Department of Health and Human Services

Part 1. Overview Information

Key Dates

** ELECTRONIC APPLICATION SUBMISSION REQUIRED**

NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 Information
   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 FOA is intended to provide funding for: (1) joint analysis and harmonization of ADSP sequence and genotype data by the NIA CGAD, and (2) infrastructure support for the ADSP Replication Phase Studies (RPS) that will be funded under the companion FOA, RFA-AG-16-002, entitled, "ADSP Replication Phase Studies (U01)". 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.

Discovery 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 late 2014 or early 2015.

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 in at least one major paper reporting the results of the ADSP to be jointly submitted by all of the members.

Replication Phase of the ADSP

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.

This CGAD FOA will fund infrastructure, analysis, coordination, and certain data generation costs for a portion of the replication phase 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 the companion FOA for the ADSP Replication Studies.

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 joint analysis and data harmonization for the 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. Applicants to this FOA may also apply for the companion FOA, RFA-AG-16-002.

The Replication Phase as a whole will likely require production and analysis of a variable combination of studies that may not be exclusive to the following:

• 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 who may carry a specific variant.
• Genotyping by custom chip of genes/regions/loci where the association with late onset AD 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.
• Quality control checks including the matching of GWAS or other genotype data to sequence data; imputation of GWAS data; and estimation of population structure.
• Data tracking: receiving and managing genotype, phenotype, and sequence data.
• Recoding of phenotype data according to the phenotype specification defined by the ADSP.
• Collection, processing, recalling/joint calling, and imputation of Replication Phase sample set sequence data and/or genotype data.
• Data Harmonization: Examples of data harmonization include: (1) Harmonization of Discovery Phase WGS and WES data with other sequence or genotype data generated by the ADSP. (2) Harmonization of Discovery Phase WGS and WES data with other sequence data generated outside of the ADSP. An example of data that have been generated outside of the ADSP includes whole genome sequence data generated by the Alzheimer's Disease Neuroimaging Initiative (ADNI http://www.adni-info.org/ ). Application for ADNI data can be made either through the Laboratory of Neuroimaging (LONI) http://loni.usc.edu/ or NIAGADS https://www.niagads.org/ . Additional whole genome and whole exome sequence datasets may be harmonized with ADSP data as they become available. (3) Harmonization of Replication Phase data across multiple studies. (4) Harmonization of Discovery Phase data with Replication Phase data. (5) Harmonization of study phenotype data across multiple studies.
• Analysis of Replication Phase targeted sequence and genotype data that are provided by the LSACs, and those data provided under awards to the companion FOA, RFA-AG-16-002, and/or those provided by analysis of other related datasets.
• Development of additional analytical approaches to replication studies for discovery of therapeutic targets such as bioinformatics, biophysical modeling, and biological assays.

The items above are the elements of a Replication plan as anticipated by NIA. The above list is not intended to be all inclusive.

NIA seeks applications in research areas related to a subset(s) of the critical portions of a Replication Phase plan indicated above. Applicants are free to propose additional or alternative elements, as long as they are well justified within the context of the central goal of providing an efficient and complete Replication study to complement the Discovery Phase of the ADSP. Data generated under cooperative agreement awards for this FOA and the companion FOA, RFA-AG-16-002, will be shared with the ADSP and the research community at large as appropriate. Every effort should be made to maximize the use of existing research resources and to avoid redundancies in infrastructure or effort beyond what presently exists in the ADSP.

The present FOA, "NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease" (CGAD) will provide funds for data analysis and data harmonization for the ADSP Replication Phase and the aggregate of studies related to the ADSP as a whole, along with infrastructure support for ADSP Replication Phase.

The intent of this FOA is to encourage a cooperative and diverse group of investigators to form and interact in a highly collaborative manner within the ADSP. The Coordinating Center awardee(s) will be expected to lead Replication Phase work in a cooperative way under the auspices of the ADSP. It is expected that analysis plans proposed will be consistent with the intentions of the ADSP Replication Study research plan https://www.niagads.org/sites/all/public_files/ADSPdocs/ADSP-SUMMARY-PLAN-41513.pdf . The design of the final Replication Phase analysis plan is a joint responsibility of the Coordinating Center and the ADSP as a whole. Successful applicants, along with the Large Scale Sequencing and Analysis Centers, are expected to work cooperatively to build a single Replication Phase plan under the auspices of the ADSP. In addition to presenting and actualizing the research plan, it is the responsibility of the Coordinating Center to lead the Replication Phase analysis in a manner that takes into account how awardees will work within the ADSP as a whole and awardees of cooperative agreements funded under the companion FOA, RFA-AG-16-002. Applicants are encouraged to propose further analyses that add scientific value to the current plan. It is understood that individual grantee plans for analysis will likely need to be coordinated with the harmonization scheme in CGAD to allow optimal data availability.

Production and analysis of the following will be subsumed partly or completely under the U54.

• Capture of ADSP Replication Phase targeted sequence, genotype, and analysis data from the LSACs and from the FOA funded under the companion U01 FOA, RFA-AG-16-002; processing/ reprocessing of these data using the ADSP consensus calling workflow. Joint analysis of the aggregate of Replication Phase data in collaboration with awardees of the companion FOA, RFA-AG-16-002, and members of the ADSP as a whole.
• Harmonization of ADSP Replication Phase datasets. Joint/meta-analysis of the harmonized datasets to identify and validate risk and protective factors for AD.
• Capture of sequence and genotype data from studies outside of the ADSP; integration, harmonization of these data with ADSP data; joint/meta-analysis of these data with ADSP data across studies to identify and validate risk and protective factors for AD.
• Capture of sequence, genotype, and analysis data from the ADSP Discovery Phase studies funded under NIA PAR-12-183 http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html ; integration, harmonization, and joint/meta-analysis of Discovery Phase and Replication Phase data. Data analysis of the aggregate of all types of harmonized Discovery Phase and Replication Phase data related to the project to identify and validate risk and protective factors for AD.
• Data sharing: receiving and managing genotype, sequence, and phenotype data for the Replication Phase; facilitation of rapid data sharing according to existing ADSP and NIA policies. Providing all types of data to the ADSP NIAGADS/dbGaP database https://www.niagads.org/adsp/
• Development of additional analytical approaches to replication studies for discovery of therapeutic targets such as bioinformatics, biophysical modeling, and biological assays.

