Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute on Aging (NIA)

Funding Opportunity Title

National Institute on Aging Analysis of Alzheimer's Disease Genome Sequencing Project Data [U19]

Activity Code

U19 Research Program – Cooperative Agreements

Announcement Type

New

Related Notices

  • April 5, 2013 - See Notice NOT-AG-13-006. Notice of Availability of Updated Sequencing Plan.
  • February 8, 2013 - See Notice NOT-AG-13-001. Notice of Termination as of May 29, 2013.
  • January 4, 2013 - See Notice NOT-AG-12-023. Notice of Availability of a Sequencing Plan.
  • September 28, 2012 – See Notice NOT-OD-12-161. NIH Announces Plans to Transition to Electronic Submission of Multi-Project Applications
  • August 1, 2012 - See Notice NOT-AG-12-013. This Notice cancels the August 7, 2012 and September 25, 2012 application dates, and extends by one additional submission date.

Funding Opportunity Announcement (FOA) Number

PAR-12-183

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.866

Funding Opportunity Purpose

The National Institute on Aging invites applications specific to the analysis of whole exome and genome sequencing data provided by the National Human Genome Research Institute Large-Scale Sequencing Program for the Alzheimer's disease research community.

Key Dates
Posted Date

May 14, 2012

Letter of Intent Due Date

July 8, 2012

Application Due Date(s)

(Extended to January 25, 2013 per NOT-AG-12-013), then Standard dates apply, Originally August 7, 2012 

AIDS Application Due Date(s)

Standard dates

Scientific Merit Review

Standard dates

Advisory Council Review

Standard dates

Earliest Start Date(s)

February 2013

Expiration Date

(New Date May 29, 2013 per NOT-AG-13-001), Previously (Extended to January 8, 2014 per NOT-AG-12-013), Originally September 8, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, 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.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Electronically website.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Research Objectives and Background

This Funding Opportunity Announcement (FOA) is issued by the National Institute on Aging (NIA), National Institutes of Health (NIH) in response to a Presidential Initiative on Alzheimer's Disease (AD).  The overarching goals of the research are to:  (1) identify new genes contributing to increased risk of developing the disease,  (2) identify new genes contributing to protection against developing AD,  (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 National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (LSSP) will produce the sequence data and potentially variant call data, which will be made available to the scientific community through an NIA approved data repository.  Analysis of the sequencing data is anticipated to identify new genetic risk and protective factors in older adults at risk for AD.  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 proposed study should describe a comprehensive plan to develop leading edge innovative approaches for the analysis of whole genome sequencing data to extend previous discoveries that may ultimately result in new directions for AD therapeutics.  Grant applications will be evaluated and funded based on the strongest potential to reveal novel genetic markers for AD based on comprehensive analytical methods.  

Research Strategy and Scope  

Under the award, the investigator will lead comprehensive analyses of whole exome and/or whole genome sequencing data 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.  Specifically, the aims of the Alzheimer's Disease Sequencing Project 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/drugs for prevention.  

NHGRI LSSP will provide whole exome and/or whole genome sequencing data via an NIA approved data repository for analysis.  Specifically, the NHGRI LSSP will provide read data with essential quality control information, and may provide initial analysis results that identify variants (variant calling).  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.

Both the sequencing data provided by the NHGRI LSSP and the outcome data derived from the analyses will be stored at an NIA approved data repository.  Data derived from the analyses of the sequencing data will be made available for analysis by the AD research community through the NIA approved data repository.

The samples for the Alzheimer's Disease Sequencing Project 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.  The sequencing data are expected to contain the genomes of at least 2,500 subjects.  Principal Investigators (PI[s]s) funded through this FOA will obtain from the NIA approved data repository:  (1) cleaned, quality control checked sequencing data,  (2) information on the composition of the study cohorts (e.g. case-control, family based, and epidemiology cohorts),  (3) descriptions of the study cohorts included in the analysis,  (4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures, and  (5) epidemiological information such as educational level and certain environmental data available on the subjects genotyped.

