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

Limited Competition: NIA Genome Center for Alzheimer's Disease (GCAD) (U54 Clinical Trial Not Allowed)

Activity Code

U54 Specialized Center- Cooperative Agreements

Announcement Type

Reissue of RFA-AG-16-001

Related Notices
  • August 23, 2019 - Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137.
  • July 26, 2019 - Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128.
Funding Opportunity Announcement (FOA) Number

PAR-19-288

Companion Funding Opportunity

PAR-19-234 , U01 Research Project – Cooperative Agreements


PAR-17-214, U01 Research Project – Cooperative Agreements

 
PAR-18-890, U01 Research Project – Cooperative Agreements

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

 93.866 

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites applications to continue the operations of the NIA Genome Center for Alzheimer's Disease (GCAD) to facilitate and support the Alzheimer's Disease Sequencing Project (ADSP) activities. GCAD will serve as the focal point for all phases of ADSP quality control checking, data harmonization, and meta-analysis. The FOA is intended to support a major component of the full range of analysis for the ADSP. The spectrum of the Center's activities comprises a multidisciplinary attack on Alzheimer's disease (AD) and AD-related dementias (ADRD), in keeping with NIA's programmatic needs. The Center will serve as a national resource for the specific purpose of identifying potential avenues for therapeutic approaches and prevention of the disease.

Key Dates

 

Posted Date

May 23, 2019

Open Date (Earliest Submission Date)

August 25, 2019

Letter of Intent Due Date(s)

August 25, 2019

Application Due Date(s)

Standard dates apply by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

 Not Applicable

Scientific Merit Review
Advisory Council Review
Earliest Start Date
Expiration Date

September 26, 2022

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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


There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Table of Contents

    Part 1. Overview Information
    Part 2. Full Text of the Announcement

    Section I. Funding Opportunity Description
    Section II. Award Information
    Section III. Eligibility Information
    Section IV. Application and Submission Information
    Section V. Application Review Information
    Section VI. Award Administration Information
    Section VII. Agency Contacts
    Section VIII. Other Information


    Part 2. Full Text of Announcement
    Section I. Funding Opportunity Description

    In response to the National Alzheimer's Project Act (NAPA), an initiative called the Alzheimer's Disease Sequencing Project (ADSP) was launched in 2012. 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 to 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 can be found at https://dss.niagads.org/sample-sets/adsp-discovery/.

    This FOA is intended to provide continued funding for: (1) quality control checking, data harmonization, and joint and meta data analysis of ADSP sequence, genotype, and phenotype data by the NIA Genome Center for Alzheimer's Disease (GCAD); and (2) infrastructure support for the ADSP Follow UP Study (FUS) sequencing and analysis that will be funded under a number of cooperative agreements and individual grants to NIA-funded investigators. Together, these grants and cooperative agreements will generate ADSP Discovery Phase, Discovery Extension Phase, and FUS data. Funds are provided through this FOA for management and analysis of a variety of types of data that will be generated.

    In 2017, NIH released NOT-AG-17-007.html. It aligns the Alzheimer's disease concept with the term as used in NAPA and Public Law 111-375. Under NAPA, Alzheimer’s disease is defined to include the Alzheimer’s disease related dementias (ADRDs) in research and other activities that will lead to a decrease in the growing public heath burden caused by dementia in our aging population (see NAPA 2012 2013 and NAPA 2016). The National Plan to address Alzheimer’s disease defines ADRDs to include: 

    1.    Frontotemporal Dementia (FTD) including Frontotemporal Lobar Degeneration (FTLD), Primary Progressive Aphasia (PPA), Progressive Supranuclear Palsy (PSP), Corticobasal degeneration (CBD), and Pick’s Disease
    2.   Lewy Body Dementia (LBD) including Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD)
    3.   Vascular Dementia including vascular dementia, vascular cognitive impairment (VCI), multi-infarct dementia, post-stroke dementia, and vascular brain injury
    4.   Dementia due to mixed pathologies
    5.   Dementia due to Down syndrome

    Data sets included under the present FOA are considered to include AD and ADRDs as defined in NOT-AG-17-007. The use of the term "AD" should be taken in this funding opportunity announcement to include both AD and ADRD.

    ADSP data sets and samples have been selected from well-characterized, ethnically diverse study cohorts of individuals with or without an AD/ADRD diagnosis and with 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 (NIAGADS): https://www.niagads.org/adsp/.

