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

The National Institute on Aging (NIA) invites current NIA Cooperative Agreement project directors to submit revision applications to expand the scope of a current award specific to the area of the genetics of Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD). The proposed topic must both be related to the current focus of the funded research and be relevant to the mission of the NIA. The revision may propose to expand existing projects or create new projects as defined in PAR-16-406. Please refer to PAR-16-406 for specific details about the project and the roles of the entities to whom sub-contracts are provided under this cooperative agreement. NIA applications that propose supporting Revision applications should be submitted as appropriate to the science being proposed. For example, if two different ideas are being considered then they should be submitted as two different revisions. A revision application may be submitted only after the Parent U01 project has been funded.

This Funding Opportunity Announcement (FOA) is issued as an initiative in response to the National Alzheimer's Project Act (NAPA) Public Law 111-375 NAPA 2012 2013, and NAPA 2016. The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genes involved in AD, (2) identify gene alleles contributing to increased risk for or protection against the disease, (3) provide insight as to why individuals with known risk factor genes escape from developing AD, and (4) identify potential avenues for therapeutic approaches and prevention of the disease. This study of human genetic variation and its relationship to health and disease involves a large number of study participants from ethnically diverse populations and will capture not only common single nucleotide variations but also rare copy number and structural variants that are increasingly thought to play an important role in complex disease. The ADSP Discovery Phase has identified a number of variations in the genomes of individuals affected with AD. These findings are being pursued in the ADSP Follow-Up Study (FUS).

Through unanticipated cost savings, driven by reduced sequencing costs, technological advances, and the fact that more funds have been made available for the study of Alzheimer's Disease (AD), there is the ability to sequence more subjects and to include ethnically diverse sample sets in larger numbers than originally proposed. ADSP investigators have identified as many as 10,000 additional samples from ethnically diverse cohorts for this effort. This will in turn extend the need for funds essential for quality control checking, data harmonization, data sharing, and data analysis on the additional samples accrued under the financial windfall. This augmented dataset will boost statistical power for the analysis of data in ethnic subpopulations and may therefore augment the likelihood of identifying therapeutic targets for the disease.

Program Directors/Principal Investigators (PDs/PIs) are expected to engage in the study of existing cohorts where possible; samples for many of these subjects are already in hand. When necessary to augment the ability of the researchers to attain appropriate statistical power in the diversity sample sets that are already part of the study, investigators will recruit, cognitively test, and adjudicate subjects. Where additional subjects for ethnic cohorts are selected for the ADSP FUS, an appropriate number of unaffected individuals, as determined by power calculations, from the same population should be included in the study to enable assessment of population substructure and other factors related to the cohort. Investigators will ensure appropriate informed consent has been obtained from study participants.

For this revision FOA if sequencing is a component of the application:

ADSP investigators will submit applications that include: the National Cell Repository for Alzheimer's Disease (NCRAD) for any needed sample handling; the Genome Center for Alzheimer's Disease (GCAD) for quality control (QC) checking and data harmonization; and the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) for data sharing with the research community at large, and as subcontracts to the study. ADSP investigators will also include sequencing centers, as appropriate. Due to significant cost savings in the area of whole genome sequencing (WG S), NIA supports engaging the Uniformed Services University for the Health Sciences (USUHS) sequencing center called "The American Genome Center" (TAGC) when additional/follow-up sequencing is needed. NIA-funded ADSP genetics investigators and sequencing centers will collaborate and provide DNA and sequence data for the ADSP FUS. All data included in the ADSP FUS will be called and QC'd on the ADSP pipeline. Under this FOA, when the application includes sequencing, investigators must include a funding stream (subcontract) for the four entities that are considered essential NIA infrastructure for the ADSP, as they are not otherwise supported for their efforts in this initiative. These are: (1) NCRAD, (2) USUHS TAGC or another NIA-approved sequencing center, (3) GCAD, and (4) NIAGADS.

Funds will be provided:

• To ADSP investigators to identify, assemble, and send additional DNA samples from selected ethnic populations with well phenotyped subjects affected with AD for WGS to NCRAD.
• For NCRAD to receive and prepare DNA, perform QC checks, retain aliquots of DNA, plate and ship samples to sequencing centers, and track samples through the sequencing process.
• For NCRAD to acquire and archive appropriate documentation for compliance of sample and data handling with NIH policy and ensure that standard operating procedures for sample handling are followed.
• For USUHS or another NIA-approved sequencing center to perform GWAS and WGS and to process sequence data.
• For GCAD to receive and process data and perform QC checks, variant calling, and data harmonization with other ADSP data.
• For GCAD to provide these processed data to NIAGADS.
• For NIAGADS to receive and manage the WGS and GWAS data sets and coordinate ADSP phenotype and GWAS data collection, sequence data production and delivery to the research community for public data release.