Examples of the expected types of analytical assessments to be accomplished in order to provide a complete evaluation of the genomic contributions to risk and protection for AD include: gene discovery, association analysis, read mappings, variant frequencies, quality control information, coding sites, non-coding sites, and splice sites for affected genes. The grant application should fully describe:  (1) the analytical approaches to identify genetic risk and protective factors (a variety of approaches may be employed); (2) the qualities and characteristics of the genomic sequence information to be produced by the investigator; and (3) the projected funding requirements. Applicants will be allowed to re-sequence limited amounts of DNA, for example, to validate findings.

The application should describe the capabilities for sequence storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms along with a time line for accomplishing the stated goals, and the costs related to the analysis.  In the description of the data analyses, the investigator should consider phenotypes, disease-related covariates, and significance of association with the disease for common, rare, and unique sequences.  The investigator should also describe how structural rearrangements, insertions, deletions, and haplotypes as genomic changes will be analyzed and correlated with disease status. Knowledge of rearrangements may reveal new biological mechanisms in understanding and diagnosing the disease. 

Applicants are encouraged to devise analysis plans to include data from:

The award will provide funds for analyses of the data provided by the NHGRI LSSP as described above, computer software and hardware and bioinformatics and statistical analysis, along with support for the personnel needed to conduct the analyses.  A description of the design and use of large scale storage capacity with appropriate security and back up measures to support analytical capabilities should be included. The budget may include support for the formation of groups of investigators at several institutions to assemble a team with the appropriate balance, breadth, and experience. 

The successful applicant(s), hereafter called the AD "Sequencing Analysis Consortium" (SAC), should consist of a group of researchers with expertise in the genetics of complex neurological diseases and the field of whole exome/genome sequencing statisticians and other experts who will participate in study design and analysis.  The explanation of SAC procedures and functions should include:  (1) the structure of the SAC including any cores, projects, or subprojects;  (2) an external board of advisors;  (3) a committee or core to oversee the normal operations of the consortium,  (4) a committee or core responsible for data analysis;  (5) a committee or core to review material in advance of presentation at national or international meetings and before publication in peer reviewed journals; and  (6) a committee or core to review and approve applications from within the SAC itself for secondary data analysis.  Successful applicant(s) may be expected to collaborate not only within their SAC, but also with other PD(s)/PI(s) funded under this FOA, together with the NHGRI LSSP and the NIA.

Applicants should elaborate key quantitative milestones with a time line for accomplishment. 

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

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.  In keeping with the NIA Genetics of Alzheimer's Disease Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan, outcome data from the study will be deposited into dbGaP http://www.ncbi.nlm.nih.gov/gap and the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) http://alois.med.upenn.edu/niagads/ or another NIA approved data storage site for access by the AD research community.  In addition, outreach efforts should be undertaken to maximize data sharing in order to enhance research in AD; for example, the AD research community may be contacted via a list serve, or a website may be used to provide information about the study.

In summary, the NHGRI LSSP is expected to generate a large amount of sequence, annotation, and related data for the examination and comparison of the genomes of affected and unaffected individuals.  The analyses done by the successful applicant(s) will identify new genes contributing to increased risk of developing the disease or protection against developing AD with the goal of identifying potential avenues for therapeutic approaches and prevention of the disease.  Data resulting from this study will become available to qualified investigators to enable rapid identification of therapeutic targets.

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

New
Resubmission

The OER Glossary and the PHS398 Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.

NIH intends to fund an estimate of 1-3 awards, with up to $2,000,000 direct cost per award for fiscal year 2013. Future year awards will depend on annual appropriations.

Award Budget

Application budgets are not limited, but need to reflect actual needs of the proposed project.

Award Project Period

A maximum period of four (4) years.

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

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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 eligible to apply.

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

Required Registrations

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 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.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the PHS 398 Application Guide.