The Replication Phase Studies funded under the companion FOA, RFA-AG-16-002, will provide data to the CGAD. Please see the companion FOA for specific information.

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 RFA-AG-13-013 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 of RFA-13-013 can be found in the NIH Reporter: http://projectreporter.nih.gov/reporter.cfm .

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.

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 lead comprehensive analyses of targeted sequence data along with genotype data to replicate and validate data generated in the Discovery Phase of the ADSP. The aims of the ADSP as a whole, and specifically of the Replication Phase are to: (1) identify protective variants in older adults at risk for AD, (2) identify new risk variants among AD cases with low genetic risk, (3) identify new risk variants among AD cases with high genetic risk, and (4) examine these factors in multi-ethnic populations in order to identify new pathways / targets for prevention.

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. Investigators funded under this FOA will receive, harmonize, analyze and validate findings and provide analyzed data to the research community. Awardees of the U54 will provide imputed and harmonized targeted sequence and genotype data derived from existing WES and/or WGS sequence data as a research resource for rapid sharing with the scientific community as appropriate. Data from the Replication Phase will be provided to the ADSP NIAGADS/dbGaP database for analysis by the research community at large. 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 of gene discovery, association analysis, read mappings, variant frequencies, quality control information, coding sites, non-coding sites, and splice sites for affected genes. The CGAD will notify awardees of the companion FOA and the ADSP of any potential genes/regions/loci of interest for further follow up as they are identified. 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, jointly/meta-analyzed and made available for analysis by the AD research community through the ADSP NIAGADS/dbGaP database. Sequence, genotype, harmonized, and related outcome data derived from the analyses will be stored at an NIA approved data repository and shared with the ADSP NIAGADS/dbGaP database consistent with the goals of this program. 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 cooperative agreement will provide funds for analyses and harmonization of data delivered through a number of NIH funded studies as well as those funded through other organizations; computer software and hardware and bioinformatics and statistical analysis; and support for the personnel needed to conduct the analyses.

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 ADSP CGAD may utilize information from existing NIA-and NIH-funded research resources, including the following:

• 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/
• National Cell Repository for Alzheimer's Disease (NCRAD): 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 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.

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 Replication Phase of the ADSP, findings of the Discovery Phase and findings of other research groups will be confirmed and data across multiple studies will be harmonized by the Center to identify and validate risk and protective alleles for AD. Successful applicant(s) will propose analyses on the aggregate of AD genetic studies related to the ADSP. 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

Foreign Institutions

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.

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 can access 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.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

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 and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.
Telephone: 301-496-9350
Fax: 301-496-1494
Email: millerm@nia.nih.gov

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required, one
• Data Management, Harmonization, and Information Transfer Core: required, one
• Data Analysis Core: required, one

Overall Component

When preparing your application in ASSIST, use Component Type Overall .

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

SF424 (R&R) Cover -Overall

Complete entire form.

PHS 398 Cover Page Supplement -Overall

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information -Overall

Follow standard instructions.

Project/Performance Site Location(s) -Overall

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research & Related Senior/Key Person Profile -Overall

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. The successful applicant(s) for funding will consist of a group of researchers with expertise in the capacity to analyze and harmonize large datasets including whole genome and whole exome sequence data, targeted sequence data, and genotype data related to the genetics and genomics 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. Expertise in the field of Alzheimer's genetics is considered an essential component of the project.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget -Overall

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan -Overall

Specific Aims:

Concisely state the specific aims for the Center and explain how the proposed activities will enhance the overall goals of the ADSP, enhance individual ADSP activities, and increase the efficiency of moving the field toward identification of genetic factors that will improve the likelihood of decreasing the impact of AD. Concisely state an analysis plan that is in keeping with the current intentions and approach of the ADSP Replication Phase. Specify how the Center will conduct a comprehensive examination of the aggregate ADSP harmonized data that will identify and validate novel risk and protective alleles for AD and will increase the likelihood of identification of new therapeutic targets for AD.

Research Strategy:

1. Significance
   For the Center as a whole, address the plans to position the proposed activities within the framework of the ADSP and explain Core elements in the context of the plan to establish a central role for the CGAD. Explain how the proposed work is seminal to the identification and validation of genetic risk and protection against AD; how plans will constitute a substantial advance in the ability to analyze and harmonize sequence and genotype data; how proposed work will be essential to defining and refining AD phenotypes/endophenotypes; how the PD(s)/PI(s) and Core Leaders of the Center will cooperate and act in a leadership capacity working with other ADSP investigators for ADSP Replication Phase analysis goals.
2. Innovation
   Describe the strategy chosen to go beyond a service role for the Center in harmonizing genetic data to address technical and analytic needs in the area through advances in statistics, methodologies, instrumentation or analytic tools to capitalize on the data.
3. Approach
   The proposed study should describe a comprehensive plan to develop leading edge innovative approaches for data analysis and harmonization, that will allow rapid sharing of sequence and genotype data for the ADSP Replication Phase; the plan should enable the ADSP to extend previous discoveries that may ultimately result in new directions for AD therapeutics, consistent with achieving the goals of this program.
   
