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

This funding opportunity announcement (FOA) is issued in response to a Presidential initiative on Alzheimer's disease (AD) called the Alzheimer's Disease Sequencing Project (ADSP). The overarching goals of the 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 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 samples for the ADSP were selected from well-characterized, ethnically diverse study cohorts of individuals both with and without an AD diagnosis as well as with and without known risk-factor genes.

The ADSP Discovery Phase has identified a number of variations in the genomes of individuals affected with AD. These findings will be pursued in the next phase of the study, called the ADSP Follow-Up Study (FUS). The long-term goals of the ADSP FUS are: (1) to move the field closer to enabling prediction of who will develop AD; (2) to fully reveal the genetic architecture of AD in multiple ethnic groups; (3) to better understand the underpinnings of AD pathogenesis; and (4) to aid the quest for therapeutic targets. The ADSP Discovery Phase and the ADSP Follow-Up Study are described under PAR-16-406 and at the ASDP study description website.

NIA intends to support studies most likely to meet a major goal of this FOA: to identify and confirm a full set of rare variants contributing to AD phenotypes to enhance the probability of identifying potential therapeutic approaches for risk and prevention. Successful applications are anticipated to involve research conducted by multidisciplinary teams of investigators, and should describe a comprehensive plan to develop leading-edge innovative approaches for the analysis of Whole Genome Sequence (WGS) data. Analysis should encompass the criteria set out by the ADSP Replication Work group for selection of samples under PAR 16-406. In particular, these criteria include racial/ethnic diversity; autopsy-confirmed cases/controls, especially for non-European ancestry; availability of longitudinal data; no age limit for cases; cases unrelated to each other; and availability of comparable controls.

The proposed study should describe a comprehensive plan for the analysis of WGS data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Both fundamental scientific discovery and leading-edge analytical approaches will likely be needed to achieve the research goals. The study is anticipated to involve research conducted by multidisciplinary teams of investigators including a variety of sequencing centers, geneticists, and statisticians. Funds for computer software and hardware, for bioinformatics and statistical analysis, and for the personnel needed to conduct the analyses will be provided.

PD(s)/ PI(s) funded through this FOA will obtain from the NIA-approved data repository: (1) cleaned, quality-checked sequencing data; (2) information on the composition of the study cohorts (e.g. case-control, family-based, and epidemiology cohorts); (3) descriptions of the study cohorts included in the analysis; (4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures; and (5) epidemiological information such as educational level and certain environmental data available on the subjects genotyped. Examples of the expected types of analytical assessments to be accomplished include: gene discovery, association analysis, read mappings, variant frequencies, quality-control information, coding sites, non-coding sites, splice sites for affected genes, functional annotation, protective variant, and confirmatory studies. These factors are important for understanding the genomic architecture of AD and should be considered in the experimental design.

Given finite availability of funding and time constraints for the ADSP FUS, NIA will support the analysis of genome-wide association study (GWAS) and sequence data for the whole genomes of up to 10,000 AD cases and an equal number of unaffected individuals under this FOA. Applicants for the sequencing component of the ADSP Follow-Up Study under PAR-16-406 are proposing to sequence selected study cohorts at selected sequencing centers. Applicants under the present FOA may propose to analyze either the entire dataset (cases and controls and family-based data) generated under the ADSP FUS PAR-16-406, or only the component that they themselves proposed be sequenced under PAR-16-406. Justification for the choice of the approach must be provided. Applicants proposing to analyze only a component of the total cohort (i.e. selected cohorts or ethnic subpopulations) should propose power calculations that support the likelihood of gene discovery. Applicants should design plans that clearly define which datasets, ethnic subpopulations, and/or endophenotypes that are part of the ADSP Follow-Up Study will be analyzed. The design and use of large-scale storage capacity with appropriate security and backup measures to support analytical capabilities should be considered.