    The ADSP Discovery Phase

    The initial phase of the ADSP research plan is called the Discovery Phase. As part of the Discovery Phase, the ADSP generated three sets of genome sequence data: (1) Whole Genome Sequence (WGS) for 584 samples from 113 multiplex families (two or more affected per family), (2) Whole Exome Sequence (WES) for 5,096 AD cases and 4,965 controls, and (3) WES of an enriched sample set comprised of 853 AD cases from multiply affected families and 171 Hispanic controls. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. As part of the Discovery Phase, the NIA ADSP genetics investigators funded under PAR-12-183 and the National Human Genome Research Institute (NHGRI)-funded Large-Scale Sequencing and Analysis Centers (LSACs) conducted analysis of sequence data, including quality assessments and variant calling. Analysis of the Discovery Phase sequence data has identified many new variations in the genome that may be implicated as new genetic risk or protective factors in older adults at risk for AD. Additional information on ADSP activities can be found in PAR-16-406 and PAR-17-214.

    The ADSP Discovery Extension Phase

    To assess the genomes in diversity sample sets (African American and Caribbean Hispanics) and from well-phenotyped subjects with autopsy material, additional subjects were whole genome sequenced. This portion of the study is called the Discovery Extension Phase. These data have been harmonized with Discovery Phase data, called on Hg Build 38, and made available by application to NIAGADS. Whole genome sequence data from the Alzheimer's Disease Neuroimaging Initiative were jointly called with ADSP data. GCAD performed quality control checks, variant calls, and data harmonization on a total of 5,000 whole genome sequences. Data were released to the research community in September of 2018 through NIAGADS: https://dss.niagads.org/.

    The ADSP Follow-Up Study (FUS)

    In February 2016, ADSP consultants recommended that subsequent sequencing and analysis be done on whole genomes in lieu of whole exome or targeted sequencing. Initial funding was provided for the sequencing and analysis of up to 10,000 whole genomes. Due to the increase in efficiencies and the decrease in cost of sequencing, additional funding for ADSP whole genome sequencing will be provided under a separate funding opportunity announcement.

    The present FOA is designed to maintain existing essential infrastructure to facilitate analysis on ethnically diverse sample sets on as many as 30,000 whole genomes. Variants for the disease are rare or very rare and can only be identified with a larger number of subjects in the study. Major goals for this FOA are to maintain and leverage existing infrastructure and collaborations; to ensure continuity of ADSP operations; and to provide a funding stream for ADSP quality control checking, variant calling, data harmonization, and facilitation of data sharing for data generated on a large number of samples from individuals affected by AD.  

    The large-scale sequencing center, The American Genome Center (TAGC) at the Uniformed Services University for the Health Sciences (USUHS), and/or other large-scale sequencing centers will provide data to the GCAD. It is understood that in certain limited circumstances involving diversity sample sets, foreign institutions may be unable to provide sequence data to GCAD. In these cases, with pre-approval from the NIA Science Officer, an alternative sequencing center should be selected for whole genome sequencing; arrangements for data sharing with the ADSP must be made in advance of submission of the application.

    The ADSP as a whole will likely require production and analysis of a variable combination of studies that may include, but not be limited 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 diverse ethnic groups or other datasets; (3) GWAS of family members of subjects sequenced in order to assess segregation of variants with the disease; and (4) GWAS of family members who may carry a specific variant.
    • Genotyping by custom chip of genes/regions/loci in a variety of ethnic groups where the association with late onset AD appears attributable to common, low-frequency, rare, or very rare variants.
    • Targeted sequencing: Genome sequencing of signals in regions containing variants identified in the ADSP and other NIA-funded studies with GWAS, WES, or WGS data.  
    • Quality control checks including the matching of GWAS or other genotype data to sequence data; imputation of GWAS data; estimation of population substructure; and polygenic risk scores.
    • Data tracking: Receiving and managing genotype, phenotype, biomarker, and sequence data.
    • Recoding of phenotype data according to the phenotype specification defined by the ADSP.
    • Collection, processing, recalling/joint calling, and imputation of and/or genotype data from a number of cohorts from diverse populations.
    • Data Harmonization: Examples of data harmonization include but are not exclusive to: (1) Harmonization of ASDP Discovery Phase, Discovery Extension Phase, Follow Up Study, and WGS and WES data with other sequence or genotype data generated by the ADSP; (2) Harmonization of Discovery Phase WGS and WES data with data generated by investigators outside of the ADSP; and (3) Harmonization of study phenotype data across multiple studies from diversity sample sets whose Principal Investigator(s) (PIs) may be located outside of the US.
    • Meta-analysis and joint analysis of ADSP data with data generated by other US and international consortia.
    • Development of additional analytical approaches to replication/confirmation studies for discovery of therapeutic targets such as bioinformatics, biophysical modeling, and biological assays.
    • Application of artificial intelligence, machine learning, deep learning, or neural net analytical approaches referred to here as "cognitive sciences" analysis.

