resource will have the capacity to serve as a repository of autopsy material for diagnostic accuracy and for follow-up of genetic variants and to coordinate the deposition of samples from new individuals at NCRAD and their phenotype and any genotype data to NIAGADS. The use of research environment should appropriately leverage existing resources at the applicant's Institution(s) to accomplish the research objectives of the U24 program.

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

All instructions in the SF424 (R&R) Application Guide must be followed. The PD(s)/PI(s) should have a deep understanding of the genetics of familial AD. It is expected that PD(s)/PI(s) and other personnel will have appropriate clinical experience and training for management of acquisition of biological samples and data related to large multiply affected families with AD. The PD(s)/PI(s) should have expertise in the handling and analysis of genetic, clinical, and endophenotypic data related to AD. The PD(s)/PI(s) should have expertise in archiving, processing and distributing phenotypic data and samples used for genetic analysis. The PD/PI should be facile in curation of large datasets, including genetic/genomic, and phenotypic data relevant to genetic analysis such as clinical and neuropathology data elements, and related data provided by NIA funded investigators. The PD(s)/PI(s) should have demonstrated accomplishment in effectively interacting with subjects from diverse populations both inside and outside the United States and have expertise in the genetics of complex diseases, population genetics, and statistics in order to discover risk and protective genetics factors for AD. The PD(s)/PI(s) should demonstrate significant experience with coordinating collaborative [basic and clinical] research. The PD(s)/PI(s) should have expertise in managing a large sample repository that can store DNA, brain tissue, CSF, and other biological materials for genetic and biomarker analysis. The PD(s)/PI(s) should have expertise in managing a repository of biological resources for follow-up of genetic studies in order to study biomarkers and should have experience in handling peripheral blood mononuclear cells, plasma and serum, CSF, as well as a repository of autopsy material for diagnostic accuracy and for follow-up of genetic variants. The PD(s)/PI(s) should have expertise in coordinating the deposition of samples to an NIA approved repository, phenotypes from newly recruited individuals, and any related genotype data to an NIA approved database. If the application is multi-PD/PI, investigators should have complementary and integrated expertise and skills in order to provide an appropriate leadership approach, governance, plans for conflict resolution, and organizational structure applicable to the database. The applicant should have experience overseeing selection and management of sub awards, if needed.

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

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

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

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

Specific Aims: Provide a succinct description of how the proposed work will continue to meet the overall scientific goals, the expected outcomes, and the impact of the NIA LOAD FBS should those goals be achieved. The application should describe the organization and operational procedures of the collaborative research infrastructure and how the expertise of the members will be integrated and applied to complete planning and preliminary evaluation, ascertainment and sample collection for a number of large multiplex AD families. The application should describe the processes and resources that will be used to identify and evaluate subjects to be studied over the course of the award. Please refer to the Funding Opportunity Description in Section I when formulating specific aims.

Research Strategy: The applicant(s) should present an integrated plan that will be responsive and flexible regarding the evolving needs of the scientific community especially the Alzheimer's Disease Sequencing Project and other major AD genetics projects. The applicant(s) should provide a rationale for selection of families, and the approach and rationale for selection of genotyping methodology (i.e. genome wide association, exome content array, or other genotyping methods) to be done in the study. Plans for documentation of key procedures should be included. The contributions of individual key personnel should be specified. Provide an overall description of the proposed organizational structure and project management plan, including any relevant flow charts, and show how the research will serve particular communities of researchers studying Alzheimer's disease. Describe the strategy for effectively carrying out each specific aim including the establishment of an Executive Committee comprised of lead investigators from major AD genetics studies. Show how the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic material and related data will facilitate research in Alzheimer's disease that is supported in independent projects. Please refer to the funding Opportunity Description in Section I when developing the Research Strategy.