This effort will pursue rare variants as comprehensively as possible, including consideration of statistical power and exploration of different populations containing those that are currently underrepresented in sequencing studies. An important goal of this project is to take advantage of the ethnic diversity represented in the samples collected for the sequencing project. Analysis of data from samples from different ethnic groups, especially those of non-European ancestry, are a significant element of this FOA, as certain risk or protective variants may be easier to detect in some populations, and therapeutic approaches to the disease may thereby differ. A major effort to include large cohorts of ethnically diverse cohorts is underway under PAR-15-356, PAR-16-406, and PAR-17-054. Variants occur at different frequencies in different populations and certain risk variants may be much easier to detect in some populations.

Under the present FOA the ADSP will improve the likelihood of analyzing sequence data on enough different examples of events that change the genetic architecture of AD such that these data, when analyzed with existing datasets, will enhance the ability to better understand the genetic underpinnings of AD and to obtain a better understanding of rare risk and protective variants. The availability of high-quality, extensive phenotypic information on subjects is a critical consideration. Study design should include analysis of data from samples from subjects with quantitative trait measures to more clearly define endophenotypes. Similarly, subjects whose data will be used as controls should be well characterized.

The development of computational sequence analysis methods for the purposes of improved, more efficient analysis of the data towards the goals of this initiative and the potential to collaborate with other investigators to pursue more functional follow-up studies to enhance analysis and/or validate findings may be considered in the application. The capability to bring to bear other technologies that are used in genomic analysis, and which could be directly relevant to disease variant analyses, may also be included. These could include, for example, genotyping, or production and integration of other data modalities that can readily be generated with genome sequencing platforms (e.g., transcriptomes and epigenomes) and that are directly relevant to understanding the role of variation in common disease.

Much more work is needed on developing analysis methods and resources to understand the functional significance of variants, particularly noncoding variants. Investigators should design analysis plans to inform the underlying molecular networks of AD. Approaches to this analysis should begin to deconstruct the interactions among genes, understand the driving or causal genes in a single network, and identify the interactions of genes among networks that may result in dysregulation of gene function. Sequence variants that implicate sets of genes underlying an associated phenotype provide some insight into the biology of disease, but this is inconclusive without further experimental functional validation. As resources that catalog gene and genome function grow over time, the ability to make functional inferences based on variant association data will improve. There is likely to be value in encouraging connections between variant discovery and improvement of functional validation. Analysis of functional inferences is a key component of this FOA in order to gain a systems-level understanding of the gene, protein, and metabolic networks within which these novel targets operate.

The successful ADSP applicant(s) would consist of a group of researchers with expertise in the genetics of complex neurological diseases, including AD, and the field of whole exome/genome sequencing, as well as statisticians and other experts who will participate in study design and analysis. Successful applicant(s) may be expected to collaborate not only within their own study, but also with other PD(s)/PI(s) funded under this FOA, together with the sequencing centers funded under PAR-16-406 and the NIA. Engagement of existing NIA-supported infrastructure is considered essential to the success of the project, so applicants should plan to financially support NIAGAD, NCRAD, and the Genome Center for Alzheimer's Disease (GCAD) for their efforts in the ADSP.

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, leveraging existing NIA funded resources. Both the project itself and the ADSP should benefit from unique features of the scientific environment, subject populations, or collaborative arrangements. It is expected that applicants will have the capacity to analyze GWAS and whole-genome sequence data from up to 10,000 affected and 10,000 unaffected individuals for identification and follow-up of genetic variants for the ADSP.

Applicants should develop key quantitative milestones with a timeline for accomplishment. Quality control (QC) and data harmonization will be performed by GCAD. The order and process for data transfer, quality control checking, and data harmonization will be agreed upon by the ADSP as a whole and will follow closely the existing paradigm.