    The list of items above are selected elements of the ADSP as a whole as presently anticipated by NIA and not intended to be all inclusive.

    The present FOA will provide funds for quality control checking, variant calling, data analysis (joint analysis/meta-analysis) and data harmonization for the aggregate of studies related to the ADSP as a whole, along with infrastructure support for the ADSP. NIA seeks GCAD applications in research areas related to a subset(s) of the critical portions of the ADSP, as noted 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 study to complement the Discovery Phase of the ADSP. Data generated under the cooperative agreement award for this FOA will be shared with the ADSP and the research community at large through NIAGADS. 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 intent of this FOA is to encourage a cooperative and diverse group of investigators to continue to interact in a highly collaborative manner within the ADSP. GCAD will be expected to lead ADSP work from all phases of the study 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 research plan. Successful applicants are expected to work cooperatively to build a single plan as the project evolves under the auspices of the ADSP. In addition to presenting and actualizing the research plan, it is the responsibility of GCAD to act in a cooperative manner that takes into account how investigators within the ADSP and PIs who are not part of the ADSP, including those from foreign sites, perform their research plans. Applicants are encouraged to propose analytical approaches that add scientific value to the current plan. It is understood that data generated by individual grantee plans for analysis will likely need to be coordinated with the harmonization scheme carried out at GCAD to allow optimal data availability.

    Given the volume of the data presently being generated, new analytical approaches such as artificial intelligence, machine learning, deep learning, neural net, and other related "cognitive sciences" analytical approaches should be anticipated, as they are likely to be incorporated into ADSP genetic analyses in the coming years. GCAD should be sufficiently nimble as to readily incorporate data generated by these approaches as they evolve.

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

    • Capture, quality control check, variant call, and harmonize ADSP WES, WGS, targeted sequence, genotype, and analysis data from all phases of the study and process/reprocess these data using the ADSP consensus calling workflow. Joint/meta-analysis of the aggregate of ADSP data in collaboration with members of the ADSP as a whole, other NIA- and NIH-funded investigators, and investigators from foreign countries who wish to participate in the study.
    • Capture of sequence and genotype data from studies outside of the ADSP, integration and harmonization of these data with ADSP data, and 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 all phases of the ADSP and integration, harmonization, and joint/meta-analysis of these data.
    • Capture of data generated by cognitive sciences approaches.
    • Capture of data generated by pathway, network, and genetic hub analysis.
    • Data analysis of the aggregate of all types of harmonized ADSP 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 all phases of the study, as well as facilitation of rapid data sharing through NIAGADS according to existing ADSP and NIA policies.  
    • Providing all types of data to the ADSP NIAGADS database (https://www.niagads.org/adsp/) for rapid and broad sharing with the research community.
    • Development of additional analytical approaches to replication studies for discovery of therapeutic targets such as bioinformatics, biophysical modeling, and biological assays.

    Applicants are encouraged to devise analysis plans to include data from GWAS, imputation analysis, WES, WGS, and deep sequencing analyses generated on AD subjects in other existing studies.  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, splice sites, intergenic sites for affected genes, and imputation analyses. GCAD will notify ADSP investigators 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. To the extent possible, calling pipelines should be parallel to those used in other NIH-funded large-scale sequencing projects in order to facilitate joint calling and meta-analysis across complex diseases.

    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 study. 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 ADSP research plan that maximize the likelihood of success in identifying protective alleles and therapeutic targets will be considered within the scope of this FOA. Both fundamental scientific discovery and leading-edge analytical approaches will likely be needed to achieve the research goals. Therefore, the award funded under this FOA is 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 (1) lead comprehensive analyses of sequence data along with genotype data to replicate and validate data generated in the Discovery Phase of the ADSP, (2) identify novel genes that account for risk or protection in ethnically diverse cohorts, (3) identify new risk variants among AD cases with low genetic risk, (4) identify new risk variants among AD cases with high genetic risk, and (5) identify new pathways/targets for prevention.

    It is expected that the study will result in the confirmation of AD risk and protective alleles in multi-ethnic populations that may serve as therapeutic targets. Investigators funded under this FOA will receive, harmonize, analyze, and validate findings; coordinate analyses done by the various components of the ADSP; and provide analyzed data to the research community via NIAGADS. Awardees of the U54 will provide imputed and harmonized targeted sequence and genotype data derived from existing or new GWAS, WES, and/or WGS sequence data as a research resource for rapid sharing with the scientific community through NIAGADS or another NIA-approved database. Data processed by GCAD will be provided to the NIAGADS database for analysis by the research community at large. Sequence, genotype, harmonized, and related outcome data derived from the analyses will be stored at an NIA-approved data repository or NIAGADS database consistent with the goals of this program.

