Department of Health and Human Services

Part 1. Overview Information

Key Dates

Required Application Instructions

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

Table of Contents

1. Part 1. Overview Information
2. Part 2. Full Text of the Announcement
   1. Section I. Funding Opportunity Description
   2. Section II. Award Information
   3. Section III. Eligibility Information
   4. Section IV. Application and Submission Information
   5. Section V. Application Review Informatio
   6. Section VI. Award Administration Information
   7. Section VII. Agency Contacts
   8. Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

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 https://www.niagads.org/adsp/content/home ). 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 ADSP research plan includes a Discovery Phase and a Replication Phase. The ADSP research plan can be found at: https://www.niagads.org/sites/all/public_files/ADSP%20%20SUMMARY%20PLAN%20revised%20fnl%2041513.pdf . This Funding Opportunity Announcement (FOA)

is intended to provide funding for: (1) genome wide association studies (GWAS) of subjects to be included in the Replication Phase of the study, (2) targeted sequencing of signals in regions containing variants identified in the ADSP Discovery Phase, (3) analysis of Replication Phase targeted sequence and genotype data that are provided by the Large Scale Sequencing and Analysis Centers (LSACs), and those data provided under awards to the companion FOA, RFA-AG-16-001, entitled "NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54)" and/or those provided by other through related datasets. Together these cooperative agreements will generate Replication Phase data and provide analysis of a variety of types of data that will be generated in the Replication Phase of the ADSP.

The ADSP Discovery Phase samples were selected from well-characterized, ethnically diverse study cohorts of individuals with or without an AD diagnosis and the presence or absence of known risk factor genes. Details about the samples are available at the NIA Genetics of Alzheimer's Disease Data Storage Site: https://www.niagads.org/adsp/ . The ADSP generated three sets of genome sequence data for these samples as part of the Discovery Phase: (1) Whole Genome Sequencing Study (WGS) for 583 samples from 111 multiplex families, (2) Whole Exome Sequence (WES) for 5,000 AD cases and 5,000 controls, and (3) WES of an Enriched sample set comprised of 1,000 AD cases from multiply affected families. Most of these sequence data are already available; all data are expected to be released to the Database for Genotypes and Phenotypes (dbGaP http://www.ncbi.nlm.nih.gov/gap ) by fall 2014.

As part of the Discovery Phase, the ADSP is conducting analysis of the sequence data, including quality assessments and variant calling. These activities are ongoing. Application for these data can be made at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000572.v1.p1 . Applicants can obtain: (1) cleaned, quality control checked sequence 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 demographic data available on the subjects genotyped.

NIA has provided funding for the analysis of Discovery Phase ADSP data through cooperative agreements under http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html . Much of this activity is taking place as part of the ADSP. In addition, investigators who are outside of the ADSP are encouraged to access and analyze these data. Analysis of the Discovery Phase sequence data is anticipated to identify many new sequence variants that may be implicated as new genetic risk and protective factors in older adults at risk for AD. ADSP sequence and phenotypic data are made available rapidly after generation. In keeping with the Bermuda Principles, the Ft. Lauderdale accord, and the ADSP MOU https://www.niagads.org/sites/all/public_files/ADSP%20MOU%2012%2012%2012%20final.pdf ,

ADSP phenotype and sequence data are made available to the research community at large immediately after quality control checks and variant calls are completed. In the spirit of the clear benefit that ensues from converting such data sets into community resources as rapidly as possible, and in keeping with community expectations for the use of unpublished genome sequence data, it is expected for the Discovery Phase that users of the ADSP data will withhold publication until the producers of the data have published their findings. ADSP participants will publish their data in an expeditious fashion at least one major paper reporting the results of the ADSP to be jointly submitted by all of the members.

The Replication Phase will include up to 50,000 subjects to maximize the number of confirmed AD loci. The overall objective of the Replication Phase is to generate and analyze data from ~40,000 European-ancestry subjects (~20,000 cases /~20,000 controls) who are well phenotyped and appropriately consented. In addition, ~10,000 (~5,000 cases/ ~5,000 controls) samples from other ethnic groups will be included to validate and confirm findings. Samples for the Replication Phase are expected to be available for sequencing and data analysis beginning in calendar year 2015.

The NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (CGAD) (U54) FOA, RFA-AG-16-001, will fund analysis, coordination, and certain data generation costs for a portion of the next component of the ADSP. Funds for sample acquisition are provided under separate auspices. Genome sequence data (e.g. targeted sequencing) that will be required for the Replication Phase will be provided through the NHGRI Large Scale Sequencing and Analysis Centers (LSACs) under existing funding. Funding for well-justified additional targeted sequencing and genotyping costs will be provided under this FOA.

It is anticipated that in the Replication Phase, the ADSP will examine a subset of genes/regions/loci implicated in the Discovery Phase. Relevant lists will be made available at: https://www.niagads.org/adsp/ . Applications to this FOA are related to the genotyping, targeted sequencing, and data analysis for genes/regions/loci of interest across multiple ADSP study sites. Applicants are invited from both current ADSP members and members of the research community at large. In addition, this FOA provides the opportunity to apply for NIA funding to carry out a number of components and tasks needed in the Replication Phase of the ADSP that are not otherwise provided under other award mechanisms.

The likely elements of the Replication Phase as a whole are described in the companion RFA, RFA-AG-16-001.

Studies funded under the present FOA involve a subset of the full Replication Phase work and include:

• Genotyping: (1) Genome wide association study (GWAS) of samples from subjects who are well phenotyped but have not yet been genotyped; (2) GWAS for rare variants found at higher frequency in Hispanic families or other datasets included in the Discovery phase, but not yet genotyped; (3) GWAS of family members of subjects sequenced in the Enriched sample set of the Discovery Phase in order to assess segregation of variants with the disease; (4) GWAS of family members that may carry a specific variant; (5) GWAS of samples where essential to the study design and analysis of the ADSP Replication Phase.
• Genotyping by custom chip of genes/regions/loci where the association with late onset Alzheimer's Disease appears attributable to common, low frequency, or rare variants.
• Targeted sequencing: Genome sequencing of signals in regions containing variants identified in the ADSP WES and WGS data that will be required for the Replication Phase and that are not already provided through the NHGRI LSACs.

• Analysis of Replication Phase targeted sequence and genotype data that are provided by the LSACs, and those data provided under the present award and/or those provided by other studies with related datasets. Replication phase analysis plans are expected to be in keeping with what has been proposed by the ADSP as a whole.
• Development of additional analytical approaches to Replication studies for discovery of therapeutic targets such as bioinformatics, biophysical modeling, and biological assays.
• Acquisition of samples; adjudication of AD diagnoses for subjects in these cohorts, and longitudinal follow up for well justified high value cohorts.
• Strategic plans to work collaboratively with the CGAD and the ADSP as a whole.

Studies funded under this FOA will provide data to the Center for Genetics and Genomics of AD (CGAD) funded under the companion FOA, RFA-AG-16-001, "NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54)" (CGAD), for data harmonization and analysis of aggregated ADSP data. Please see the companion FOA for specific information. Applicants for this FOA may also apply for the companion FOA, RFA-AG-16-001.

NIA is particularly interested in applications that include the means to more rapidly replicate or validate those variants most likely to lead to the rapid identification of therapeutic targets as indicated in the initial design of the Discovery Phase that sought identification of both protective and risk alleles. For example, there are reasons to believe that loss of function protective alleles may be good candidates for therapeutic targets. Approaches within the context of the Replication Phase plan that maximize the likelihood of success in identifying protective alleles and therapeutic targets will be considered within the scope of this FOA.

NIA wishes to maximize the potential of team science efforts to achieve the programmatic goals of this funding opportunity. NIA recently issued an FOA entitled, "Interdisciplinary Approach to Identification and Validation of Novel Therapeutic Targets for Alzheimer's Disease", http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-13-013.html . Studies funded under this FOA focus on the identification and validation of novel therapeutic targets within molecular networks involved in AD pathogenesis that can be pinpointed using genetic approaches. Collaborations with awardees of RFA-AG-13-013 are strongly encouraged. The list of awardees can be found in the NIH Reporter: http://projectreporter.nih.gov/reporter.cfm .

NIA wishes to maximize opportunities for leveraging resources. As for the ADSP Discovery Phase, consistent with achieving the goals of this program, rapid sharing of data with the research community in keeping with existing ADSP MOU and sharing agreements and in accord with NIA sharing policies and data distribution policies is expected.