Section IV. Application and Submission Information

1. Address to Request Application Package

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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 NIA 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:

The letter of intent should be sent to:

       Marilyn M. Miller, Ph.D.
       Program Director
       Genetics of Alzheimer's Disease
       Division of Neuroscience
       NIA / NIH / DHHS
       7201 Wisconsin ,Suite 350
       Bethesda, Maryland 20892
       Voice: 1 301-496-9350
       Fax: 1-301-496-1494
       Email: millerm@nia.nih.gov

Application Submission

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and all copies of the Appendix files must be sent to:

Dr. Ramesh Vemuri
Chief, Scientific Review Branch
National Institute on Aging
7201 Wisconsin Avenue
GW 2C218
Bethesda, MD 20892
Telephone: 1-301- 402-7700
Fax: 1-301- 402-0066
Email: Vemuri@nia.nih.gov

Page Limitations

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

How to Organize the Application

Section 1: Information for the Entire Application

Form page 1. Include the number and title of this FOA in item/line 2 of the PHS 398 face page.

Table of Contents: Modify PHS Form Page 3 to enable reviewers to find each component of the application easily. Number all pages consecutively. Because the first page of the application is the Title Page, begin the next page with the numeral "2". Do not use lettered numbers (e.g., "2A", "2B" etc.).  Use these referent numbers in the Table of Contents.

Form Pages 4 and 5: Detailed Budget for Initial Budget Period; Budget for Entire Proposed Period of Support.  Prepare a detailed composite budget (across all subprojects and cores) for all requested support categories for the first year using Form Page 4 and a summary budget for the entire proposed period of support using Form Page 5 of the PHS 398 application. If applicable, provide additional budget pages for consortium/contractual arrangements.

Biographical Sketches

When an investigator has a role in more than one part of the application, then a complete biosketch should be placed in each section where the individual has a role. As the particular qualifications for roles may differ between cores and subprojects or between different subprojects, the selected publications and the description of qualifications for the individual may differ among the several biosketches listed.

Resources

Reviewers will use information from the Resources page to evaluate the quality of the scientific environment for the research proposed. Applicants should complete separate Resources pages for all projects and cores. Reviewers will use information from the Resources page of the Administrative Core to evaluate the quality of the overall environment for the consortium.

Section 2: Overall Program Objectives

Specific Aims: Limited to one page.  Describe the aims of the overall project and outline how the component projects and cores will contribute to these aims.

Overall Research Strategy: Limited to six pages.

Items 1, 2 and 3 below are to be included in the six page limit.

1. Significance: Focusing on the project as a whole address: (i) the importance of the problem or critical barrier to progress in the field that the proposed project addresses, (ii) how the proposed project will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields, (iii) how the concepts, methods, technologies, or services that drive this field will be changed if the proposed aims are achieved, (iv) how the proposed project will identify new genes contributing to increased risk or protection of developing AD, (iv) how the proposed project will constitute a substantial advance in analytical approaches for whole genome or exome sequencing for complex diseases. (One to two pages recommended).

2. Innovation: Considering the project as a whole, show how the proposed research seeks to shift current research or clinical practice paradigms through use of novel concepts, approaches, methodologies, instrumentation, or interventions. Are these concepts, approaches, methodologies, instrumentation, or interventions novel to the research field or novel in a broad sense?  Does the proposed work refine, or improve, or apply in a new way, the concepts, approaches, methodologies, instrumentation, or interventions proposed?  Will the proposed project provide insight as to why individuals with known risk factor genes escape from developing AD? Will the proposed project identify potential avenues for therapeutic approaches and prevention of the disease? (One page recommended).

3. Approach:  Include the major approaches and studies involved in the application showing how the approaches of cores and individual projects complement each other or are inter-dependent.  Describe the mechanisms that will ensure the coherence of the overall project and maintain a multidisciplinary focus. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?  Are potential problems, alternative strategies, and benchmarks for success presented?   Is the analytical strategy feasible?  How will particularly risky aspects be managed?    (Three to four pages recommended.)