These efforts will increase statistical power to detect risk and protective genes for the ethnic subpopulations studied in the ADSP FUS.

For this revision FOA if only QC, data harmonization, and data sharing are components of the application:

For more limited applications with sequence data already in hand and that focus on QC, data harmonization, and data sharing of additional subjects, ADSP investigators will submit applications that include TAGC or another NIA-approved sequencing center for initial QC checking; GCAD for QC checking on the ADSP pipeline, and data harmonization; and NIAGADS for data sharing with the research community at large, as subcontracts to the study. Under this FOA, applications with the more limited scope must include a funding stream (subcontract) for the three entities that are considered essential NIA infrastructure for the ADSP, as they are not otherwise supported for their efforts in this initiative. These are: (1) TAGC, (2) GCAD, and (3) NIAGADS.

Funds will be provided:

• For USUHS or another NIA approved sequencing center to perform QC on sequence data and to provide sequence data to GCAD.
• For GCAD to receive and process data and perform QC checks, variant calling, and data harmonization with other ADSP data.
• For GCAD to provide these processed data to NIAGADS.
• For NIAGADS to receive and manage the WGS and GWAS data sets and coordinate ADSP phenotype and GWAS data collection, sequence data production and delivery to the research community for public data release.

NIA expects that this component of the ADSP will be highly collaborative among:

• AD geneticists funded under PAR-12-183, RFA-AG-16-001, RFA AG-16-002, PAR-16-406, and under other individual NIA grants and cooperative agreements;
• NCRAD investigators funded under PAR-15-316;
• The National Alzheimer's Coordinating Center (NACC) funded under PAR-11-213;
• Investigators funded by the NHGRI under RFA-HG-15-001;
• TAGC investigators funded under PAR-16-406 and PAR-17-214;
• NIAGADS funded under PAR-16-047; and
• GCAD funded under PAR-AG-16-001.

NIA anticipates that this project will require a high degree of collaboration with other researchers with an interest in AD in order to identify appropriate sample sets and to provide expertise for QC and variant calling. Data will be widely disseminated as a research resource, and the broad use of the data will be ensured.

Summary

In summary, ADSP investigators have generated or will generate additional sequence and related data for the examination and comparison of the genomes of individuals affected with AD from ethnically diverse populations during the ADSP FUS. Where sequencing is a component of the application, PDs/PIs will identify well characterized, ethnically diverse sample sets with related clinical/phenotypic and GWAS data. DNA from these subjects will be provided to NCRAD for processing, quality control checking, and assignment to the sequencing center(s). The sequencing center(s) will generate sequence data on whole genomes on affected and unaffected individuals and participate in the initial quality control, and variant calling sequence data will be made available to GCAD for QC checking and variant calling. These data will in turn be provided to NIAGADS for data management.

For more limited applications that focus on ADSP FUS quality control checking, data harmonization, and data sharing, investigators PDs/PIs will work with the sequencing center(s), GCAD, and NIAGADS for data management and data sharing. Studies funded under separate auspices will analyze the sequence data to identify new genes/regions/loci contributing to increased risk of developing the disease or protection against developing AD with the goal of identifying potential avenues for therapeutic approaches and prevention of the disease. Data resulting from the present study are expected to become available to qualified investigators through NIAGADS and dbGaP to enable rapid identification of therapeutic targets.

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 from this FOA.

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

Applicant Organizations

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

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

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

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

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

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

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, 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.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: millerm@mail.nih.gov

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.

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 ADSP.

