Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

?Background

This Funding Opportunity Announcement (FOA) is issued as an initiative tied to activities outlined in the National Plan to Address Alzheimer's Disease 2019 Update (See Strategy 1.B). The National Plan is updated on an annual basis in response to the National Alzheimer's Project Act (NAPA) Public Law 111-375. The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genes involved in Alzheimer’s disease and Alzheimer's disease-related dementias (AD/ADRD), (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 from ethnically diverse populations and is capturing 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 Discovery Phase has identified a number of variations in the genomes of individuals affected by AD. These findings are being pursued in the ADSP Follow-Up Study (FUS).

The ADSP FUS expects approximately 28,000 whole genomes from ethnically diverse populations to be ready for analysis in 2020-2021. By 2023, the total number of ADSP subjects with whole genome sequencing (WGS) is expected to reach approximately 50,000, including multi-ethnic cohorts from global regions such as Central and South America and Asia. NIA has supported the development of several epidemiologic cohorts that have genetic data and omic data. There are massive amounts of clinical and phenotypic data available on all of these subjects. To ensure the value of the analysis of the genetic/genomic data, harmonization of the phenotypic data must also be done. Thus, NIA has an urgent need to develop fast and efficient approaches to data harmonization to drive the field toward therapeutic target discovery.

A significant challenge to cross-study data analysis is the lack of consistency in measurement among studies, especially for important outcome measures. This is essential for genetic/genomic studies, where very large sample sizes are required to identify rare or very rare risk and protective variants. The ADSP has already harmonized genetic/genomic data and will continue to do so as the project progresses. Harmonization of phenotypic data across epidemiology cohorts, the Alzheimer’s Disease Centers, and convenience cohort phenotypic data has not been done in a substantive manner; there has been little harmonization of the outcome measures of highest relevance to the epidemiology of AD/ADRD. All of the ADSP epidemiology, clinical, and convenience cohorts have multiple layers of deep phenotype data. Many studies with cognitive data are longitudinal and extend across many years. To make the analysis of this wealth of genetic data meaningful, the phenotypic data associated with the genetic data must use consistent measures. This will substantially augment the amount of highly valuable genetic data that are available to the research community.

There are a large number of NIA-funded epidemiology cohorts, and there is a massive amount of genetic and phenotypic data available in these cohorts. Since substantial NIA funds have already been invested in these cohorts, it will be advantageous to the research community to have the outcome data harmonized. In addition to the ADSP genetic and phenotypic data, joint calling of ADSP data with data from other NIH-funded large-scale sequencing projects, including harmonized phenotypic data, is now feasible. ADSP phenotypic data harmonization efforts will be done in concert with those projects. Data harmonization will provide a means to better understand subtypes of phenotypes (endophenotypes) of AD/ADRD and thereby may step up discovery of therapeutic approaches for the disease. There is substantial enthusiasm for such data harmonization in the research community.

There are specific and persistent challenges in harmonization of phenotypic data owing to inconsistency of measurement parameters and use of different terminologies across studies. Clinical measures that may be found across many studies include AD/ADRD diagnosis, cognitive testing measures, and selected biomarker and imaging measures. Neuroimaging outcomes, including both structural and functional MRI as well as PET, are available in many studies. In addition, the ADSP has available significant quantitative neuropathology data, including measures of various proteinopathies and vascular infarcts. Diagnoses of comorbid conditions are also found in selected studies.

There is an additional ADSP effort that further requires implementation of a major data harmonization effort. In January 2019, the NIA National Advisory Council on Aging (NACA) approved an initiative to apply cognitive systems (artificial intelligence (AI), machine learning (ML), and deep learning (DL)) approaches to the analysis of the ADSP genetic and related data. An FOA was issued in 2019 for an artificial intelligence/machine learning/deep learning effort to further analyze the data (PAR-19-269 Cognitive Systems Analysis of Alzheimer's Disease Genetic and Phenotypic Data). Caveats to ensuring successful cognitive science approaches in the case of AD/ADRD genetics include the fact that access to the data should be centralized and the data should be harmonized. Thus, harmonization of the phenotypic data is essential for successful application of cognitive systems approaches. It is imperative that harmonized data be available for this effort.

New approaches to harmonization of phenotypic and endophenotypic data related to large-scale genetic studies are needed, including methods to combine data from a number of study cohorts with data that are similar, but not the same, as well as methods to incorporate functional status (both self-reported and objectively measured). Success in this effort would generate harmonization strategies useful not only to the investigators of currently participating cohorts, but potentially to newly recruited or newly constituted cohorts in the future. The need for this effort is urgent based on the number of subjects with WGS data that will be available soon and because successful analysis of the genetic data by cognitive systems approaches and by other secondary analysis approaches being used by the AD scientific community depends on the availability of these data.