Human Subjects

List the components of the application that involve human subjects and page numbers for the relevant human subjects sections.   In other words, it is requested that the applicant list all the page numbers, where human subjects are used, in sequential order.

Women, Minorities and Children

Describe the composition of the human subjects cohorts.  List the page numbers for the relevant Women, Minorities, and Children sections. For most NIA applications involving human participants, a justifiable exclusion for children is that the topic is not relevant to children. See PHS Form 398 instructions.

Section 3: Research Strategies for Individual Cores and Component Projects

There are three required cores.  Each component core should be presented according to the Table of Contents. Identify the required cores by letters as follows:

Core A = Administrative Core

Core B = Analysis and Statistics Core

Core C = Data Management and Information Transfer Core

Optional cores: Demonstrate the augmentation or enhancement of capabilities of SAC resources to make possible new activities for the applicant SAC as well as other SACs that may be funded under this FOA. Provide a description of research project(s) that will use resources of the additional core(s).

How to organize the layout of the Cores and Component Subprojects

How to Organize Cores

A core is a shared central laboratory or research facility, service, or resource whose function is essential to the scientific purpose of the consortium.  Each core is directed by an investigator with substantial expertise related to the core.  Facilities may be proposed that will enhance productivity or in other ways benefit a group of investigators to accomplish stated goals.  Several important and related considerations are: (1) the degree to which currently funded investigators within or outside the SAC will use and will benefit from core resources; (2) the degree to which the cores coordinate with each other to further the overall SAC mission; and  (3) the degree to which the resources will promote new and/or expanded AD research efforts locally, regionally, nationally, or globally.   Applicants should document and briefly describe existing, pending, and planned research, whether funded by NIH or another foreign or domestic entity, that will depend upon resources provided by the requested cores.

For all cores:  Clearly state how the core will contribute to the goals of the SAC and outline interactions of the core with each of the other cores of the consortium.

Follow instructions in the PHS 398 form with the following exceptions:

Specific Aims: (1 page)

Identify which projects the core will assist and indicate the overall role of the core in the program project.

For each of the cores organize the Research Strategy into sections on:

a. Significance: Describe how the core will enhance the outcome of the project as a whole; and

b. Approach:

Core A - Administrative Core. Describe how the Core will coordinate and integrate SAC components and activities; how the Core will support and advise the SAC PD(s)/PI(s) in oversight of the activities of the SAC; how the Core will interact with scientific communities to develop relevant goals for the SAC; how the Core will assist in coordination and organization of external and internal advisory committee meetings;  how the Core will ensure compliance with human subjects, data sharing, scientific integrity, and financial policies and practices; how the Core will interact with other SACs funded under this FOA; how the Core will interact with the NIA and NIH funded data storage sites (e.g. (NIAGADS http://alois.med.upenn.edu/niagads/; dbGaP http://www.ncbi.nlm.nih.gov/gap) and how the Core will coordinate with NIA on media coverage of the latest research findings of the SAC.

Core B - Analysis and Statistics Core. Describe how the Core will work with other components of the SAC to ensure data are represented in a fashion that can be made readily available to other qualified researchers for further analysis; how the Core will ensure that the SAC's resources are optimally utilized; how key scientific or technological challenges will be addressed; how the analysis of sequencing data will be handled; what new statistical approaches or other analytical methods will be developed that can be applied to the genetics of complex disease; how plans for collaboration with key investigators and consortia in the field of Alzheimer's genetics such as the ADGC (http://alois.med.upenn.edu/adgc/) and/or CHARGE (http://web.chargeconsortium.com/) will be developed; and how milestones will be met.