Research Strategy: The applicant(s) should present an integrated plan that will be responsive and flexible regarding the evolving needs of the scientific community and especially the ADSP and other major AD genetics projects. The applicant(s) should provide a rationale for selection of study subjects, and the approach and rationale for selection of sequencing methodology to be done in the study. Plans for documentation of key procedures and work flow should be included. The applicants should explain how cost savings have allowed the acquisition of additional samples for sequencing and how the augmentation of the number of samples in ethnic groups affects power calculations for detecting risk and protective genes for AD. 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 and Alzheimer's disease-related dementias. Describe the strategy for effectively carrying out each specific aim. Explain how this component of the ADSP FUS will interface with the existing units of the ADSP, what collaborative interactions will be established, and the type of advisory committee that will be engaged. Show how the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic material and related clinical data, GWAS data, WGS data, and QC'd and variant called data will facilitate the ADSP as a whole and other research in AD 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, augmented sample number accrued under this FOA, approaches or methodologies, or interventions used in the ADSP FUS 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 ADSP Follow-Up Study 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. Explain any innovative approaches for sample and data acquisition, WGS, QC or variant calling, and data handling for QC'd datasets.

Approach

For studies that include sequencing of additional subjects:

Applicants should describe a comprehensive plan to address the vital need for well-coordinated acquisition and handling of DNA and related clinical data, GWAS data, and WGS data from a large number of affected individuals from existing sample sets. The applicant(s) should provide a rationale for selection of new cohorts of subjects affected with AD, in particular minority cohorts. For newly organized cohorts, provide the rationale for the selection of the sample set, define methods for cognitive testing and adjudication, and provide power calculations to confirm the feasibility of inclusion of the cohort. Provide the rationale and power calculations for inclusion of controls where ethnically diverse cohorts are to be engaged. 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, evaluation, ascertainment, sample collection, WGS, QC, variant calling, and data sharing for individuals affected with AD, consistent with achieving the goals of this program.

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, and the methods used for sample acquisition and handling and WGS, QC, variant calling, and data sharing. Explain the plan to obtain informed consent for newly identified subjects. Explain the approach and rationale for selection of genotyping and sequencing methodology to be used in the study.

For more limited studies that include only quality control checking, data harmonization, and data sharing:

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, QC, variant calling, and data sharing consistent with achieving the goals of this program. Applicants should describe the methods used for sample acquisition and handling and WGS, QC, variant calling, and data sharing.

Whether the proposed study includes sequencing and sample/data management or just QC, data harmonization, and data sharing, the application should 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. Describe how the proposed study will ensure the collection, storage, and sharing of data and augment the existing ADSP analyses as appropriate and consistent with achieving the goals of the program. Explain how this component of the ADSP FUS study will facilitate the mission of the ADSP, and how the ADSP FUS applicants 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 proposed approach is feasible, how particularly risky aspects will be managed and how the ADSP FUS 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. Define milestones and a time line for key events for the project.

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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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 the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated 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 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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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?

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.

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 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 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:

• 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.

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 Council 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.

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 Parts 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.

Each revision made under this FOA will be subject to the same terms and conditions specified for the original U01 award. Applicants should consult the Notice of Award for their current U01 for the specifics of those terms and conditions.

The PD(s)/PI(s) will have 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); the 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 PAR-12-183; the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54) (RFA-AG-16-001); the Alzheimer's Disease Sequencing Project (ADSP) Replication Phase Analysis Studies (U01) (RFA-AG-16-002); and other NIA funded investigators.

The ADSP FUS 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. Insofar as is possible, the existing ADSP external consultants will provide membership to the ADSP FUS. Consultants will be selected as individuals who are not involved in AD genetics research but who could advise the awardees with an emphasis on sequencing and genotyping approaches, population diversity, sample banking, and biomarkers for AD. The external 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.

The PD/PI(s) of the cooperative agreement will be involved in collaborations with the ADSP, NIAGADS, dbGaP, 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, https://www.nia.nih.gov/research/adc), 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 Genome Center for Alzheimer's Disease (GCAD) 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/are 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 ADSP FUS 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, lead ADSP FUS Program Director(s), in consultation with the NIA Project Scientist, will be members of an Executive Committee for internal decision making. Insofar as is possible, the existing ADSP Discovery Phase Executive Committee will provide membership to the ADSP FUS. The Executive Committee will hold meetings and conference calls to facilitate development and implementation of common measures, policies, and practices. The ADSP Executive Committee will define the rules regarding access to, and publication of, findings from analyses of NIA LOAD FBS samples and related data. 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 ADSP FUS staff may attend the Executive Committee Meetings as needed. As needed members of the Executive Committee for NIAGADS may 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.

Dispute Resolution:

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

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and 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)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: millerm@mail.nih.gov

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: ramesh.vemuri@nih.gov

Jillian Morris
National Institute on Aging (NIA)
Telephone: 301-496-8986
Email: morrisjil@mail.nih.gov

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.