    Applications considered for funding must effectively leverage NIA and NIH investment in infrastructure to support studies related to the genetics of Alzheimer’s disease. Every effort should be made to engage the existing ADSP database, NIAGADS (https://www.niagads.org/), a key research resource for the effort. Creation of infrastructure that is redundant to that supported under the funding opportunity announcements (grants and cooperative agreements) related to the ADSP, in particular NIAGADS (funded under PAR-16-047), should be avoided.

    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, as well as bioinformatics and statistical analysis;
    • "cognitive sciences" approaches; and
    • support for the personnel needed to conduct the analyses.

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

    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 in multiple ethnic groups. Findings of the ADSP and other research groups will be confirmed, and data across multiple studies will be harmonized by GCAD to identify and validate risk and protective alleles for AD. Successful applicant(s) will propose analyses using existing and novel approaches on the aggregate of AD genetic studies related to the ADSP. Studies will identify new genes/regions/loci contributing to increased risk of developing AD or protection against developing AD, with the goal of identifying potential avenues for therapeutic approaches to 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.

    See Section VIII. Other Information for award authorities and regulations.

    Section II. Award Information
    Funding Instrument

    Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.  

    Application Types Allowed

    New
    Renewal
    Resubmission
    Revision

    The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

    Clinical Trial?

    Not Allowed: Only accepting applications that do not propose clinical trials

    Need help determining whether you are doing a clinical trial?

    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 one award, corresponding to approximately $2.5 million in direct costs, for fiscal year 2020. Future year amounts will depend on annual appropriations.

    Award Budget

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

    Award Project Period

    The scope of the proposed project should determine the project period. The maximum project period is 5 years.

    NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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:

    o   Hispanic-serving Institutions

    o   Historically Black Colleges and Universities (HBCUs)

    o   Tribally Controlled Colleges and Universities (TCCUs)

    o   Alaska Native and Native Hawaiian Serving Institutions

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

    Nonprofits Other Than Institutions of Higher Education

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

    For-Profit Organizations

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

    Governments

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

    Other

    • Independent School Districts
    • Public Housing Authorities/Indian Housing Authorities
    • Native American Tribal Organizations (other than Federally recognized tribal governments)
    • Faith-based or Community-based Organizations
    • Regional Organizations
    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  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) – 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.
    • o   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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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).
    Section IV. Application and Submission Information
    1. Requesting an Application Package

    The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

    2. Content and Form of Application Submission

    It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, 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.

    Letter of Intent

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

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

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

    The letter of intent should be sent to:

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

    Page Limitations

    Available Component Types

    Research Strategy/Program Plan Page Limits

    Overall

    12

    Administrative Core

    6

    Data Management Core (Use for Data Management, Harmonization, and Information Transfer Core)

    6

    Data Analysis Core (Use for Biostatistics and Data Analysis Core)

    6

    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.

    Revision applications must include an Overall component and the components that are affected by the revision. Therefore, the component requirements listed below may not apply to the revision application.

    The application should consist of the following components:

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

    When preparing your application, 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 (1) researchers with expertise in the capacity to quality control check, call genetic variants of, harmonize, and meta-/jointly analyze 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 (2) 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)

    Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

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

    Significance
    For the Center as a whole, address plans to position the proposed activities within the framework of the ADSP. Explain Core elements in the context of the plan to establish a central role for GCAD. 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; and how the PD(s)/PI(s) and Core Leaders of the Center will cooperate and act in a leadership capacity while working with other ADSP investigators for analysis of the aggregate of the ADSP data.

    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. Explain how the work plan provides sufficient flexibility to incorporate "cognitive systems analysis" (artificial intelligence, machine learning, deep learning, neural networks) by working with investigators to advance the field and by engaging various analytical approaches to capitalize on the data. Describe the strategy chosen to analyze and compare data from several diverse populations.

    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 data as a whole and for individual projects. 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 continuity with existing infrastructure and collaborations will be maintained.

    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 GCAD 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, to foster rapid data sharing with the research community, and to collaborate with other investigators in the ADSP and with awardee(s) of other NIH-funded studies. Provide diagrams of workflow.

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts. Proposed projects should present 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.

    Define milestones and a timeline for key events for the project.

    Letters of Support: Provide letters of support for the overall Center that address how the ADSP will be advanced by collaborations, how the study will proceed efficiently, and how infrastructure will be effectively supported.