Applications considered for funding must effectively leverage NIA and NIH investment in infrastructure to support studies related to the genetics of Alzheimer’s disease. The investigators funded under this FOA may utilize information from existing NIA- and NIH-funded research resources such as:

• The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS)
• The NIA Genomic Center for Alzheimer's Disease (GCAD)
• The National Cell Repository for Alzheimer's Disease (NCRAD)
• The National Alzheimer's Coordinating Center (NACC)
• The Database of Genotypes and Phenotypes (dbGaP)
• The Alzheimer's Disease Genetics Consortium (ADGC)
• The Alzheimer's Disease Centers (ADCs)
• Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
• The Alzheimer's Disease Neuroimaging Initiative (ADNI)
• The National Alzheimer’s Project Act (NAPA) and the related milestones
• Information relevant to Alzheimer's Disease Related Dementias (ADRD)
• Other websites designed to store and distribute data related to AD

The PD(s)/PI(s) is/are expected to optimize accessibility and usefulness of the information generated by the study and to provide data to the AD research community through an NIA-approved data storage site. NIA has issued a sharing policy specific to the genetics and genomics of Alzheimer's disease to which investigators will be expected to adhere; outcome data from the study will be deposited into dbGaP and NIAGADS or another NIA-approved data storage site for access by the AD research community. In addition, outreach efforts should be undertaken to maximize data sharing in order to enhance AD research; for example, the AD research community may be contacted via a list serve, or a website may be used to provide information about the study.

NIA expects that this element of the ADSP will need to be highly collaborative among AD geneticists funded under: (1) PAR-12-183, RFA-AG-16-002, PAR-15-356, RFA-AG-17-054 and under other individual NIA grants and cooperative agreements; (2) NCRAD investigators funded under PAR-15-316; (3) the National Alzheimer’s Coordinating Center (NACC) funded under PAR-11-213; (4) investigators funded by NHGRI under RFA-HG-15-001; (5) NIAGADS funded under PAR-16-047; and (6) The NIA Genomic Center for Alzheimer's Disease (GCAD) funded under RFA-AG-16-001.

In summary, a large amount of sequence data will be generated under PAR-16-406 for the examination and comparison of the genomes of affected and unaffected individuals. The analyses of these data (up to 10,000 affected and 10,000 unaffected subjects) under the present FOA to be done by the successful applicant(s) will identify new genes 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 this study will become available to qualified investigators 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 in response to this FOA.

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Only PD/PIs, key personnel, and collaborators supported under ADSP-related PAR-12-183, PAR-14-070, RFA-AG-16-001, RFA-AG-16-002, and PAR-16-406 may be PDs/PIs of applications for this Limited Competition FOA.

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Fax: 301-496-1494
Email: millerm@nia.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. For sample and data acquisition, the PD(s)/PI(s) should document a deep understanding of the genetics of AD and the operations of the ADSP. The PD(s)/PI(s) should demonstrate accomplishment in effectively analyzing data from subjects from diverse populations and have expertise in the genetics of complex diseases, population genetics, bioinformatics, and statistics in order to discover risk and protective genetics factors for AD.

It is expected that key personnel will have appropriate clinical experience and training for analysis and management of whole-genome, GWAS, and clinical data related to existing epidemiological, case/control, family-based, and other sample sets from a variety of ethnic groups where AD is the underlying form of dementia. Key personnel should also have expertise in the following areas:

• The analysis of GWAS and WGS data and the handling and analysis of genetic, clinical, population substructure, and endophenotypic data related to complex diseases including especially AD.
• Archiving, processing and distributing genotypic, genomic, and phenotypic data and samples used for genetic analysis.
• The 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.
• Managing data generated by a large-scale sequencing project including appropriate QC measures.
• Harmonization of data from diverse sample sets, ethnically diverse populations, and a variety of sequencing platforms on a large scale used for WGS data.
• Coordinating collaborative basic or clinical research and data handling.
• Managing a large data repository that can store analysis data for genetic and biomarker analysis.
• Coordinating the deposition of data to an NIA-approved data repository, including phenotypes from newly recruited individuals, and any related genotype data to an NIA-approved database.
• A record of collaboration with NIA-funded AD investigators.

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 data. The applicant(s) should have experience overseeing selection and management of sub-awards, if needed.