Context for the Study Design: The ADSP Harmonization Consortium (ADSP-HC)

This FOA requires that competitive applicants, with deep understanding of all types of ADSP data, present plans and propose techniques for data harmonization in target domains that are common across studies. The intention is that, under a single cooperative agreement (U24), this initiative will support phenotypic data harmonization on subjects with genetic data, and these data will become a long-lived legacy data set that will be perpetually curated. Studies under this FOA will bring together a single vanguard network of researchers with deep understanding of ADSP data and expertise in genetics, epidemiology, and clinical specialties who will work with the ADSP investigators and with study cohort leads engaged in data harmonization efforts. Cohorts considered eligible for this activity are those that have genetic data in the ADSP (epidemiology cohorts, case-control, family-based, Alzheimer’s Disease Centers, and convenience cohorts) and related study cohorts with genetic/genomic data. Study leads engaged in analysis of other AD or ADRD cohorts with genetic data are also welcome to participate in this harmonization effort. The team will focus on cohorts where genetic data that includes genome wide association study (GWAS) data, whole exome (WES) or whole genome sequence (WGS), and robust phenotypic data are available in order to better understand subtypes of phenotypes (endophenotypes) of AD and ADRD. Data harmonization activities on agreed-upon measures will be carried out across cohort studies with similar measures.

The ADSP Harmonization Consortium (ADSP-HC), a component of the ADSP-FUS, should generate harmonized data sets that will be shared through a central data repository for data (genetic, genomic, annotation, analysis, statistical, and phenotypic) collected by other NIA-funded studies with the capability to work in the cloud environment. The ADSP-HC will generate milestones for the project. Milestones will be designed to deliver mechanisms to provide genetically and phenotypically harmonized data sets generated under agreed-upon principles that will meet the needs of genetic/genomic research on AD and related neurodegenerative diseases, with an emphasis on deep endophenotypes. In the five-year funding period, it is expected that the ADSP-HC will ensure that the harmonized ADSP data will be made available to a variety of other harmonization efforts being done globally. Cross-validation or cross-walking projects should also be completed by awardees. Given the desire to leverage existing investments, investigators that already have strong knowledge of multiple existing cohorts and ADSP efforts and have been productively engaged in relevant activities would be strongly encouraged to apply.

Milestones

For this effort, the following milestones regarding phenotypic data harmonization must be met. Additional milestones may be added, and milestones may be modified with concurrence of the Program Official for this FOA before the application is submitted. Failure to meet milestones will result in restriction or termination of the award.

Milestone 1. Delineation of the research resource, including definition of the types of data to be harmonized.

Milestone 2. Generation of related descriptive data files and code books, data dictionaries, and other related supporting materials to be made available to the research community.

Milestone 3. ?Definition of the endophenotypic data that are available and generation of related descriptive data files and code books, data dictionaries, and other related supporting materials. Definition of the types of data to be harmonized. ?

Milestone 4. Harmonization of individual cohort data, including those for epidemiology, case-control, family-based, early-onset AD, autopsy/brain bank, and ADNI data. Endophenotypic data to be harmonized include, but are not limited to, cognitive data, structural imaging data, functional imaging data, longitudinal clinical data, neuropathologic data, cardiovascular risk data, and biomarker data.

Milestone 5. ?Harmonization in aggregate of all cohort data, including those for epidemiology, case-control, family-based, early-onset AD, autopsy/brain bank, and ADNI data. Endophenotyic data are as above.

Milestone 6. Harmonization of ADSP ?phenotypic data with data from selected large-scale efforts, such as UK BioBank and others noted below, and large-scale efforts for functional genomics data resources. Data types are noted below.

Milestone 7. Deposition of harmonized phenotypic data and related descriptive data files and code books, data dictionaries, and other related supporting materials to be made available to the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) for sharing with the research community

Types of Data to be Harmonized

Please contact the Program Officer for this announcement for specific details on available data for this effort. ADSP sequence data have been and will continue to be harmonized, funded under other auspices. Early efforts towards phenotypic data harmonization have been driven by geneticists, clinicians, and epidemiologists associated with the ADSP. For example, the National Alzheimer’s Coordinating Center (NACC) has a variety of harmonized data types that are obtainable for the present effort. Although not an exhaustive list, any or all of the following types of data and data sets may be included in analytical plans that are appropriate for this FOA:

• Total number of cohorts available to date: Approximately 47 ADSP cohorts from US and international study sites with various types of phenotypic data, all with cognitive measures.
• Epidemiology cohorts with genetic/genomic data: A partial list includes: Adult Changes in Thought (ACT) Study; Age, Gene/Environment Susceptibility Study (AGES); Atherosclerosis Risk in Communities (ARIC) Study; ARIC Neurocognitive Study (Trans-Omics for Precision Medicine, or TOPMed); Baltimore Longitudinal Study on Aging; Cache County Study of Aging; Chicago Health and Aging Study; Einstein Aging Study; Framingham Heart Study Original Cohort (TOPMed); Framingham Study Offspring Cohort (TOPMed); Rotterdam Study; Health and Retirement Study; Indianapolis Ibadan Dementia Study; Multi-Ethnic Study of Atherosclerosis (MESA) Ancillary Studies (TOPMed); Northern Manhattan Study (NOMAS); Religious Orders Study (ROS); Accelerating Medicines Partnerships - Alzheimer's Disease (AMP-AD); Rush Memory and Aging Project (MAP) (AMP-AD); and the Washington Heights-Inwood Community Aging Project (WHICAP).
• Case-control data: 24 cohorts generated by the Alzheimer’s Disease Genetics Consortium (ADGC).
• Family-based data: 8 cohorts generated by ADGC and ADSP investigators.
• Early onset AD: 2 cohorts.
• Autopsy/brain bank data: 3 cohorts from multiple sources.
• Alzheimer’s Disease Neuroimaging Initiative data: 2 cohorts with imaging, biomarker, and cognitive data (includes mild cognitive impairment).