   Explain how the Center organization will facilitate the mission of harmonization of ADSP data, and its analysis including any features of the approach chosen that are cross-Core or otherwise integral to the Center as a whole. Describe how the CGAD will work cooperatively with the ADSP as a whole. Describe the rationale and approach the PD(s)/PI(s).will take to developing and maintaining a Center environment that fosters both traditional and novel approaches to multi-disciplinary research and team science in the field of AD genetics. Explain why the analytical strategy is feasible, how particularly risky aspects will be managed and how the Center will advance and augment the development of novel therapeutics for AD. Explain how potential problems, alternative strategies, and benchmarks for success will be carried out. State plans to participate actively in data exchange and to collaborate with other investigators in the ADSP and with awardee(s) of the companion FOA as appropriate. Define milestones and a time line for key events for the project.

Letters of Support:

Provide letters of support for the overall center. Letters that support the definition of how the ADSP Replication Phase will be advanced by collaborations; how the study will proceed efficiently; and how infrastructure will be effectively supported should be included here for the Center.

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

• As for the ADSP Discovery Phase, 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. Methods for rapid data sharing across ADSP studies and with the research community at large should be clearly delineated in the application as appropriate.
• A fundamental goal of this study is to make the data derived from the analyses widely available to the Alzheimer's research community to accelerate the development of therapeutic approaches and prevention of AD. It is expected that data will be shared in accordance with existing NIH and NIA protocols and policy. Consistent with achieving the goals of this program, all data should be placed in the public domain and shared freely by methods and within time periods to be specified by NIA and NIH policy, and particularly as specified by the NIA Genetics of Alzheimer's Disease Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) Data Distribution Agreement: https://www.niagads.org/sites/all/public_files/NIAGADS%20Data%20Dist%20Agree%2020121024.pdf. Outcome data from the study will be deposited into dbGaP http://www.ncbi.nlm.nih.gov/gap / NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) http://alois.med.upenn.edu/niagads/ for access by the AD research community as appropriate.
• 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. Data storage sites must be approved by NIA. In addition, outreach efforts should be undertaken to maximize data sharing in order to enhance research in AD and collaboration within the genetics community. For example, an interactive website may be provided for researchers outside the Center facility to address queries on what data are available and how to access data.
• 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.

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.

Administrative Core

When preparing your application in ASSIST, use Component Type Admin Core.'

The Administrative Core is a shared research facility that provides a service to the scientific community. It provides an essential resource whose function is indispensable to the scientific purpose of the ADSP. The Core is directed by an investigator with substantial expertise related to the Core and will enhance productivity or in other ways benefit a group of investigators to accomplish stated goals.

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

SF424 (R&R) Cover - Administrative Core

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement Administrative Core

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information Administrative Core

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) - Administrative Core

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile - Administrative Core

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget - Administrative Core

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan - Administrative Core

Specific Aims:

Concisely state the specific aims for the Core. Explain how the proposed activities will enhance the overall goals of the ADSP, collaboration across the ADSP and individual ADSP activities, how the Core will increase the efficiency of moving the AD genetics field toward the identification of genetic factors that will improve the likelihood of decreasing the impact of AD.

Research Strategy: Organize the Research Strategy into sections on: Significance, Innovation and Approach.

Significance:

Address plans to position the proposed activities within the framework of the ADSP and the Center as a whole. Address how services that the Core provides will change the field if the proposed aims are achieved. Explain how the Core will provide a mechanism to synergize substantial advances in analytical and statistical approaches for sequence and genotype data for complex diseases and how collaboration and cooperation with the ADSP as a whole will enhance the field. Important and related considerations are the degree to which: (1) currently funded investigators within or outside the ADSP will use and benefit from Core resources, (2) how the Core coordinates with other Cores to further Center and ADSP missions and, (3) how the Core will promote new and/or expanded AD genetics efforts locally, regionally or nationally.

Innovation:

What plans are in place for collaboration and cooperation with other ADSP investigators and other key investigators in Alzheimer's research that will augment the likelihood of discovery of new AD genes/regions/loci? How will collaborations facilitated by the Administrative Core accelerate the detection of new potential therapeutic approaches?

Approach:

Describe the most important contributions the Core will make to research in AD genetics. Any developmental work to be carried out by the Core should be presented. Applications should describe preliminary organizational work, experience with AD genetics, the potential for developing new and exciting research, and specific plans for implementation of the new program. The approach should consist of an explanation of Center procedures and functions including the structure of the Center; the composition and role of an external board of advisors; the composition of a committee to oversee the normal operations of the Center; and the composition and function of a committee responsible for data analysis. Explain the process by which the Core Leader(s) will notify the research community and the recipients of awards under RFA-AG-16-002 of newly identified gene/regions/loci for follow up studies.

Describe how the Core will coordinate and integrate ADSP Replication Phase components and activities including the Replication Phase PD(s)/PI(s) funded under the companion FOA, RFA-AG-16-002. Explain how the Core will integrate/facilitate the ADSP Discovery Phase with Replication Phase activities. Define efforts to ensure collaboration and cooperation with the ADSP Steering Committee and investigators, the LSACs, NHGRI, NIA, and other ADSP investigators funded under other NIA awards. Define how the Core will interact with the scientific community, and particularly the ADSP, to develop relevant goals for the Center. Define how staff will cooperate and collaborate on multiple projects, with Cores within the Center, and with Discovery Phase investigators. Explain how a cooperative spirit will be fostered by the Center.

Delineate how the Core will interface with existing NIA and NIH funded infrastructure. Present plans for data acquisition and data handling. Explain how the Core will ensure timely and routine transmission of appropriate Center data sets to NIAGADS and dbGaP. Primary and secondary analysis data will be deposited into dbGaP http://www.ncbi.nlm.nih.gov/gap and the NIA Genetics of AD Data Storage Site http://alois.med.upenn.edu/niagads/ or another NIA approved data storage site for access by the AD research community in compliance with the NIA Genetics of AD Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan.

Collaborations that will accelerate the detection of new potential therapeutic approaches should be formed. The plan should explain how staff will collaborate on multiple projects and Cores within the Center and a statement of agreement to collaborate with other cooperative agreements funded under NIA FOAs. Explain how existing NIA funded infrastructure will be leveraged to maximize the use of NIH funds.