All instructions in the SF424 (R&R) Application Guide must be followed. Applications should fully describe the projected funding requirements. Funds to perform the following operations for coordination of ADSP data analysis should be an aspect of the budget:

• Request and obtain the WGS data generated by the participating ADSP sequencing center(s) funded under RFA-AG-16-406.
• Request and obtain WGS data from up to 10,000 unaffected individuals from existing large-scale sequencing projects.
• Fully analyze the QC'd/harmonized data obtained from GCAD for variations in the AD genome.
• Coordinate activities with contributing study/studies and site(s) in accordance with existing ADSP infrastructure where GCAD will perform quality control and data harmonization steps.
• Coordinate with other contributing studies/sites for data transfer to and from GCAD.
• Ensure that data are provided to GCAD in an ADSP-agreed-upon format.
• Ensure that data are shared with the research community via an NIA-approved database at the time that QC checks are complete, consistent with achieving the goals of the program.

Subcontracts to one or more sequencing centers funded under PAR-16-406, NCRAD, NIAGADS, and GCAD must be provided. The budget may include support for the formation of groups of investigators at several institutions to assemble a team with the appropriate balance, breadth, and experience.

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. Describe the organization and operational procedures of the collaborative research including the use of established infrastructure and how the expertise of the members will be integrated and applied to complete the analysis of WGS data derived from up to 10,000 ethnically diverse samples and up to 10,000 unaffected individuals. Describe the processes, analytical approaches, and resources that will be used to identify and validate rare variations in the genomes of 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: Present an integrated plan for analysis of GWAS and WGS data for up to 10,000 subjects affected with AD and up to 10,000 unaffected individuals. If proposing to analyze only a component of the total data, provide justification and power calculations that support the likelihood of gene discovery. Provide a rationale for selection of analytical, statistical, and bioinformatic approaches. Include documentation of plans for key procedures, work flow, and relevant timelines. Specify the contributions of individual key personnel. Describe the strategy for effectively carrying out each specific aim. Explain how the analysis of WGS data from the ADSP FUS will interface with the existing components (Discovery, Discovery Extension [family-based and case-control], Follow-Up Study) 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, coordinate receipt of, store, process, and distribute genetic data 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. Provide a clear data flow plan that assures QC'd and variant-called data using the established ADSP pipeline are analyzed, shared widely with the research community through NIAGADs/dbGaP as appropriate and consistent with achieving the goals of the program, and provided to GCAD for harmonization meta-analysis with the rest of the ADSP data.

Fully describe: (1) the analytical approaches to identify genetic risk and protective factors for AD (a variety of approaches may be employed); and (2) the qualities and characteristics of the genomic sequence analysis information to be produced by the investigator. Include a timeline for accomplishing the stated goals. Limited amounts of DNA may be re-sequenced, for example, to validate findings. Examples of the expected types of analytical assessments to be accomplished include: gene discovery, association analysis, read mappings, variant frequencies, quality control information, coding sites, non-coding sites, functional annotation, and splice sites for affected genes.

Describe analysis methods for associating variants with specific endophenotypes to determine whether genetic subgroups can be identified that will point toward specific therapeutic approaches for the disease. Include consideration of power and sample number; phenotypes and endophenotypes; disease sub-groups and extremes; power calculations for gene discovery of risk and protective factors; and justification for inclusion of unaffected individuals in ethnic cohorts. Describe the capabilities for sequence data storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms. In the description of the data analyses, address disease-related covariates, population substructure, and significance of association with the disease for common, rare, and unique sequences. Describe how structural rearrangements, insertions, deletions, and haplotypes as genomic changes will be analyzed and correlated with changes in gene function and disease status.

Design plans that clearly define which datasets, ethnic subpopulations, and/or endophenotypes that are part of the ADSP Follow-Up Study will be analyzed, keeping in mind that meta-analysis will be performed by GCAD. Include a description of the design and use of large-scale storage capacity with appropriate security and backup measures to support analytical capabilities. Analysis plans to include existing ADSP genetic and phenotypic data are expected. The approach to analysis should follow the ADSP Replication Work Group criteria.