The ultimate aim of this FOA is to identify the genomic contributions to both risk for AD and protection against AD, and the correlations between human genetic variation and the relationship to health and disease. Under the award, the investigator(s) will generate Replication phase data and lead comprehensive analyses of the targeted sequence data along with genotype data to replicate and validate data generated in the Discovery Phase of the ADSP and provide these data to the awardees of the companion FOA for harmonization and joint/meta-analysis of ADSP data as a whole. Both fundamental scientific discovery and leading edge analytical approaches will likely be needed to achieve the research goals. Therefore awards funded under this FOA are anticipated to involve research conducted by multidisciplinary teams of investigators. Applications will be evaluated and funded based on the strongest potential to identify and confirm novel genetic markers for AD using comprehensive analytical approaches.

It is expected that the study will result in the confirmation of AD risk and protective alleles in Caucasian and multi-ethnic populations that may serve as therapeutic targets. Consistent with achieving the goals of this program, awardees under this FOA are expected to: (1) provide imputed and targeted sequence and/or genotype data derived from existing WES and/or WGS sequence data for rapid sharing with the scientific community through the NIAGADS/dbGap database https://www.niagads.org/adsp/content/home for analysis by the scientific community at large; (2) provide these data to the CGAD funded under the companion FOA (see RFA-AG-16-001) for joint analysis and data harmonization; and (3) receive analyzed data from the CGAD for follow up assessments; the CGAD will notify awardees of this FOA as new targets are identified.

Examples of the types of analytical assessments that are expected in order to provide a complete evaluation of the genomic contributions to risk and protection for AD include: identification of genes/regions/loci for confirmation/validation of gene discovery, association analysis, read mappings, structural variants, variant frequencies, quality control information, coding sites, non-coding sites, and splice sites for affected genes. Applicants may propose their own variant calling, especially if the need for variant calling for the disease is likely to extend beyond routine analysis or will require additional validation steps.

Data derived from multiple analyses of the Replication Phase data will be harmonized and joint/meta-analyzed at the CGAD with the aggregate ADSP data and made available for analysis by the AD research community through the ADSP NIAGADS/dbGaP database. Every effort should be made to engage the existing ADSP databases, i.e. the NIA Genetics of Alzheimer's Disease Data Storage Site https://www.niagads.org/ and dbGaP http://www.ncbi.nlm.nih.gov/gap , as key research resources for the effort. Creation of infrastructure that is redundant to that supported under the Discovery Phase which is funded through cooperative agreements under http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html or through the cooperative agreement that supports the NIA Genetics of Alzheimer's Disease Data Storage Site, https://www.niagads.org/adsp/ should be avoided.

Applicants are encouraged to devise analysis plans to include data from: genome wide association studies (GWAS) for AD (for example http://www.ncbi.nlm.nih.gov/pubmed/?term=Meta-analysis+of+74%2C046+individuals+identifies+11+new+susceptibility+loci+for+Alzheimer%E2%80%99s+disease ); whole exome and exome chip data (for example: http://www.ncbi.nlm.nih.gov/pubmed/24336208 ); and whole genome AD sequencing efforts (for example: http://www.nature.com/nature/journal/v488/n7409/full/nature11283.html ); and related genetic data including WGS, WES, and deep sequencing analyses generated on AD subjects in other existing studies.

The RPS may utilize information from existing NIA and NIH funded research resources such as:

• Alzheimer's Disease Sequencing Project (ADSP) https://www.niagads.org/adsp/
• NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS); https://www.niagads.org/
• Alzheimer's Disease Genetics Consortium (ADGC): http://alois.med.upenn.edu/adgc/
• Cohorts for Heart and Aging Research in Genomic Epidemiology" (CHARGE) Consortium: http://web.chargeconsortium.com/
• International Genomics of Alzheimer's Project (IGAP): http://www.alzheimersreadingroom.com/2011/02/international-genomics-of-alzheimers.html
• Alzheimer's Disease Neuroimaging Initiative (ADNI): http://adni.loni.ucla.edu/
• National Cell Repository for Alzheimer's Disease (NCRAD): http://ncrad.iu.edu/
• National Alzheimer's Coordinating Center (NACC): http://www.alz.washington.edu/
• Data Base of Genotypes and Phenotypes (dbGaP): http://www.ncbi.nlm.nih.gov/gap
• Alzheimer's Disease Research Centers (ADRCs): http://www.nia.nih.gov/alzheimers/alzheimers-disease-research-centers
• NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC): http://www.genome.gov/27546191
• Other organizations/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 CGAD, and the AD research community through an NIA-approved data-storage site. In keeping with the NIA Genetics of Alzheimer's Disease Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan , outcome data from the study will be deposited into the ADSP NIAGADS/dbGaP database https://www.niagads.org/adsp/

for access by the AD research community, as appropriate. In addition, outreach efforts should be undertaken to maximize data sharing in order to enhance research in AD; 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.