Provide the timeline for activities and milestones for the Administrative Core.

Letters of Support: Provide only letters of support that are specific to this Core.

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 - Administrative Core

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 - Administrative Core

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

Data Management, Harmonization, and Information Transfer Core

When preparing your application in ASSIST, use Component Type Core.

The Data Management, Harmonization and Information Transfer Core has the responsibility of establishing and maintaining a research resource that provides valuable, well-documented assets for cutting edge AD genetics research for both Center personnel and the wider AD research community.

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

SF424 (R&R) Cover -Data Management, Harmonization, and Information Transfer Core

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement - Data Management, Harmonization, and Information Transfer Core

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information- Data Management, Harmonization, and Information Transfer Core

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s)- Data Management, Harmonization, and Information Transfer Core

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile - Data Management, Harmonization, and Information Transfer Core

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget- Data Management, Harmonization, and Information Transfer Core

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan- Data Management, Harmonization, and Information Transfer Core

Specific Aims:

Clearly state how the Core will contribute to the goals of the ADSP and outline interactions of the Core with each of the other Cores of the Center. Indicate the role of the Core in the ADSP as a whole. Indicate the role of the Core in data capture and analysis of ADSP Discovery Phase and Replication Phase data. Indicate the role of the Core in the ADSP Replication Phase as a whole. Identify which projects in the ADSP Replication Phase the Core will assist.

Research Strategy:

Organize the Research Strategy into sections on: Significance and Approach. Explain how the Core will establish and maintain a research resource for the AD research community. If the Core will include studies on special populations, the applicant must describe the characteristics of the population and justify the added scientific value to research at the Center resulting from the inclusion of this group.

Significance:

Describe the potential for developing new and exciting research, and specific plans for implementation of the new program. Provide an explanation of the Core's leadership role in the harmonization of ADSP Discovery and Replication Phase data including genotype, sequence, and phenotype data. Explain how the Core will harmonize the various types of data associated with the Replication Phase to help identify AD risk and protective genes/regions/loci. Explain the role of the Core in the Center as a whole and as a resource for other ongoing genetics activities in AD. Address the importance of the problem or critical barriers to progress in the field that the proposed Core addresses such as: how the proposed Core will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields; how the concepts, methods, technologies, or services that drive this field will be changed if the proposed aims of the Core are achieved; how the proposed Core will augment the ability to identify new genes contributing to increased risk or protection of developing AD; how the proposed Core will provide a substantial advancement in the capacity of analytical approaches for whole genome, whole exome, targeted sequencing and genotyping for complex diseases; and how the Core will work with existing databases for efficient data transfer, management, and analysis to leverage existing resources.

Approach:

Provide an explanation of how the Core will act in an oversight capacity for ADSP data harmonization. A key aspect of the approach is the Core's role is in harmonizing aggregate ADSP Discovery Phase data including genotype/genomic, sequence, and phenotype data; provide an explanation of how the Core will coordinate and integrate the various components of these harmonization activities. Define how the Core will: (1) Harmonize Discovery Phase Data Sets: Describe the approaches for capturing and harmonizing data from the diverse ADSP Discovery Phase datasets including Discovery Phase WGS and WES data with other sequence or genetic/genomic data generated by the ADSP investigators and those outside the ADSP. (2) Harmonize Replication Phase Data Sets: Describe the process for data harmonization for the diverse types of ADSP Replication Phase data. Define analytical and statistical approaches for data harmonization. (3) Harmonize Discovery Phase Data Sets with Replication Phase Data Sets: Define the plan for data harmonization of the Discovery Phase Data with the Replication Phase data set. Discovery Phase data are being analyzed under separate funding: (http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html). Data are available by application through http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000572.v1.p1. (4) Harmonize Phenotype data across multiple studies and data sets. Provide an explanation of the Core's role in harmonizing aggregate ADSP Discovery Phase and Replication Phase data (genotype/genomic, sequence, and phenotype); an explanation of how the Core will coordinate and integrate the various components of these harmonization activities; an explanation of how the Core will act in an oversight capacity for ADSP harmonization activities in working with other ADSP investigators. Provide an explanation of how tasks will be done as needed by the ADSP Work Groups and awardees of the companion U01s such as SNP imputation. Explain how the harmonized data will be provided to the Biostatistics and Data Analysis Core for analysis. Define any key scientific or technological challenges upon which the rest of the approach to harmonize the data depends.

Delineate any potential problems, alternative strategies, and benchmarks for success. Show how the approaches of the Core will complement the other Cores and how the Cores are inter-dependent. Describe the plan to accept and use the sequence data from awardees of the companion U01 FOA, RFA-AG-16-002, including data flow schemes; the capacity of the data storage facility; how the Core will ensure that the ADSP's resources are optimally utilized; how key scientific or technological challenges will be addressed; and how the Center will ensure the coherence of the overall project and maintain a multidisciplinary focus. Define how the strategies, methodologies, and analyses to be done by the Core are appropriate to accomplish the specific aims of the project as a whole. Define how particularly risky aspects will be managed.

Explain how the Core will coordinate and integrate ADSP Replication Phase activities using the current ADSP Replication Phase plan. Define the process to work collaboratively with the existing ADSP Work Groups to establish protocols for joint calling of the various types of data available. Explain the approach to capture and process ADSP Replication Phase data from providers; to process/reprocess targeted sequence data using the ADSP consensus calling workflow and to provide assistance in joint analysis of the aggregate of Replication Phase targeted sequence and genotype data in collaboration with awardees of the companion FOA. Include an explanation of how tasks will be done such as: receiving, managing, and sharing genotype, sequence, and phenotype data; providing data to Core C for analysis; receiving data for sharing with other sites/databases. Explain how shared efforts will be coordinated and how the Core will capture, process, and quality control check ADSP Replication Phase data that are provided by investigators involved in other aspects of ADSP data analysis or those outside of the ADSP.

Define milestones for the Core; define a time line for key events.