Innovation: Explain how the concepts, approaches or methodologies, or interventions used in the augmentation of the NIA LOAD FBS are novel to the field of AD research. Explain how refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed are novel to the field of AD research. Explain any novel organizational concepts, management strategies, or analytical approaches in coordinating the research projects that the NIA LOAD FBS will serve. Describe any concepts, strategies, or approaches that are novel to the genetics and genomics of AD research or that are applicable in a broad sense. Explain any refinement, improvement, or new application of organizational concepts, management strategies or instrumentation that will be employed in the research.

Approach: The proposed study should describe a comprehensive plan to address NIA's vital need for well-coordinated acquisition and handling of DNA and related clinical data from large multiply affected AD families. Describe how the proposed study will facilitate the collection, storage, and sharing of DNA and augment the repository of autopsy material and related data from large multiplex AD families for research in the area of the genetics of AD. Explain any innovative approaches for sample and data acquisition. Explain how the NIA LOAD FBS will facilitate the mission of the ADSP. Describe how the NIA LOAD FBS will work cooperatively with the ADSP as a whole. Explain how the research plan will enable the ADSP to extend previous discoveries that may ultimately result in new directions for AD therapeutics, consistent with achieving the goals of this program. Explain why the approach is feasible, how particularly risky aspects will be managed and how the NIA LOAD FBS will advance and augment the development of novel therapeutics for AD. Explain how potential problems, alternative strategies, and benchmarks for success will be carried out. State plans to participate actively in sample and data exchange and to collaborate with other investigators in the ADSP and with awardee(s) of other NIA grants and cooperative agreements in order to enhance the likelihood of identifying therapeutic targets for AD. Define milestones and a time line for key events for the project.

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.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan that is consistent with the NIA Genomics of Alzheimer's Disease Sharing Policy and the goals of the NIA Genetics of Alzheimer's Disease program. It is the policy of the NIA that all Genomic Data derived from NIA funded studies for the genomics of late onset Alzheimer’s disease, including secondary analysis data, be deposited at NIAGADS or another NIA approved site or both whenever possible. As a resource, more information can be found at: https://www.nia.nih.gov/research/dn/alzheimers-disease-genomics-sharing-plan.

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

Form only available in FORMS-D application packages for use with due dates on or before January 24, 2018.

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

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow our Post Submission Application Materials policy.

Important Update: See NOT-OD-18-228 for updated inclusion and human subjects review language for due dates on or after January 25, 2019.

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 proposed project address the needs of the research resource that it will serve? Is the scope of activities proposed for the project appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research resource?

How well will the plan coordinate receipt and distribution of genetic samples and related phenotypic data from diverse sample sets to augment the existing NIA LOAD FBS collection? How responsive and flexible will the proposed NIA LOAD FBS be to the evolving needs in the AD research community including its ongoing collaborations and existing interactions with stakeholders? How well will coordinated receipt and distribution of genetic samples and related phenotypic data from diverse sample sets facilitate or expedite AD research that would be delayed or infeasible if conducted as independent projects? What advantages will the NIA LOAD FBS bring to the AD research programs it services? How responsive is the proposed study to the need to serve as an interface between the ADSP, the AD research community, and related infrastructure such as NCRAD, NACC, and the ADCs? How well will the proposed study leverage the investments already made related to investigation of the core causes of the disease? How efficiently will the research resource provide a large sample set of DNA and related phenotypic data for broad use by the research community? How well will the study develop and sustain a unique, large, well phenotyped and population diverse sample set for the AD research community at large?

Are the PD(s)/PI(s) and other personnel well suited to their roles in the project? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing Alzheimer's disease research? Do the investigators demonstrate significant experience with coordinating collaborative basic and clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, plans for conflict resolution, and organizational structure appropriate for the research resource? Do the applicants have experience overseeing selection and management of subawards, if needed?