Core C - Data Management and Information Transfer Core. Describe the plan to accept and use the NHGRI LSSP sequencing data; data flow schemes; the capacity of the data storage facility; how the Core will ensure that the SAC's resources are optimally utilized; what system of identifying a specific subject's data will be in place that will work across Projects, Cores, and other SACS funded under this FOA; what measures will be taken to de-identify subjects' data; how key scientific or technological challenges will be addressed; what milestones will be developed; what filing systems will be put in place for assessment of progress by the investigators and the NIA; what filing systems will be put in place for raw and curated data to work across Cores and Projects; what mechanisms will be established to track data edits (i.e. data freezes); how the data management plan will address sequence quality and sequencing of entire genomes as well as exomes; how collaborations with other SACs will be established; when outcome data will be placed in an NIA approved data storage sites (e.g. NIAGADS http://alois.med.upenn.edu/niagads/; dbGaP http://www.ncbi.nlm.nih.gov/gap) to permit expeditious access to the AD research community; and what collaborations with key AD investigators in the field of data analysis and data management will be established.

How to Organize Subprojects

Following Instructions in the PHS 398 form, the Research Strategy should be organized into sections on: a. Significance; b. Innovation; and c. Approach.

Subproject(s): The application must have at least one subproject with the goal of identifying AD risk and protective factors.  The Research Strategy for this required subproject should include:

     Significance

How will collaborative efforts with existing entities occur?  An important element in the reviewers' scoring decisions is the ability to maximally engage existing resources. Examples of existing infrastructure include:       

Innovation

     Approach

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide, with the following modifications:

If not adding any modifications, replace the text above “with the following modifications” with “.” and delete the bullets below. If using either bullet 1 or bullet 2 as a modification, delete the bullet you are not using.  DO NOT KEEP BOTH BULLETS.

A fundamental purpose 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. Data will be shared in accordance with existing NIH and NIA protocols and policy. All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan that is in keeping with the NIA Genetics of Alzheimer's Disease Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan. The data sharing plan must be approved by the NIA Program Officer in advance of making the award.  The 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.   Outcome data from the study will be deposited into dbGaP http://www.ncbi.nlm.nih.gov/gap and the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) http://alois.med.upenn.edu/niagads/ or another NIA approved data storage site for access by the AD research community.  In addition, outreach efforts should be undertaken to maximize data sharing in order to enhance research in AD. For example, an interactive website may be provided for researchers outside the SAC to address queries on what data are available and how to access data.

To oversee the distribution of data generated from the study, a Data Allocation Review Committee (DARC) should be established as a component of an internal operations committee (IOC) (see terms and conditions of award).  The IOC will nominate members from within for DARC.  This group will review applications for use of the data within the SAC such as for secondary analysis by subgroups of investigators who are members of the SAC or collaborators who are outside of the SAC.  The format of the application and criteria for the use of data within the consortium, will be developed by the DARC with advice and approval from the IOC and made available to qualified potential users.  Membership on this committee will rotate periodically according to a procedure developed by the DARC. Final approval of members of the DARC will be made by the NIA Program Officer.

All data shall be placed in the public domain and shared freely by methods and within time periods to be specified by the NIA and NIH policy, and particularly as specific by the NIA Genetics of Alzheimer's Disease Sharing Policy http://www.nia.nih.gov/research/dn/alzheimers-disease-genetics-sharing-plan

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide.

Foreign Institutions

Foreign (non-US) Institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the PHS398 Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. 

Information on the process of receipt and determining if your application is considered “on-time” is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 postmarked on or before the due dates in Part I. Overview Information.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.  

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/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria - Overall and Project Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the proposed work identify genetic risk to the disease through comprehensive analyses of existing genetic and genomic data sets?  Are the plans sufficiently bold to constitute a substantial advance in the ability to analyze whole genome and exome sequencing data? 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 and project(s) integrate the activities and add value to the individual parts?

Investigator(s)

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

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 overall project and the individual project(s) will new statistical approaches or other analytical methods be developed that can be applied to the genetics of complex disease? Are novel approaches to integrating the analysis of genome wide association study data, exome sequencing data, and/or whole genome sequencing data employed?  Will novel approaches to analyzing intergenic regions of the genome be developed? Are there innovative strategies for analysis of existing genomic data sets that will lead to the development of new paradigms for analyzing genotype-phenotype relationship in AD research? Does the proposed work lead to the development of innovative bioinformatics approaches or novel computational tools to analyze and interpret multiple high-throughput genomic data sets? 