Letters of Support: Provide only letters of support that are specific to this Core.

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- Data Management, Harmonization, and Information Transfer Core

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- Data Management, Harmonization, and Information Transfer Core

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

Biostatistics and Data Analysis Core

When preparing your application in ASSIST, use Component Type Core.

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

SF424 (R&R) Cover- Biostatistics and Data Analysis Core

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement- Biostatistics and Data Analysis Core

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information- Biostatistics and Data Analysis Core

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s)- Biostatistics and Data Analysis Core

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile- Biostatistics and Data Analysis Core

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of 'Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget- Biostatistics and Data Analysis Core

Budget forms appropriate for the specific component will be included in the application package.

PHS 398 Research Plan- Biostatistics and Data Analysis Core

Specific Aims:

Specify how the Biostatistics and Data Analysis Core will assume a leadership role in the overall data analysis of the ADSP harmonized Discovery and Replication Phase data. Specify how new statistical and bioinformatics approaches will be developed for data analysis. Specify how the aggregate ADSP harmonized data will be comprehensively analyzed to identify and validate novel risk and protective alleles for AD. Specify how genetic data from different ethnic groups will be analyzed and data validated. Specify what data (i.e. genes/regions/loci) can be expected as an outcome of the analysis of the harmonized datasets. Specify how outcome data may lead to the identification of new therapeutic targets for AD.

Research Strategy:

Organize the Research Strategy into sections on: Significance and Approach.

Significance:

Define the Core's leadership role in the analysis/validation of aggregate harmonized ADSP Discovery Phase/Replication Phase data. Describe how new statistical tools and analytic approaches appropriate to the scale of data that the CGAD will manage will be developed to move the field of AD genetics forward. Describe how novel comprehensive analytical and statistical approaches will identify genetic risk of or protection against AD and guide analysis of targeted sequencing and genotype data for AD. Delineate how novel approaches to the primary analysis of harmonized genetic and genomic data sets will facilitate secondary data analysis. The significance of the study will be enhanced by collaboration by the ability to maximally engage existing resources and rapid sharing: define efforts to ensure collaboration with NHGRI LSACs, the NIA, awardees of the companion FOA, investigators involved in the Discovery Phase, and investigators involved in genetics/genomic studies outside of the ADSP in order to identify risk and protective genes/regions/loci for AD.

Approach:

The description and rationale for the approach should include an explanation of Analysis of: Harmonized Discovery Phase Data Sets, Harmonized Replication Phase Data Sets, and Harmonized Discovery Phase Data Sets together with Replication Phase Data Sets including targeted sequence data and genotype or custom chip data. Describe methodical and statistical approaches for analysis and validation of genes/regions/loci for harmonized data. Explain how the Core will advise the PD(s)/PI(s) funded under the companion FOA in the selection of genes/regions /loci of interest for follow up analysis. Explain how the proposed methods and technology will address sequence or genotype quality problems.

Clearly define an analysis plan for joint/meta data analysis that is in keeping with the current intention and approach of the ADSP Replication Phase plan and explain the rationale for the approach. Provide an explanation of how the Core will act in an oversight capacity that fosters cooperation for analysis activities in working with other ADSP investigators and how the overall strategy, methodology, and analyses done by the Core are appropriate to accomplish the specific aims of the Center project and the goals of the ADSP. Delineate the objectives, approaches, analysis protocols, and statistical approaches to be used. Explain how data will be selected and prioritized for analysis. Provide an explanation of statistical or other analytical approaches. Provide the framework for analysis that considers such factors as how data from diverse ethnic groups will be analyzed and validated; how technological challenges upon which the rest of the approach depends will be overcome; and how analysis of harmonized data across datasets will help define AD phenotypes. Explain how the project will avoid redundancy of existing infrastructure and will leverage existing resources. Explain how high risk plans will be counterbalanced to manage inherent risks. Define any key scientific, statistical, or technological challenges upon which the rest of the approach to analyze the data depends. Explain how analysis of the various harmonized ADSP data sets will augment the ADSP Discovery Phase and Replication Phase analysis and the ADSP as a whole. Explain how analysis of specific regions of the genome will be done, how data will be annotated with potential functional assignments, and how genes/regions/loci of interest will be validated.

Define the formats and operational mechanisms by which analyzed/validated data will be prepared and provided to the Data Management and Information Transfer Core. Provide an explanation of how the Core will work with the other Cores and how data will be provided to awardees of companion U01s for any necessary follow up.

Provide the timeline and milestones for the project.

Letters of Support: Provide only letters of support that are specific to this Core.

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- Biostatistics and Data Analysis Core

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- Biostatistics and Data Analysis Core

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

Foreign Institutions

Not Applicable

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) using ASSIST or other electronic submission systems. 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.

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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads 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.

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 (SAM). 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 Vemuri@nia.nih.gov 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 - Overall

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center 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 Center proposed). What is the likelihood that the project will achieve the overarching goals of the ADSP to identify and validate new genes/regions/loci, gene alleles contributing to increased risk for or protection against the disease involved in AD; and potential avenues for therapeutic approaches and prevention of the disease?

Scored Review Criteria - Overall

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 Center that by its nature is not innovative may be essential to advance a field.

Significance

Does the Center address an important problem or a critical barrier to progress in the field? If the aims of the Center 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 of AD through comprehensive analyses of existing genetic and genomic data sets? Are the plans sufficiently bold as to constitute a substantial advance in the ability to harmonize and analyze whole genome, exome sequencing, targeted sequencing, and genotype data to identify and validate AD genes/regions/loci? Does the proposed work have the potential to define and refine AD phenotypes? 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 of the Cores integrate with the activities of the ADSP as a whole and add value to the individual parts? Does the proposed work provide a plan for a leadership role to engender a spirit of cooperation and collaboration across the ADSP? Does the applicant adequately describe how collaboration and cooperation with the ADSP as a whole will enhance the field? What is the likelihood that the project 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? 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? Are investigators thoroughly familiar with the genetics/genomics of AD? Are the applicants a group of researchers with expertise in the capacity to analyze large datasets including whole exome sequence data, targeted sequence data, and genotype data related to the genetics of complex neurological diseases and the field of sequence and genotype statisticians and other experts who will participate in study design and analysis? Do the PD(s)/PI(s) and Core Leaders have proven capabilities in complex bioinformatics and data storage for large and complex data sets? Do the PD(s)/PI(s) and Core Leaders have appropriate expertise in the field of Alzheimer's genetics and related complex neurological diseases?