How experienced are the PD(s)/PI(s) in handling AD genetic samples, samples for biomarkers, autopsy material, study related genetics data and phenotype data? How appropriate is their record of accomplishments in effectively managing large sample sets like the NIA LOAD FBS? How experienced are they in handling sample and datasets for complex diseases? Do the PD(s)/PI(s) and staff have sufficient appropriate experience and training for management of large scale sample and phenotypic data acquisition with expertise in curation and distribution of large sample sets including: pedigrees, genetic, genomic, and phenotypic data relevant to genetic analysis, clinical and neuropathology data elements, and related data? Do the PD(s)/PI(s) have sufficient experience and an ongoing record of accomplishments in effectively managing a sample repository in order to discover risk and protective genetics factors for AD? How successful is the plan to form an effective executive committee to oversee the work that will ensure that the AD community is well served by the NIA LOAD FBS likely to be?

Does the application propose novel organizational concepts, or management strategies in coordinating the research resource? Are the concepts or strategies novel to the field of AD research or AD genetics? Is a refinement, improvement, or new application of organizational concepts or management strategies proposed?

How well does the application explain any refinements, improvements, or new application of instrumentation that will be employed in the research? Is community outreach an aspect of the proposed study and likely to be effective in bringing subjects into the NIA LOAD FBS?

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research resource that the project will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the resource, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the resource is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the resource? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects? How well do the PD(s)/PI(s) describe their plans for documentation of the key procedures that they will include in the project? How well will the proposed strategy maintain the continuity of the existing family based study? How likely to be successful is the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic material and related data? How adequate are plans to augment the existing repository of autopsy material? How well will the proposed NIA LOAD FBS assist the research community and NIA in achieving the goals of the Alzheimer's disease research programs it proposes to serve? How well is the expertise of the members integrated and applied to complete planning, ascertainment, evaluation, and sample collection for a number of large multiplex AD families? How well do the PD(s)/PI(s) describe the processes and resources that will be used to identify and evaluate subjects to be studied? How well integrated and flexible is the plan that will be put in place to the evolving needs of the scientific community especially the Alzheimer's Disease Sequencing Project and other major AD genetics projects? 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 institutional environment in which the project will operate contribute to the probability of success in facilitating the research program it serves? 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 institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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 Data Sharing Plan (GDS).

For resources 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 NIA, 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:

• Will receive a written critique.

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. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Committee on Aging. 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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.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 https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/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 https://www.hhs.gov/ocr/about-us/contact-us/index.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.

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:

The PD/PI(s) will have primary authorities and responsibilities to define objectives, approaches, and analysis protocols; sample and data acquisition and distribution. The PD/PI(s) will work directly with members of the NIA Alzheimer's Disease Genetics Consortium (ADGC), the National Alzheimer's Coordinating Center (NACC), the National Cell Repository for Alzheimer's Disease (NCRAD), the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), the Alzheimer's Disease Centers (ADCs), Alzheimer's Disease Genetics Consortium (ADGC), the Consortium for Alzheimer's Sequence Analysis (CASA), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer's Disease Sequencing Project (ADSP), NHGRI, NIA, the ADSP Discovery Phase cooperative agreement studies funded under https://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54) - https://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-001.html#sthash.CkRnSTCU.dpuf and the Alzheimer's Disease Sequencing Project (ADSP) Follow-Up Phase Analysis Studies (U01): https://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-002.html#sthash.DDPm7mTO.dpuf and other NIA funded investigators.

The NIA Late Onset of Alzheimer's Disease (LOAD) Family Based Study (FBS) Program Director(s) in consultation with the NIA Project Scientist will establish a board of external consultants to provide guidance on sample acquisition and advances in methodology appropriate for use in this context. Consultants will be selected as individuals who are not involved in AD genetics research but who could advise the awardees with an emphasis on population diversity, sample banking, iPS cell methodology, and biomarkers for AD. The PD/PI(s) and key NIA LOAD FBS personnel and selected awardees of the Alzheimer's Disease Sequencing Project (ADSP) Discovery Phase and Follow-Up Phase, in consultation with the NIA Project Scientist, will be members of an Executive Committee. The Executive Committee will hold meetings and conference calls to facilitate development and implementation of common measures and practices. The Executive Committee will define the rules regarding access to, and publication of, findings from analyses of NIA LOAD FBS samples and related data. The NIA LOAD FBS will transfer samples to NCRAD for distribution to the research community at large.