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

For the overall project and the individual project(s), how well will the project(s) and cores be integrated? Are key scientific or technological challenges on which the rest of the approach depends, identified and addressed early in the project?  Does the proposed technology address sequence quality and the sequencing of entire genomes?  Is the approach to the analysis of sequencing 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 the timeline and milestones logical and realistic?  Are key technical barriers and dependencies identified? Are milestones adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NIA?  Are plans to participate actively and openly in data sharing sufficiently clear?  Are plans to collaborate with other SACs funded under the award forthcoming so as to contribute substantially to advancement of the field?

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 project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Review Criteria for the Cores

Core A: the Administrative Core

Significance

Investigator(s)

Approach

Environment

Core B: Analysis and Statistics Core

Significance

Investigator(s)

Approach

Environment

Core C: Data Management and Information Transfer Core

Significance

Investigator(s)

Approach

Environment

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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

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

Renewals

Not applicable.

Revisions

Not applicable.

Additional Review Considerations - Overall

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

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

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

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

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. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center and 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) 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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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 PI(s)s is anticipated during the performance of the activities.  Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities.  Consistent with this concept, the dominant role and prime responsibility resides with the PI(s) for the project as a whole, although specific tasks and activities may be shared among the PI(s)s and the NIH as defined below.

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

The PD(s)/PI(s) of the project(s) will work collaboratively with key investigators and core leaders via the SAC to participate in study design and analysis.  The primary governing body of the study will be the Internal Operations Committee (IOC).  The PD(s)/PI(s) will be responsible for the formation of the IOC, which will have responsibility for the final details of study design, policy decisions, overall management of the study and will define the rules regarding access to data and samples.  The IOC will be comprised of the SAC PD(s)/PI(s) and the Project and Core PIs/PLs 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 cores, committees, the NHGRI LSSP, the NIA, and other SACs funded under this FOA.  The IOC should develop and implement systems necessary for communication between the various study components and supporting Centers, Repositories, and any collaborating SACs, including but not exclusively:

The IOC will facilitate the design and refinement of all protocols, manuals of operations, and forms.  A committee that is comprised of the PD/PI of the Analysis Core, key staff in the Analysis Core, and selected members of the IOC should develop and implement approaches necessary for data analysis, statistical analysis and final outcome data. 

A committee that is responsible for data sharing within the SAC will be established (see the section herein on the Resource Sharing Plan).

In the event of multiple awards under this FOA the PD(s)/PI(s) of each SAC should agree to work cooperatively with the other SACs.  In this event, the IOC of each of the SACs should develop and implement systems necessary for communication between the various SACs. 

Collaborating institutions providing genome wide association data, exome sequencing data or other types of data to the SAC will retain custody and primary rights to the site-specific data developed under their individual awards, subject to Government rights of access, consistent with current HHS, PHS, and NIH policies.

Institutions that are award recipients will retain custody of and have primary rights to the data and software developed under the award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.  

External Board of Advisors: In consultation with NIA, an external board of advisors will be selected, to be comprised of individuals not directly involved in the SAC to provide guidance in data analysis or other aspects of the SAC.

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

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. 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 director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The IOC 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.

Each full member of the IOC, which should include the NIA Project Scientist, 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 projects 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.

In the event of multiple awards under this FOA, a committee comprised of members of each of the SACs should develop and implement systems necessary for communication between the various study components in collaboration with the NIA Scientist. 

Dispute Resolution:

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

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) 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 sub-awards 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 Sub-award Reporting System (FSRS) available at www.fsrs.gov on all sub-awards 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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Marilyn M. Miller, Ph.D.
National Institute on Aging
Tel.: 301-496-9350
Email: millerm@nia.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Ms. Linda Whipp
National Institute on Aging (NIA)
Tel.: 301.402.7731
Email: WhippL@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.


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