In summary, the ADSP has generated a large amount of sequence, annotation, and related data for the examination and comparison of the genomes of affected and unaffected individuals during the Discovery Phase of the project. Other research groups have generated similar data. During the ADSP Replication Phase, findings of the Discovery Phase and findings of other research groups will be confirmed. Successful applicant(s) for this FOA will generate sequence and/or genotype data, analyze these data, and will provide analyzed data to the CGAD for harmonization and analysis of aggregated ADSP Replication Phase data. Studies will 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 this study are expected to become available to qualified investigators to enable rapid identification of therapeutic targets.

Section II. Award Information

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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the "Apply for Grant Electronically" button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

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

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

Letter of Intent

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: 301-496-9350
Email: [email protected]

Page Limitations

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

Instructions for Application Submission

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed. Expertise in the field of Alzheimer's disease genetics is considered an essential aspect of the project. The successful applicant(s) for RPS funding should consist of a group of researchers with expertise in the capacity to generate and analyze large datasets including sequence and genotype data related to the genetics of complex neurological diseases and the field of whole genome /whole exome /targeted sequencing and genotyping statisticians and other experts who will participate in study design and analysis. Likewise capabilities in the complex bioinformatics and data storage of large and complex data sets must be clearly demonstrated.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed. The cooperative agreement will provide funds for the generation of data for Replication Phase studies; relevant data may be delivered through a number of NIH-funded studies as well as those funded through other organizations. Analysis costs may include computer software and hardware and bioinformatics and statistical analysis; and support for the personnel needed to conduct the analyses. 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.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Describe the aims of the overall project and outline how the project(s) will contribute to these aims.

Research Strategy:

1. Significance: Focusing on the RPS as a whole address: (i) the importance of the problem or critical barrier to progress in the field that the proposed project addresses, (ii) how the proposed project will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields, (iii) how the concepts, methods, technologies, or services that drive this field will be changed if the proposed aims are achieved, (iv) how the proposed project will identify new genes contributing to increased risk or protection of developing AD, (v) how the proposed project will constitute a substantial advance in analytical approaches for whole genome sequencing, exome sequencing, targeted sequencing, and/or genotyping and data harmonization for complex diseases, (vi) how collaborative efforts will enhance the field of AD genetics. Describe how the proposed work will identify novel genetic AD risk and protective factors for disease through comprehensive analyses of existing or newly generated genetic and genomic data sets. Describe how the proposed work will identify genetic risk to the disease through comprehensive analyses of existing or newly generated genetic and genomic data sets. Explain how the study will constitute a substantial advance in the ability to harmonize and analyze sequence and genotype data. Explain how the study will define and refine AD phenotypes. Explain how the work will enhance cooperation and collaboration in the ADSP. Delineate how a new therapeutic approach for AD will be an outcome of the study. Explain how the organization of the proposed studies will integrate with the activities of the ADSP and add value to the ADSP gene discovery mission. Explain how defining the structure of the genome of subjects with AD will advance the field. Define efforts to enhance cooperation and collaboration in the ADSP. Delineate how a new therapeutic approach for AD will be a likely study outcome. Explain how the proposed work will reveal the structure of the genome of subjects with AD. Explain how proposed studies will integrate with the activities of the ADSP and add value to the ADSP gene discovery mission.
2. Innovation: The applicant(s) should describe a comprehensive plan to develop leading edge innovative approaches for the analysis and that will provide a mechanism for rapid transfer of sequence and genotype data for the ADSP Replication Phase to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Explain how the proposed research seeks to shift current research or clinical practice paradigms through use of novel concepts, approaches, methodologies, instrumentation, or interventions. Explain how these concepts, approaches, methodologies, instrumentation, or interventions are novel to the research field or novel in a broad sense. Explain how the work will refine, improve, or apply in a new way, the concepts, approaches, methodologies, instrumentation, or interventions proposed. Delineate how the proposed project will provide insight as to why individuals with known risk factor genes escape from developing AD. Define how the proposed project will identify potential avenues for therapeutic approaches and prevention of the disease. For the overall project delineate any new statistical approaches or other analytical methods that will be developed that can be applied to the genetics of complex disease. Define any novel approaches to integrating the analysis of genotype data, exome sequencing data, whole genome sequencing data, and targeted sequencing data employed. Explain any novel approaches to analyzing intergenic regions of the genome that will result from the study. Define any 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. Define how the proposed work will lead to the development of innovative therapeutic approaches for AD. Define bioinformatics approaches, or novel computational tools to analyze and interpret multiple high-throughput genomic data sets.
3. Approach: Define the plan to: (1) identify and validate protective variants in older adults at risk for AD, (2) identify and validate new risk variants among AD cases with low genetic risk, (3) identify and validate new risk variants among AD cases with high genetic risk. Plans for examination of these factors in multi-ethnic populations in order to identify new pathways or targets for prevention must be well justified. Include the major approaches and studies involved in the application showing how the approaches complement each other or are inter-dependent. Describe the mechanisms that will ensure the coherence of the overall project and maintain a multidisciplinary focus.
   