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? For the Center and the individual Cores, will new statistical approaches or other analytical methods be developed that can be applied generally to the genetics of complex disease? Are novel approaches to integrating the analysis of genotype and sequence data employed? Are novel approaches to genomic annotation proposed? 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 relationships in AD research? Does the proposed work lead to the development of innovative bioinformatics and novel statistical approaches or novel computational tools to analyze and interpret multiple high-throughput genomic data sets? Will the project identify and validate genetic risk and protective factors for AD, and potential therapeutic targets for AD?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? 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 Center 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?

For the overall Center, and the individual Cores, how well will the Cores be integrated? Are key scientific or technological challenges upon which the rest of the approach depends identified and addressed early in the project? Does the proposed technology address sequence or genotype quality and the sequencing of entire genomes or specific regions of the genome? Is the approach to the data harmonization, analysis, annotation and validation of sequence and genotype data well developed and well-informed relative to the state of the technology? 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 robust collaborations with ADSP members and Work Groups likely to enhance the success of the project? 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? Are plans to cooperate and collaborate with other investigators in the ADSP and with awardee(s) of the companion FOA forthcoming so as to contribute substantially to advancement of the field? Will this study augment the ADSP Discovery Phase and Replication Phase analysis? Will the project avoid redundancy of existing infrastructure and leverage use of existing resources? Are the studies as proposed likely to identify and validate genetic risk and protective factors and potential therapeutic targets for AD? Is the approach to collaboration and cooperation likely to be successful? Is an appropriate leadership plan in place that ensures collaboration among the various studies, cores, disciplines, investigators, and institutions? Are milestones appropriate for the time frame of the study? Are clear plans in place to effectively leverage existing NIA funded infrastructure that will maximize the use of NIH funds?

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 - Overall

As applicable for the Centers 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 Center 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 - Overall

As applicable for the Center 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

Not Applicable

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) Genome Wide Association Studies (GWAS).

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.

Scored Review Criteria - Administrative Core

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

Are plans to position the proposed activities within the framework of the ADSP and the Center as a whole presented? Will services that the Core provides change the field if the proposed aims are achieved? Will the Core provide a mechanism to synergize substantial advances in analytical approaches for sequence and genotype/genomic data for complex diseases? Specifically, will sufficient efforts be undertaken to ensure collaboration and cooperation with the ADSP Steering Committee and investigators, the LSACs, NHGRI, NIA, other ADSP investigators, and AD researchers funded under other NIA awards? Are collaborations appropriate for the advancement of the ADSP and well coordinated to enhance the functions of the Center? Is it likely that, as proposed, collaboration and cooperation with the ADSP as a whole will enhance the field? Are plans presented to ensure that currently funded investigators within or outside the ADSP will have use of and will benefit from Core's resources? Are plans presented that describe how the Core coordinates with other Cores to further Center and ADSP missions? Are plans presented that define how the Core will promote new and/or expanded AD genetics efforts locally, regionally or nationally? Will existing NIA funded infrastructure be leveraged to maximize the use of NIH funds?

Investigators

Are the core leadership, collaborators, and other researchers well suited to the project? Do they have appropriate experience and training to accomplish the aims of the Core? Have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Core is collaborative do the investigators have complementary and integrated expertise; are their leadership approaches, governance and organizational structure appropriate for the project?

Innovation

Are plans are in place for collaboration and cooperation with other ADSP investigators and other key investigators in Alzheimer's research that will augment the likelihood of discovery of new AD genes/regions/loci? How likely is it that collaborations facilitated by the Administrative Core will accelerate the detection of new potential therapeutic approaches?

Approach

How likely is it that the Core will make important contributions to research in AD genetics? Are preliminary organizational work, experience with AD genetics, potential for developing new and exciting research, and specific plans for implementation of the new program clearly defined and likely to be successful? Are Center procedures and functions including the structure of the Center well defined and workable? Is the process by which the Core Leader(s) will notify the other Cores, the awardees under the companion FOA, and the research community of newly identified gene/regions/loci for follow up studies well defined and efficient?

Is the organization of the Core appropriate to efficiently assist in accomplishing the stated goals of the ADSP? Will the Center adequately coordinate and integrate with Replication Phase studies funded under the companion FOA? How well will the Core coordinate and integrate ADSP Replication Phase components and activities including working cooperatively with the Replication Phase PD(s)/PI(s) funded under the companion FOA? Will the Core adequately coordinate and integrate other components of the ADSP Replication Phase and with the various components of the Discovery Phase? Is internal infrastructure appropriately organized to efficiently accomplish the stated goals of the ADSP? Will the Core support and advise the overall activities of the ADSP? Will the Core integrate/facilitate the ADSP Discovery Phase with Replication Phase activities effectively? Are efforts to ensure collaboration and cooperation with the ADSP Steering Committee and investigators, the LSACs, NHGRI, NIA, and other ADSP investigators funded under other NIA awards defined? How well will the Core interact with the scientific community, and particularly the ADSP to develop relevant goals for the Center? How appropriate are the plans to work with Discovery Phase investigators and with investigators supported under the companion RFA (AG16-002)? How well have the leadership of the administrative core integrated activities across the separate cores?