Include an explanation of how the existing components of the ADSP will be engaged in the ADSP FUS, including:

(1) the structure of the existing ADSP including any new projects or subprojects;

(2) the external board of consultants that draws upon the expertise of the existing board;

(3) the Executive Committee comprised of signatories of the ADSP Memorandum of Understanding (MOU);

(4) the Analysis Coordination Group comprised of key members of ADSP Work Groups to oversee the normal operations of the consortium;

(5) the individual Work Groups responsible for various components of data analysis (e.g. Family-Based Analysis, Case-Control Analysis, Structural Variant Analysis, Phenotypes, Annotation, Protective Variants, Data Flow, and Replication);

(6) the committee that reviews material in advance of presentation at national or international meetings and before publication in peer-reviewed journals; and

(7) the committee that reviews and approves applications from within the ADSP for secondary data analysis.

Elaborate key quantitative milestones with a timeline for accomplishment. Data should be QC'd/harmonized using the infrastructure, platform, pipeline(s), and HG build that the ADSP employs at the time of award.

Innovation: Explain how refinement, improvement, or new application of theoretical concepts, analytical approaches or methodologies, instrumentation, or interventions proposed are novel to the field of AD research. 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, bioinformatics, analytical approaches, or instrumentation that will be employed in the research. Explain how the ADSP Follow-Up Study will advance and augment the development of novel therapeutics for AD.

Approach: The approach to the analysis should follow the ADSP Replication Work Group criteria. Explain how the ADSP Follow Up Study will facilitate the mission of the ADSP, and how applicants will work cooperatively with the ADSP as a whole. Describe the organization, data sharing as appropriate and consistent with achieving the goals of the program, and operational procedures of the collaborative research infrastructure, as well as the expertise of the members, and explain how these will be integrated and applied to the study consistent with achieving the goals of this program. Explain how the study will coordinate activities with other analysis projects funded under the present FOA. Explain the approach and rationale for selection of data to be used in the study. Plans for documentation of key procedures should be included. State plans to participate actively in data exchange and to collaborate with other investigators in the ADSP, other awardees of this FOA, and with awardee(s) of other NIA grants and cooperative agreements in order to enhance the likelihood of identifying therapeutic targets for AD.

For minority cohorts and for newly organized cohorts, provide the approach for data analysis that can integrate outcomes of cognitive testing and adjudication into existing data. Provide power calculations to confirm the feasibility of inclusion of the selected cohorts in the analysis plan.

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, 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 the instructions for post-submission materials, as described 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? Will the proposed work identify genetic risk to AD through comprehensive analyses of existing genetic and genomic data sets? Are the plans sufficiently bold to constitute a substantial advance in the ability to analyze whole-genome sequencing, genotypic and phenotypic data? Does the proposed work have the potential to define and refine AD phenotypes? Does the proposed work use an approach that will aid the discovery of changes in gene function that may impact the expression of endophenotypes? If the aims of the project are achieved, is a new therapeutic approach for AD a likely outcome? Does the proposed work have a strong likelihood of revealing the structure of the genome of subjects with AD? For the overall application, does the organization integrate the activities and add value to the individual parts?

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? How experienced are the key personnel in handling study-related AD genomic, genotypic, and phenotype data? How appropriate are the experience and training of the key personnel for analysis of ethnically diverse cohorts? How appropriate is their record of accomplishments in effectively managing whole genome sequence and genotypic data from large sample sets like the ADSP FUS? How experienced is/are the applicant(s) in handling datasets for complex diseases? How appropriate is their experience with coordinating collaborative research? How appropriate are the leadership approach, governance, organizational structure for the ADSP FUS, and plans for conflict resolution? Do the PD(s)/PI(s) have enough experience overseeing selection and management of sub-awards? Do the PD(s)/PI(s) and staff have sufficient experience and training for management of largescale genetic and phenotypic data acquisition with expertise in curation and distribution of large data sets including: pedigrees, genetic, genomic, and phenotypic data relevant to genetic analysis, clinical and neuropathology data elements, sequence data and related data? How adequate are the key personnel’s experience and ongoing record of accomplishments in effectively managing data handling to discover risk and protective genetic factors for AD? Does the applicant(s) have a demonstrated record of analyzing large volumes of WGS data; have a record of collaboration with NIA-funded AD investigators; have a strong working knowledge of the activities of the ADSP; and have a record of participation in genetics analysis of complex diseases?