    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 modifications:

    • ·    It is expected that the NIA policy of rapid data sharing with the community at large will be maintained in keeping with existing ADSP practices, existing sharing agreements, NIA policies, and NIAGADS data distribution policies. 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 rapidly make the data derived from the analyses widely available to the Alzheimer's research community to accelerate the development of therapeutic approaches to and prevention of AD. It is expected that data will be shared in accordance with existing NIH and NIA protocols and policies. 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 NIAGADS Data Distribution Data Distribution Agreement (https://www.niagads.org/sites/all/public_files/NIAGADS-DDA.pdf).
    • ·    Outcome data from the study will be deposited into 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, either though GCAD or NIAGADS, to address queries on what data are available and how to access data.
    • ·    Applicants are expected to comply with the NIH Genomic Data Sharing Policy (https://osp.od.nih.gov/scientific-sharing/genomic-data-sharing/).
    • ·    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

    PHS Human Subjects and Clinical Trials Information (Overall)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

    PHS Assignment Request Form (Overall)

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

    Administrative Core

    When preparing your application, use Component Type ‘Administrative 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. Directed by an investigator with substantial expertise related to the Core, the Administrative Core 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)

    Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

    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. Explain 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

    Explain 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. Describe how collaborations facilitated by the Administrative Core will 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. Include plans for outreach to, and inclusion of, a diverse community of investigators to enhance potential for developing new and exciting research. 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 ADSP investigators of newly identified gene/regions/loci for follow-up studies.

    Explain how a cooperative spirit will be fostered by the Center. The plan should explain how staff will collaborate on multiple projects and Cores within the Center. The plan should include a statement of agreement to collaborate with other cooperative agreements funded under NIA FOAs. Describe how the Core will coordinate and integrate components and activities of the ADSP including the Discovery Phase, Discovery Extension Phase, and the Follow-Up Study. Define efforts to ensure ongoing collaborations are maintained and new collaborations are developed. Define efforts for cooperation with the ADSP Steering Committee and ADSP investigators and work groups; the various components of NIA-funded infrastructure (NCRAD, ADCs, NACC, TAGC and other sequencing centers, and NIAGADS); awardees of studies funded by other NIH institutes; and other investigators funded under other NIA awards. Provide diagrams of work flow. Define how the Core will interact with the scientific community, and particularly the ADSP, to develop relevant and mutually beneficial goals for the Center. Define how staff will cooperate and collaborate on multiple projects with Cores within the Center. Collaborations that will accelerate the detection of new potential therapeutic approaches should be formed. Explain how existing NIA-funded infrastructure will be leveraged to maximize the use of NIH funds.

    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. Primary and secondary analysis data will be deposited into 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).  

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts. Projects proposed should present 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.

    Provide the timeline and milestones for Administrative Core activities.

    Letters of Support: Only provide letters of support that are specific to this Core.

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

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    PHS Human Subjects and Clinical Trials Information (Administrative Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

    Data Management, Harmonization, and Information Transfer Core

    When preparing your application, use Component Type ‘Data Management 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.

    The Application Guide states that Project Narrative is required; however, it is only required for the Overall component.

    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)

    ASSIST will default to “Project Lead.” If you would like to use a different category, then replace “Project Lead” below with a different Category (e.g., Core Lead).

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project 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)

    Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

    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 all phases of the ADSP data. Identify which ADSP projects the Core will assist with.

    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. The Core will include studies on special populations; the applicant must describe the characteristics of the populations and justify the added scientific value to research at the Center resulting from the inclusion of each group.

    Significance

    Describe the potential for developing new and exciting research and specify plans for implementation of the new program. Provide an explanation of the Core's leadership role in the harmonization of all phases of the ADSP data, including genotype, sequence, and phenotype data. Explain how the Core will harmonize the various types of data and 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 the following: 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 of or protection from 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 in harmonizing aggregate ADSP Discovery Phase data including genotype/genomic including imputation data, sequence, and phenotype data; provide an explanation of how the Core will coordinate and integrate the various components of these harmonization activities. Define analytical and statistical approaches for data harmonization. Define how the Core will:

    (1) Harmonize ADSP Data Sets from all phases of the study:

    (a) Describe the approaches for capturing and harmonizing data, including GWAS, WGS, and WES data, with other sequence or genetic/genomic data generated by investigators within and outside of the ADSP.

    (b) Describe the approaches for capturing and harmonizing data from the diverse populations of ADSP datasets. Describe the process for data harmonization for the diverse types of ADSP data.

    (2) Harmonize phenotypic data across multiple studies, data sets, and ethnicities.