Will the Core interface well with existing NIA and NIH funded infrastructure? Are cogent plans for data acquisition and data handling presented? Will the Core ensure timely and routine transmissions of appropriate Center data sets to NIAGADS and dbGaP? Are clear mechanisms and efficient methods for data acquisition and handling presented? Are clear mechanisms in place for deposition of data into NIA approved data storage sites in place? Are collaborations that will accelerate the detection of new potential therapeutic approaches likely to be formed?

Are a timeline and milestones for the project presented and appropriate?

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 - Administrative Core

As applicable for the Core 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 Center 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 - Administrative Core

As applicable for the Core 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

Not Applicable

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) Genome Wide Association Studies (GWAS).

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.

Scored Review Criteria - Data Management, Harmonization, and Information Transfer Core

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 Core meet the needs of the overall ADSP project? Are the following factors addressed and likely to be successful? (i) the importance of the problem or critical barriers to progress in the field that the proposed Core addresses, (ii) how the proposed Core 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 of the Core are achieved, (iv) how the proposed Core will augment the ability to identify new genes contributing to increased risk or protection of developing AD, (iv) how the proposed Core will provide a substantial advancement in the capacity of analytical approaches for whole genome, whole exome, targeted sequencing and genotyping for complex diseases, (v) how the Core will work with existing databases for efficient data transfer, management, and analysis to leverage existing resources. If the aims of the Core are achieved, will scientific knowledge, technical capability, and/or AD research be improved? If successful will the Core augment the ability to identify new genes contribution to increase risk or protection against developing AD? Is the Core well integrated with the other components of the Center?

How likely to be successful is the Core's leadership role in the harmonization of ADSP Discovery and Replication Phase data including genotype/genomic, sequence, and phenotype data? Is the plan to harmonize the various types of data associated with the Replication Phase to help identify AD risk and protective genes/regions/loci likely to be successful? Does the proposed work have the potential to better define and refine AD phenotypes?

Investigators

Are the core leadership, collaborators, and other researchers well-suited to the project? Do they have appropriate experience and training to accomplish the aims of the Core? Have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Core is collaborative, do the investigators have complementary and integrated expertise; are the leadership approaches, governance and organizational structure appropriate for the project?

Approach

Is the Core's role in harmonizing aggregate ADSP Discovery Phase data including genotype/genomic, sequence, and phenotype data likely to provide data that will lead to the identification of new AD risk or protective factors? How well will the Core coordinate and integrate the various components of these harmonization activities? How likely to be successful will the process to Harmonize Discovery Phase Data Sets, Replication Phase Data Sets, and Discovery Phase Data Sets with Replication Phase Data Sets be? Are appropriate approaches for capturing and harmonizing data from the diverse ADSP datasets proposed? Are plans for harmonizing ADSP data with datasets generated by investigators outside of the ADSP likely to be successful? Are key scientific or technological challenges upon which the rest of the approach to harmonize the data depends clearly recognized and meaningful alternative approaches presented? Are approaches to harmonizing Phenotype data across multiple studies and data sets likely to be effective? Is an adequate explanation of how the Core will coordinate and integrate the various components of data harmonization activities presented? Are plans for the Core to act in an oversight capacity for ADSP harmonization activities adequate?

Is there strong potential for developing new and exciting research, and specific plans for implementation of the new program? Are potential problems, alternative strategies, and benchmarks for success presented? Will the approaches of the Core complement the other Cores? Is the plan to accept and use the sequence data from awardees of companion U01s including data flow schemes efficient and workable? Is the capacity of the data storage facility adequate? Will the Core ensure that the ADSP's resources are optimally utilized? Is an appropriate system of identifying a specific subject's data in place that will work across the various components of the ADSP and the Center Cores? How likely are collaborations with other ADSP investigators to be successful? Will the Core work effectively to ensure the coherence of the overall project and maintain a multidisciplinary focus? Will proposed strategies, methodologies, and analyses done by the Core be appropriate to accomplish the specific aims of the project as a whole? Will particularly risky aspects be managed effectively?

Does the research strategy include an appropriate explanation of how the Core will coordinate and integrate ADSP Replication Phase activities? Are procedures and mechanisms for receiving, and managing the genotype, sequence, and phenotype data appropriate? Are mechanisms for receiving data from other studies likely to be implemented effectively? How well will these efforts be coordinated among the Cores? How well will the Core capture, process, and quality control check ADSP Replication Phase data?

Are plans for cooperation and collaboration across the ADSP and its work groups likely to be successful? Will successful completion of the aims aid the ADSP in meeting its overall goals? If successful, will concepts, methods, technologies, treatments, services, or preventative interventions result that may advance AD research? Will the Core provide substantial advancement in the capacity of analytical approaches for sequence and genotype/genomic data for complex diseases? Is the Core well integrated with the other components of the ADSP Discovery Phase; and with the other components of the ADSP Replication Phase?

Are a timeline and milestones for the project presented and appropriate?

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 - Data Management, Harmonization, and Information Transfer Core

As applicable for the Core 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 Center 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 - Data Management, Harmonization, and Information Transfer Core

As applicable for the Core 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

Not Applicable

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) Genome Wide Association Studies (GWAS).

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.

Scored Review Criteria - Biostatistics and Data Analysis Core

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

Will new statistical tools and analytic approaches appropriate to the scale of data that the CGAD will manage be developed to move the field of AD genetics forward? Will new comprehensive analytical and statistical approaches be developed that are likely to identify genetic risk of or protection against AD? Will novel analytical and statistical approaches as proposed guide the field toward accurate analysis of targeted sequencing and genotype data for AD? Are novel approaches to the primary analysis of harmonized genetic and genomic data sets likely to facilitate secondary data analysis? Will the Core assume a strong leadership role in the analysis/validation of aggregate harmonized ADSP Discovery Phase/Replication Phase data? Are efforts to ensure collaboration with NHGRI LSACs, the NIA, awardees of the companion FOA, investigators involved in the Discovery Phase, and investigators involved in genetics/genomics studies outside of the ADSP in order to identify risk and protective genes/regions/loci for AD defined?