   Define the analytical strategy and explain its feasibility. Provide well-reasoned and appropriate approaches, methodology, and analyses in order to accomplish the specific aims of the project. The application should describe the capabilities to distinguish between sequencing errors and real polymorphisms along with a time line for accomplishing the stated goals, for sequencing, sequence storage, data analysis, and annotation accuracy. Define potential problems, alternative strategies, and benchmarks for success. Explain how particularly risky aspects of the project will be managed. Describe the analytical approaches to identify/confirm genetic risk and protective factors (a variety of approaches may be employed); the qualities and characteristics of the genomic sequence information to be produced by the investigator; and the projected funding requirements; how the applicant(s) plan to cooperate and collaborate with the ADSP and the CGAD.
   
   In the description of the data analyses, consider phenotypes and endophenotypes, disease-related covariates, 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 disease status. Explain how understanding rearrangements of the genome may reveal new biological mechanisms in understanding and diagnosing the disease. Define how proposed studies will be integrated into the ADSP as a whole. Delineate how key scientific or technological challenges upon which the rest of the approach depends will be identified and addressed. Address the issue of sequence quality and the sequencing of entire genomes or specific regions of the genome. Delineate the approach to the analysis and harmonization of sequencing and genotyping data. Define how bold plans will be counterbalanced to manage inherent risk to the study. Explain how key technical barriers will be identified and overcome.
   
   If appropriate to the study design, describe the capabilities for sequencing, sequence storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms as appropriate. Describe the design and use of large scale storage capacity and external backup systems with appropriate security and back up measures to support analytical capabilities should be included if appropriate.
   
   Applicants should elaborate key quantitative milestones with a time line for accomplishment. Explain how the milestones as set forth are achievable within the timeline of the study.

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

• All applications submitted for the January 25, 2015, due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Provide a clear scheme to facilitate cooperation and collaboration in the analysis and rapid sharing of data provided by the LSACs, investigators funded to perform analysis on Discovery Phase data, the NIAGADS / dbGaP portal, the CGAD funded under the companion RFA-AG-16-001 and investigators performing similar analysis outside of the ADSP. Describe what outreach efforts the team will employ to advertise the availability of the data, what additional steps will be used to protect confidentiality and confirm informed consent, and what, if any, screening will be done of requests for the data to allow access to all and only qualified researchers. Explain mechanisms, procedures, and infrastructure available to prepare and provide data to the awardees of the companion FOA (RFA-AG-16-001). Methods and mechanisms for effectively making data available to other members/studies in the ADSP, such as the use of websites should be clearly delineated.

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.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

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

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.

6. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information

1. Criteria

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.

Overall Impact

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).

Scored Review Criteria

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is the proposed project likely to identify new genes contributing to increased risk or protection of developing AD? Will the proposed project constitute a substantial advance in analytical approaches for whole genome sequencing, exome sequencing, targeted sequencing, and/or genotyping and data harmonization for complex diseases? Will proposed collaborative efforts enhance the field of AD genetics? How likely is it that the proposed work will identify genetic risk to the disease through comprehensive analyses of existing or newly generated genetic and genomic data sets? Will the study better define and refine AD phenotypes? Will the work enhance cooperation and collaboration in the ADSP? How likely is it that a new therapeutic approach for AD will be an outcome of the study? How well will the organization of the proposed studies integrate with the activities of the ADSP and add value to the ADSP gene discovery mission? How likely is it that the way the study will define the structure of the genome of subjects with AD will advance the field? Does the proposed work identify genetic risk to the disease through comprehensive analyses of existing or newly generated genetic and genomic data sets?