    Provide an explanation of the Core's role in harmonizing aggregate ADSP data (genotype/genomic, sequence, and phenotype); how the Core will coordinate and integrate the various components of these harmonization activities; and 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 other NIA-funded genetic studies. Explain how the work plan will incorporate "cognitive systems analysis" (artificial intelligence, machine learning, deep learning, and neural networks) by working with investigators to advance the field, if needed. 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 data harmonization 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 interdependent. Describe: the plan to accept and use the sequence data from ADSP investigators and those outside of the ADSP/U.S., 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 activities using the current ADSP work plan. Define the process to work collaboratively with the existing ADSP Work Groups to use established protocols for joint calling of the various types of data available. Explain the approach to capture and process new ADSP 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 ADSP sequence and genotype data. Include an explanation of how tasks will be done, such as receiving, managing, and sharing genotype, sequence, and phenotype data; providing data to the Biostatistics and Data Analysis Core for analysis; and 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 aggregate ADSP data. Describe how new statistical tools and analytic approaches, including evolving "cognitive systems" approaches (artificial intelligence, machine learning, deep learning, and neural networks) appropriate to the scale of data that the GCAD will manage, will be developed to move the field of AD genetics forward.

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts. Projects proposed should present 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.

    Define milestones for the Core. Define a timeline for key events.

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

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

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    The PHS Human Subjects and Clinical Trials Information form replaces the Human Subjects section of the Research Plan form. FOAs that do not allow clinical trials use this form for human subjects. See https://nih-extramural-intranet.od.nih.gov/d/sites/default/files/PHSHumanSubjectsandClinicalTrialsInformationForm-Internal_Use_Only.pptx for more information.

    PHS Human Subjects and Clinical Trials Information (Data Management, Harmonization, and Information Transfer Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).  All instructions in the SF424 (R&R) Application Guide must be followed

    Biostatistics and Data Analysis Core

    When preparing your application, use Component Type ‘Data Analysis 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.

    Application guide states that Project Narrative is required. However, it is only required for the Overall component.

    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)

    ASSIST will default to “Project Lead.” If you would like to use a different category, then replace “Project Lead” below with a different Category (e.g., Core Lead).

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project 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.

    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 (Biostatistics and Data Analysis Core)

    Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

    Specific Aims:

    Specify how the Biostatistics and Data Analysis Core will assume a leadership role in the overall analysis of the ADSP quality-control-checked, variant-called, harmonized data from multiple diversity populations and from foreign entities. Specify how new statistical and bioinformatics approaches will be developed for data analysis. Specify how the aggregate ADSP harmonized data will be comprehensively analyzed and annotated 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/annotation/validation of aggregate harmonized ADSP data from diverse populations. Describe how new statistical tools and analytic approaches, including evolving "cognitive systems" approaches (artificial intelligence, machine learning, deep learning, and neural nets) appropriate to the scale of data that the GCAD 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 and by the ability to maximally engage existing resources and rapid sharing; define efforts to ensure collaboration with ADSP, other U.S., and international geneticists 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 all harmonized data sets, including targeted sequence data and genotype or custom chip data. Emphasis on analysis of data from ethnically diverse populations is key for a successful application. Describe methodical and statistical approaches for analysis and validation of genes/regions/loci for harmonized data. Explain how the Core will advise the AD genetics community, both inside and outside of the ADSP, 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. 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. Provide work flow diagrams.

    Clearly define an analysis plan for joint/meta data analysis on diverse populations that is in keeping with the current intention and approach of the ADSP; 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 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.

    Define the formats and operational mechanisms by which analyzed/validated data will be prepared and provided to the Data Management, Harmonization, 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.

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts. Projects proposed should present 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.

    Provide the timeline and milestones for the project.

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

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

    All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

    Appendix:

    Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    The PHS Human Subjects and Clinical Trials Information form replaces the Human Subjects section of the Research Plan form. FOAs that do not allow clinical trials use this form for human subjects. See https://nih-extramural-intranet.od.nih.gov/d/sites/default/files/PHSHumanSubjectsandClinicalTrialsInformationForm-Internal_Use_Only.pptx for more information.

    PHS Human Subjects and Clinical Trials Information (Biostatistics and Data Analysis Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials, follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

    3. Unique Entity Identifier and System for Award Management (SAM)

    See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

    4. Submission Dates and Times

    Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

    Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. 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.

    7. 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    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 ramesh.vemuri@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 the policy. Any instructions provided here are in addition to the instructions in the policy.

    Section V. Application Review Information
    1. Criteria

    Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission 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).

    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? Is the prior research that serves as the key support for the proposed project rigorous?  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? 

    What is the likelihood that the project will achieve the overarching goals of the ADSP to identify and validate new genes/regions/loci or gene alleles contributing to increased risk for or protection against AD in diverse populations and potential avenues for therapeutic approaches and prevention of the disease? Will the proposed work identify genetic risk of AD through comprehensive analyses of existing and new 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 in diversity cohorts? 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 those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? 