A Sample Use Committee will be selected jointly by the NIA Project Scientist and the PD/PI(s) of the cooperative agreement. The Sample Use Committee will be formed which will act in a decision making capacity for use of the NIA LOAD FBS samples that are stored at NCRAD. Samples will be distributed in keeping with Institutional Review Board approval, and subject to Government rights of access, consistent with current HHS, PHS, and NIH policies.

The Program Director(s) of the NIA LOAD FBS will work collaboratively with other investigators to develop the study analysis design, and collect appropriate samples and data for the AD genetics community as approved by the Executive Committee in consultation with the NIA Project Scientist.

The PD/PI(s) of the cooperative agreement will be involved in collaborations with the Alzheimer's Disease Genetics Consortium (ADGC, http://alois.med.upenn.edu/adgc/), the Consortium for Alzheimer's Sequence Analysis (CASA), the Alzheimer's Disease Centers (ADC, http://www.nia.nih.gov/Alzheimers/ResearchInformation/ResearchCenters/), the National Cell Repository on Alzheimer's Disease (NCRAD http://ncrad.iu.edu/), the National Alzheimer's Coordinating Center (NACC http://www.alz.washington.edu/), and the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (CGAD) during all phases of the award. The PD/PI(s) of the cooperative agreement will administer the establishment, operation, and quality control of genotypic and phenotypic data, including the development of procedures for assuring data quality control, and procedures for transfer of data. The Program Director(s) of the cooperative agreement is responsible for working cooperatively with study sites and sponsoring organizations and for overseeing the implementation of, and adherence to, common protocols, as well as assuring quality control of the samples collected. In addition to organizing and attending regular meetings, the Program Director(s) of the cooperative agreement will be expected to maintain close communications with the NIA Project Scientist and, where appropriate, the Program Director(s) of the ADSP and the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease. The Program Director(s) will ensure that ADSP data are made available immediately upon deposition into the Data Storage Site. The NIA Project Scientist will have substantial scientific involvement that is above and beyond the normal stewardship role in awards, as described below.

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

The NIA Program Official will be responsible for normal program stewardship including assessing the progress toward the accomplishment of specified milestones, and for recommending release of additional funds to the project. The designated NIA Project Scientist will have scientific involvement during conduct of this activity, through technical assistance, advice and coordination, assisting in those aspects of the award as described below. The NIA Project Scientist will monitor the deposition of samples into NCRAD to ensure that NIA funded investigators have appropriately deposited data and have properly acknowledged the use of the NIA LOAD FBS in the publication of their work. The NIA Project Scientist will review protocols for work flow and data sharing before they can be implemented. The NIA Project Scientist will be a non-voting "ex officio" member of the Executive Committee and all key subcommittees.

Areas of Joint Responsibility include:

For areas of joint responsibility, an Executive Committee including Program Director(s) of the NIA LOAD FBS, selected Program Director(s) from the ADSP, the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease, and the NIA Project Scientist should be formed. The Executive Committee will serve as the main decision-making body for the shared aspects of the study and will devise common protocols related to data sharing among collaborators, stakeholders, and the AD research community. Appropriate NIA LOAD FBS staff may attend the Executive Committee Meetings as needed. Members of the Executive Committee for the Data Storage Site will contribute to the effort by accessing and assessing appropriate genetic and phenotype data, and providing expertise in the analysis of genetics data from specific AD cohorts. The Executive Committee will meet bi-monthly, or as needed. The External Board of consultants will advise the Program Director(s) on methodological approaches; phases of the award will proceed only after review of the common protocols and approval by the Executive Committee, and acceptance by the NIA.

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.

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: https://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 CenterTelephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9666
Email: [email protected]

Robin Laney
National Institute on Aging (NIA)
Telephone: 301-496-1473
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.