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? For the overall project, will new statistical approaches or other analytical methods be developed that can be applied to the genetics of complex disease? Are novel approaches to integrating the analysis of genome wide association study data, and whole genome sequence data employed? Will novel approaches to analyzing intergenic regions of the genome be developed? Will functional genomics be applied to the data in such a way as to reveal how genes and gene sets interact? Are there innovative strategies for analysis of existing genomic data sets that will lead to the development of new paradigms for analyzing genotype-phenotype relationship in AD research? Does the proposed work lead to the development of innovative bioinformatics approaches or novel computational tools to analyze and interpret multiple high-throughput genomic data sets? How innovative are approaches for QC or variant calling and data handling for QC'd datasets?

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?

For the overall project, how well will the study be integrated? How successful is the approach to analyzing up to 10,000 whole genomes from affected individuals and 10,000 whole genomes from unaffected individuals likely to be? If applicants are proposing to analyze only a component of the total cohort, do they provide appropriate justification and power calculations that support the likelihood of gene discovery? How well reasoned are the operational plans and organizational structure? Will data be readily available to ADSP members and GCAD for harmonization with the rest of the ADSP data? Does the applicant explain how the study will coordinate activities with other analysis projects funded under the present FOA? Are plans to collaborate with ADSP investigators funded under this and related awards forthcoming so as to contribute substantially to advancement of the field? Are plans to participate actively and openly in data sharing sufficiently clear? Does the approach clearly define which cases and controls in selected datasets/ethnic subpopulations/endophenotypes will be analyzed? Is the approach to the analysis of sequencing data well developed and well-informed, relative to the state of the technology? Are key scientific or technological challenges on which the rest of the approach depends identified and addressed early in the project? Does the proposed technology address analysis of sequence quality and the sequencing of entire genomes? Are bold plans counterbalanced to manage the inherent risk, for example by firm theoretical basis, reasonable preliminary data (depending on the mechanism), the track record of the lead investigators, and an outstanding scientific and management plan? Are the timeline and milestones logical and realistic? Are key technical barriers and dependencies identified? Are milestones adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NIA? How well will the study integrate discoveries made in other phases of the project (Discovery and Discovery Extension Phases)? How closely does the research plan follow the ADSP Replication Work Group recommendations for study priorities?

How comprehensive is the plan to address the need for well-coordinated acquisition and handling of genomic, genotypic, and related clinical data from a large number of affected and unaffected individuals from existing data sets? How well will expertise of the members be integrated and applied to complete planning and execution of the study? How likely to be successful are the overall scientific goals and the expected outcomes? How likely to be successful is the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic and related clinical data, GWAS data, WGS data, QC'd data, and variant-called data? How likely is it that analytic approaches used on data from diverse populations will reveal new AD risk and protective genetic factors? How appropriate and statistically well powered is the plan to study controls in the case of diversity population or epidemiology sample sets? How well will the proposed strategy maintain the continuity of the existing study? How well will the proposed ADSP FUS assist the research community and NIA in achieving the goals of the Alzheimer's disease research programs it proposes to serve?

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? How adequate 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 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 appropriate national Advisory Council or Board. 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 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; NIH 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, as well as 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 PAR-12-183, the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54), the Alzheimer's Disease Sequencing Project (ADSP) Replication Phase Analysis Studies (U01), 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 that engages existing representation 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, 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), the Consortium for Alzheimer's Sequence Analysis (CASA), the Alzheimer's Disease Centers (ADC), the National Cell Repository on Alzheimer's Disease (NCRAD), the National Alzheimer's Coordinating Center (NACC), and the NIA Genetics and Genomics 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 will be convened, and it will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9666
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.