    Are investigators thoroughly familiar with the genetics/genomics of AD? Are the applicants a group of (1) researchers with expertise in the capacity to analyze large datasets from diverse populations including whole exome sequence data, targeted sequence data, and genotype data related to the genetics of complex neurological diseases, and (2) 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, as well as potential therapeutic targets for AD? Are new statistical tools and analytic approaches, including evolving "cognitive systems" approaches (artificial intelligence, machine learning, deep learning, and neural networks), that are appropriate to the scale of data that GCAD will manage being developed to move the field of AD genetics forward?

    Approach

    Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?  Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

    If the 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 individuals of all ages (including children and older adults), 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 in diverse populations? 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 in order 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? 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?

    Will this study augment the ADSP data 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 in diverse populations? 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 Center 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 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 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 Individuals Across the Lifespan  

    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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    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

    For Renewals, the committee will consider the progress made in the last funding period.

    Revisions

    For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

    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

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts.

    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.

    Reviewers will assess whether plans to access and share data from foreign institutions/entities are likely to substantially increase the probability of gene discovery in diversity sample sets.

    Select Agent Research

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

    Resource Sharing Plans

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


    Authentication of Key Biological and/or Chemical Resources

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    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

    Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

    Are 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 support the genetics 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 members, work groups, infrastructure, and geneticists outside of the ADSP? 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 of 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?

    Investigator(s)

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

    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?   

    Are plans 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?

    Are the internal infrastructure and organization of the Core appropriate to efficiently assist in accomplishing the stated goals of the ADSP? Will the Core adequately coordinate and integrate with all phases of the study? How well will the Core coordinate and integrate ADSP components and activities? Will the Core support and advise the overall activities of the ADSP? Will the Core integrate/facilitate the various phases of the ADSP effectively? Are efforts to ensure collaboration and cooperation with the ADSP Steering Committee and investigators, the NIA-funded infrastructure, foreign collaborators, and 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 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 other NIA-approved data storage sites? 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? 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 Center 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 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 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 Individuals Across the Lifespan

    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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain, and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    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

    For Renewals, the committee will consider the progress made in the last funding period.

    Revisions

    For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

    Additional Review Considerations - Administrative Core

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

    Applications from Foreign Organizations

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts.

    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.

    Reviewers will assess whether plans to access and share data from foreign institutions/entities are likely to substantially increase the probability of gene discovery in diversity sample sets.

    Select Agent Research

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

    Resource Sharing Plans

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


    Authentication of Key Biological and/or Chemical Resources

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    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: (1) the importance of the problem or critical barriers to progress in the field that the proposed Core addresses; (2) how the proposed Core will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields; (3) how the concepts, methods, technologies, or services that drive this field will be changed if the proposed aims of the Core are achieved; (4) how the proposed Core will augment the ability to identify new genes contributing to increased risk or protection of developing AD; (5) 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 (6) 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, including genotype/genomic, sequence, and phenotype data from diversity sample sets? Is the plan to harmonize the various types of data across studies/ethnicities likely to help successfully identify AD risk and protective genes/regions/loci? Does the proposed work have the potential to better define and refine AD phenotypes?

    Investigator(s)

    Are the core leadership, collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the core 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?  

    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?   

    Approach

    Is the Core's role in harmonizing aggregate ADSP data, including genotype/genomic, sequence, and phenotype data from diverse populations, 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? Is the process to harmonize ADSP data sets likely to be successful? Are appropriate approaches for capturing and harmonizing data from the diversity ADSP datasets proposed? Are plans for harmonizing ADSP data with datasets generated by investigators outside of the ADSP or outside the U.S. likely to be successful? Are key scientific or technological challenges upon which the rest of the approach to data harmonization 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? Are there 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 in place for identifying a specific subject's data 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 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 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?

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

    Protections for Human Subjects

    For research that involves human subjects but does not involve one of the 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 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 Individuals Across the Lifespan  

    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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain, and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    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

    For Renewals, the committee will consider the progress made in the last funding period.

    Revisions

    For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

    Additional Review Considerations - Data Management, Harmonization, and Information Transfer Core

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

    Applications from Foreign Organizations

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts.

    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.

    Reviewers will assess whether plans to access and share data from foreign institutions/entities are likely to substantially increase the probability of gene discovery in diversity sample sets.

    Select Agent Research

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

    Resource Sharing Plans

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


    Authentication of Key Biological and/or Chemical Resources

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    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

    Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?   

    Will new statistical tools and analytic approaches appropriate to the scale of data that the GCAD 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 data? Are efforts defined to ensure collaboration with ADSP investigators and investigators outside of the ADSP, whether inside or outside of the U.S.?