Investigator(s)

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

Do applicants(s) have sufficient expertise to generate and/or analyze large datasets including sequence and genotype data for complex neurological diseases? Do applicants(s) have sufficient expertise in the field of AD genetics? Do applicants(s) have sufficient expertise in complex bioinformatics and data storage for large datasets?

Innovation

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 . Do the applicant(s) describe a comprehensive plan to develop leading edge innovative approaches for the analysis that will provide a mechanism of rapid transfer of sequence and genotype data to other investigators engaged in the study for the ADSP Replication Phase? Will the proposed project provide insight as to why individuals with known risk factor genes escape from developing AD? Will the proposed project identify potential avenues for therapeutic approaches and prevention of the disease? 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 genotype data, exome sequencing data, whole genome sequencing data, and targeted sequencing data employed? Will novel approaches to analyzing intergenic regions of the genome be developed? 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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

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?

How likely to be successful are the plans to: (1) identify and validate protective variants in older adults at risk for AD, (2) identify and validate new risk variants among AD cases with low genetic risk, (3) identify and validate new risk variants among AD cases with high genetic risk? Are plans for examination of these factors in multi-ethnic populations in order to identify new pathways or targets for prevention well justified? Do major approaches and studies involved in the application complement each other? Will the project be coherent and maintain a multidisciplinary focus?

Is the analytical strategy feasible? Are the investigators likely to be able to distinguish between sequencing errors and real polymorphisms along with a time line for accomplishing the stated goals, for sequencing, sequence storage, data analysis, and annotation accuracy? Are the analytical approaches to identify/confirm genetic risk and protective factors well-conceived? Is it likely that the applicant(s) plan to cooperate and collaborate with the ADSP and the CGAD will be successful? Will the work result in improved definitions of endophenotypes? Is the analysis of genomic changes such as structural rearrangements, (e.g. insertions, deletions, and haplotypes) to be analyzed likely to be successful? Will new biological mechanisms in understanding and diagnosing the disease be a likely outcome of the study?

Does the team adequately describe the capabilities for sequencing, sequence storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms? Are the design and use of large scale storage capacity and external backup systems appropriate?

For the overall project how well will the studies be integrated? Are key scientific or technological challenges upon which the rest of the approach depends, identified and addressed early in the project? Is the approach to the analysis and harmonization of data well developed and well informed relative to the state of the technology? Is the approach to collaboration and cooperation likely to be successful? Are appropriate mechanisms, procedures, and infrastructure available to prepare and provide data to the awardees of the companion FOA (RFA-AG-16-001)? Is an appropriate leadership plan in place that ensures collaboration among the studies, investigators, and institutions? Are clear plans in place to effectively leverage existing NIA funded infrastructure that will maximize the use of NIH funds? Is the proposed strategy likely to enhance cooperation and collaboration within the ADSP? Will this study augment the ADSP Discovery and/or Replication Phase analysis? Will the project avoid redundancy of existing infrastructure and leverage use of existing resources? Are milestones appropriate for the time frame of the study?

Environment

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?

Additional Review Criteria

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.

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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.

Applications from Foreign Organizations

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

Select Agent Research

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).

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

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.

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

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the principal investigators (PI)s 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 PI(s) for the project as a whole, although specific tasks and activities may be shared among the PI(s)s and the NIH as defined below.

The PD(s)/PI(s) of the RPS will have the primary responsibility for the following:

The PD(s)/PI(s) of the RPS will work collaboratively with study leaders, investigators funded under the companion U54 RFA, members of the ADSP, collaborators with the ADSP, NHGRI, and NIA. The RPS PI(s) will participate in study design and analysis. The primary governing body for the RPS will be the Alzheimer's Disease Sequencing Project Steering Committee (ADSP SC) which operates under an MOU signed by the Directors of the NHGRI funded Large Scale Sequencing Centers (LSACs) and PIs of NIH funded grants and cooperative agreements https://www.niagads.org/adsp/content/about.