Investigators

Are the PD(s)/PI(s), Core Leaders, collaborators, and other researchers well suited to the project? Do they have appropriate experience and training to accomplish the aims of the Core? Have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Core is collaborative, do the investigators have complementary and integrated expertise; are their leadership approaches, governance and organizational structure appropriate for the project?

Approach

Is the approach to analysis of: Harmonized Discovery Phase Data Sets, Harmonized Replication Phase Data Sets, and Harmonized Discovery Phase Data Sets together with Replication Phase Data Sets including targeted sequence data and genotype/genomic or custom chip data likely to be successful? Are methodical and statistical approaches for analysis and validation of the diverse ADSP datasets for harmonized genotype and phenotype data likely to provide meaningful data or provide break through approaches to analysis of the genome? Are approaches to validate targets (genes/regions/loci) identified likely to be successful? Is a plan for the Core to advise the PD(s)/PI(s) funded under the companion FOA for follow up analysis in place? Will proposed methods and technology address sequence or genotype quality problems?

Is the analysis plan for joint/meta- data analysis in keeping with the current ADSP Replication Phase plan? Is the approach likely to be successful? Will the overall strategy, methodology, and analyses done by the Core be appropriate to accomplish the specific aims of the Center project and the goals of the ADSP? Will the objectives, approaches, analysis protocols, and statistical approaches to be used provide key information to identify potential genes/regions/loci important to AD? Will data and statistical or other analytical approaches applied to studies of unique populations or diverse ethnic groups be generated and are they likely to be successful? Are technological challenges upon which the rest of the approach depends likely to be overcome? Will analysis of harmonized data across datasets be likely to help define AD phenotypes? Will the project avoid redundancy of existing infrastructure and leverage existing resources? Are high risk plans counterbalanced to manage inherent risks? Are key scientific, statistical, or technological challenges upon which the rest of the approach to analyze the data depends clearly defined and alternative approaches proposed? How likely is analysis of the various harmonized ADSP data sets to augment the ADSP Discovery Phase and Replication Phase analysis and the ADSP as a whole? Does the plan include an explanation of the role the Core will play in ADSP activities as a whole, and an explanation of how the Core will coordinate and integrate ADSP Discovery and Replication Phase analysis components and activities?

Will the Core, working cohesively with other ADSP investigators and other Cores appropriately manage, coordinate, and integrate joint/meta-analysis activities? Is the plan to act in an oversight capacity one that fosters cooperation? Are protocols and mechanisms for receiving, managing, and making available the genotype, sequence, and phenotype data to other Cores for analysis appropriate? Are protocols and mechanisms for receiving and processing data from other studies effective? How well will these efforts be coordinated among the other Cores? How well will the Core analyze ADSP Replication Phase data? Is an appropriate and efficient mechanism proposed to work with investigators funded under the companion FOA to generate Replication Phase data, the NIAGADS / dbGaP portal, and investigators performing similar analysis outside of the ADSP in place? Will the Core interact with the various components of the ADSP and the AD research community efficiently and effectively?

Are an appropriate timeline and milestones for the project proposed?

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 - Biostatistics and Data Analysis Core

As applicable for the core 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 coret 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 Biostatistics and Data Analysis Core

As applicable for the core 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

Not Applicable

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) Genome 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 Project Director/Principal Investigator (PD(s)/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 Project Director/Principal Investigator (PD(s)/PI(s))of the Center will have the primary responsibility for the following:

The Core Leaders will work collaboratively with key Core leaders, investigators funded under the companion FOA and other NIA awardees, members of the ADSP, NHGRI, and NIA. The Center will participate in ADSP study design and analysis. The primary governing body for the Replication Phase 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 Center 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 Center PIs/PL(s) that will serve in a decision making capacity for the cooperative agreement in collaboration with the NIA Project Scientist. The IOC should agree to work cooperatively with the ADSP SC and ADSP Working Groups, awardees of the companion RPS FOA, the ADSP Steering Committee, 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 Principal Investigators and Core Leaders should develop and implement approaches necessary for data analysis, data harmonization, statistical analysis and final outcome data. A committee that is responsible for data sharing among the various components of the ADSP Discovery Phase and Replication Phase components will be established using existing ADSP infrastructure (see the section herein on the Resource Sharing Plan).

The IOC should develop and implement systems necessary for communication between the various awardees of the companion RPS FOA, awardees of cooperative agreements funded under http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html, and the ADSP membership at large.

To oversee the distribution of data generated by the ADSP Replication study, a Data Use Committee (DUC) should be established for use of ADSP Replication Data in keeping with ongoing ADSP operations and existing NIA policies and that engage dbGaP, the dbGaP Data Access Committee, and the NIAGADs DUC https://www.niagads.org/content/about-niagads. The Center DUC will work collaboratively with the NIAGADS DUC on data deposition and data access tasks. An internal operations committee (IOC) comprised of investigators funded under the Center will nominate members from within for the DUC. Committee membership will rotate periodically according to a procedure that is agreed upon by the ADSP Steering Committee. Final approval of members of the DUC will be made by the NIA Program Officer.

Collaborating institutions providing genome wide association, exome chip, whole genome, whole exome sequence data, genotype data or other types of data to the Center 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.

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

The designated 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 Official 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, which should include 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 Center and the companion FOA will hold teleconferences as needed and 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 and Subcommittees appointed by the IOC, comprised of appropriate staff from the Cores and the NIA Project Scientist, 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 FOA should develop and implement systems necessary for communication between the various study components in collaboration with the NIA Scientist.

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 Center to provide guidance in data analysis or other aspects of the Center efforts, the ADSP Replication Phase of the study, and integration of outcomes between the ADSP Discovery Phase and Replication Phase

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: commons@od.nih.gov

Grants.gov Customer Support(Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

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

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

John Bladen
National Institute on Aging (NIA)
Telephone: 301-402-7731
Email: bladenj@nia.nih.gov

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.