    Investigator(s)

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

    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?   

    Approach

    Is the approach to analysis of harmonized ADSP data sets 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 breakthrough approaches to analysis of the genome? Are approaches to validate targets (genes/regions/loci) identified likely to be successful? 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 research 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, 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 data analysis depends clearly defined and alternative approaches proposed? Does the research plan include an explanation of the role the Core will play in ADSP activities as a whole?

    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? Is an appropriate and efficient mechanism proposed to work with investigators from NIAGADS and investigators performing similar analysis outside of the ADSP? 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 project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit and in providing an overall impact score but will not give separate scores for these items.

    Protections for Human Subjects

    For research that involves human subjects but does not involve one of the 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 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 Individuals Across the Lifespan  

    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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    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

    For Renewals, the committee will consider the progress made in the last funding period.

    Revisions

    For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

    Additional Review Considerations - Biostatistics and Data Analysis Core

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

    Applications from Foreign Organizations

    GCAD investigators may collaborate with investigators from foreign countries in order to share genetic samples or data from diversity cohorts.

    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.

    Reviewers will assess whether plans to access and share data from foreign institutions/entities are likely to substantially increase the probability of gene discovery in diversity sample sets.

    Select Agent Research

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

    Resource Sharing Plans

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


    Authentication of Key Biological and/or Chemical Resources

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    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.

    Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

    • Scientific and technical merit of the proposed project as determined by scientific peer review.
    • Availability of funds.
    • Relevance of the proposed project to program priorities.  
    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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

    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.

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

    Cooperative Agreement Terms and Conditions of Award

    The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 5, 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 PD(s)/PI(s) will work collaboratively with key Core Leaders, investigators funded under the ADSP-related U01s and other NIA awardees, members of the ADSP, and investigators funded by other NIH institutes and NIA. The Center will participate in ADSP study design and analysis. The primary governing body will be the Alzheimer's Disease Sequencing Project Steering Committee (ADSP SC) which operates under an ADSP-MOU.

    The PD(s)/PI(s) of the Center will maintain the existing operations and will augment them with new components of the project as agreed upon in consultation with the ADSP Steering Committee and NIA Project Scientist. GCAD will have responsibility for the final details of the project design, policy decisions, overall management of the study. Working with the NIA Project Scientist, GCAD will define the rules regarding data handling and provision of the data to NIAGADS for broad sharing with the research community. GCAD should work cooperatively with the ADSP SC and ADSP Working Groups, awardees of the ADSP-related cooperative agreements, and NIA-funded investigators who are not members of the ADSP. GCAD 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:

    GCAD will facilitate the design and refinement of all protocols, manuals of operations, and forms.  Principal Investigators and Core Leaders should maintain existing approaches and develop and implement new approaches necessary for quality control checking, variant calling, data harmonization, meta and joint analysis, statistical analysis, and final outcome data. GCAD is responsible for data sharing with NIAGADS that allows the various components of the ADSP to work cohesively as a group. Procedures will be established to facilitate data sharing with foreign entities. Components of the project will be established using existing ADSP infrastructure (see the section herein on the Resource Sharing Plan).

    GCAD should develop and implement systems necessary for communication between the various awardees of cooperative agreements funded under a variety of NIH funding instruments. To oversee the distribution of data generated by the ADSP, the Data Use Committee (DUC) should be maintained, in keeping with ongoing ADSP operations and existing NIA policies that engage NIAGADS, the NIAGADS Alzheimer's Disease Data Access Committee (NADAC), and the NIAGADS DUC. Committee membership will rotate periodically according to a procedure that is agreed upon by NIA program staff. 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 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 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 GCAD and the NIA Project Scientist will have primary responsibility for finalizing standard definitions, procedures, and measures common for all the protocols. The GCAD 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 will hold teleconferences as needed. All major scientific decisions will be determined by majority vote of the GCAD Project Lead and Core PIs/PLs. Members will be required to accept and implement policies approved by the GCAD Project Lead and Core PIs/PLs. Committees and Subcommittees appointed by the GCAD Project Lead and Core PIs/PLs, 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. In collaboration with the NIA Scientist, a committee comprised of the GCAD Project Lead and appropriate staff from the Cores should develop and implement systems necessary for communication between the various study components.

    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 various phases of the ADSP, and integration of outcomes between the various phases of the ADSP.

    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 internal operations committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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

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

    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 Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

    Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
    Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

    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: ramesh.vemuri@nih.gov

    Financial/Grants Management Contact(s)

    Traci Lafferty
    National Institute on Aging (NIA)
    Telephone: 301-402-7731
    Email: laffertt@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 Part 75.    

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