The PD(s)/PI(s) of the RPS will be responsible for the formation of an internal operations committee (IOC), which will have responsibility for the final details of the project design, policy decisions, overall management of the study and will define the rules regarding access to data. The IOC will be comprised of the RPS PI(s) that will serve in a decision making capacity for the cooperative agreement in collaboration with the NIA Project Scientist. The RPS IOC should agree to work cooperatively with the ADSP Steering Committee and ADSP Working Groups, awardees of the companion RFA, the NHGRI LSACs, the NIA, and awardees of cooperative agreements funded under http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html. The IOC should develop and implement systems necessary for communication between the various study components and supporting Centers, Repositories, and any collaborating entities, including but not exclusively limited to:

• NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) https://www.niagads.org/National Cell Repository for Alzheimer's Disease: http://ncrad.iu.edu/
• Alzheimer's Disease Genetics Consortium (ADGC): http://alois.med.upenn.edu/adgc/
• Cohorts for Heart and Aging Research in Genomic Epidemiology" (CHARGE) Consortium: http://web.chargeconsortium.com/
• International Genomics of Alzheimer's Project (IGAP): http://www.alzheimersreadingroom.com/2011/02/international-genomics-of-alzheimers.html
• Alzheimer's Disease Neuroimaging Initiative (ADNI): http://adni.loni.ucla.edu/
• National Cell Repository for Alzheimer's Disease (NCRAD): http://ncrad.iu.edu/
• National Alzheimer's Coordinating Center (NACC): http://www.alz.washington.edu/
• Data Base of Genotypes and Phenotypes (dbGaP): http://www.ncbi.nlm.nih.gov/gap
• Alzheimer's Disease Research Centers (ADRCs): http://www.nia.nih.gov/alzheimers/alzheimers-disease-research-centers
• NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC): http://www.genome.gov/27546191

The IOC will facilitate the design and refinement of all protocols, manuals of operations, and forms. A committee that is comprised of the PD/PI(s), key RPS staff, and selected members of the IOC should develop and implement approaches necessary for data analysis, statistical analysis and final outcome data. A committee that is responsible for data sharing (see the section herein on the Resource Sharing Plan) and communication within the RPS, the CGAD and the various components of the ADSP will be established.

Collaborating institutions providing genotype, sequence, or other types of data to the RPS will retain custody and primary rights to the site-specific data developed under their individual awards, subject to Government rights of access, consistent with current HHS, PHS, and NIH policies. Institutions that are award recipients will retain custody of and have primary rights to the data and software developed under the award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

External Board of Advisors: In consultation with NIA, an external board of advisors will be selected, to be comprised of individuals not directly involved in the RPS to provide guidance in data analysis or other aspects of the ADSP Replication Phase analysis, and integration of outcomes between the ADSP Discovery Phase and Replication Phase.

NIH staff have substantial programmatic 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 including the NIA Project Scientist will serve as a member of the IOC and have substantial scientific/programmatic involvement during conduct of this cooperative agreement, through technical assistance, advice, and coordination above and beyond normal program stewardship of grants. The PD(s)/PI(s) agree(s) to accept assistance from the designated NIA Project Scientist. This person will participate, through the IOC and other key committees, in the monitoring of issues relating to development, follow-up, and adherence to protocols and will assist in the development and/or adjustment of study protocols.

Additionally, an agency program official or NIA program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The IOC, comprised of appropriate RPS staff and the NIA Project Scientist, will have primary responsibility for finalizing standard definitions, procedures, and measures common for all the protocols. The IOC will hold bi-weekly teleconferences or as otherwise needed, and meet at least annually with the external board of advisors, or as dictated by the needs of the study. In addition, awardees of the RPS and the companion RFA that supports the ADSP Replication Phase Core Facilities will hold teleconferences as needed meet at least once annually. Each full member of the IOC will have one vote, and all major scientific decisions will be determined by majority vote of the IOC. Members of the IOC will be required to accept and implement policies approved by the IOC. Committees appointed by the IOC, will be involved in the design of protocols and manuals of operations, and in ongoing functions of the study such as preparation of publications. A committee comprised of members of the IOC and awardee(s) of the companion RFA should develop and implement systems necessary for communication between the various study components in collaboration with the NIA Scientist.

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 IOC 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.

3. Reporting

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.

Section VII. Agency Contacts

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

Application Submission Contacts

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

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

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

Scientific/Research Contact(s)

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

Peer Review Contact(s)

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]

Financial/Grants Management Contact(s)

John Bladen
National Institute on Aging (NIA)
Telephone: 301-402-7731
Email: [email protected]

Section VIII. Other Information

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.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.