Endophenotypic Data Available

There are several major areas of phenotype data to be harmonized with high priority:

• Cognitive data.Data for at least 30,000 subjects will be available. Emphasis for this portion of the effort is on pre-statistical harmonization (e.g., compiling information about the various cognitive measures, grouping them by domain, and documenting decisions). Cohorts are ethnically diverse; data have been gathered from a number of US and foreign sites.
• Structural imaging - brain MRI. There are approximately 12,000 subjects from 8 existing cohorts with MRI data. Cohorts with genetic, cognitive, and structural brain imaging data include ADNI, the Alzheimer’s Disease Centers, and other sites. Many have longitudinal measures.
• Functional imaging amyloid PET. Approximately 4,000 subjects with PET imaging and GWAS are undergoing an initial harmonization process. Approximately 3,000 additional scans will be available for harmonization. Many have longitudinal measures.
• Longitudinal clinical data relevant to the diagnosis of AD for all cohorts.
• Neuropathology data.Approximately 5,000 subjects with WGS or WES data, cognitive data, and neuropathology data will be harmonized with the data set.
• Cardiovascular risk factor data.Data from approximately 13,300 individuals from several cohorts with cardiovascular data and GWAS. Other data points are available from the National Alzheimer’s Coordinating Center (NACC) and the NIA Late Onset of Alzheimer’s Disease (NIA LOAD) Family Study, thus providing a total of approximately 18,000 subjects with longitudinal data.
• Biomarker data. Data from studies with genetic, cognitive, and cerebrospinal fluid or peripheral biomarkers are available. These data sets are relatively small and are of lower priority for this effort.

In the longer term, there are several types of data that may be included as resources in the effort:

• Biobank and other large efforts with genetic data for complex diseases, such as the UK Biobank and All of Us.
• Functional genomics: Genotype-Tissue Expression (GTEx) with tissue-specific gene expression, induced pluripotent stem cell (iPSC), Roadmap Epigenomics, FANTOM 5 (enhancers), ENCODE, PsychENCODE, and DASHR (noncoding RNAs).
• Data types from genetic/genomic ADSP-related studies, such as those in AD/ADRD functional genomic studies not part of the initial effort, include but are not limited to GWAS, exome chip, whole exome sequence (WES), whole genome sequence (WGS), and targeted sequencing related to the ADSP; Haplotype Reference Consortium (HRC) reference panel of human haplotypes created by combining sequencing data from multiple cohorts; expression data on brains from neuropathology studies; ChIP Seq and transcriptomic (RNA seq) data; DNA methylation array; epigenomic data; metabolomic data; proteomic data; and single cell data, including single cell whole genome sequencing.

Approaches to Phenotypic Data Harmonization

NIH policy will be considered at all stages of the effort, as will any legal or data sharing restrictions, such as the European General Data Protection Regulation (EU GDPR). Study investigators should be compliant with the Health Insurance Portability and Accountability Act (HIPAA), NIA/NIH human subjects and genetic data sharing policies, data transfer agreements, and related qualified access agreements. The ADSP's goal of rapid and transparent data sharing will be a central standard for the effort. ADSP-HC teams will ensure appropriate data sharing is approved by local IRBs. Where possible, team members will participate in community genomics standards groups such as the Global Alliance for Genomics and Health (GA4GH) and NIH efforts where institutes are developing standard programmatic interfaces for managing, describing, and annotating phenotypic data.

This milestone-driven project will need a lead investigator, as well as domain experts including, but not limited to, a biostatistician; a neuropsychologist for decision making on cognitive testing data; domain experts in biomarker, imaging, and risk factor data; a bioinformatician; a data manager; and a programmer. Given the massive amount of data, it will likely take five years to complete the process at a granular level. Focus in the initial years will be on data sets that have the largest amount of common phenotypic data. The effort will use community standards for data elements, data types, and file formats.

The ADSP-HC, in consultation with NIA, will determine the harmonization approach to be used, create as many harmonized variables as possible, and create study-specific variables to allow for later pooled analysis. This will enable further investigation of other interactions (e.g. environment). ADSP-HC teams with category expertise will be created. Cohorts to be included in each category will be identified.

Feasibility to harmonize cohorts by rapid turnaround will be established for a small set of phenotypes, including cognitive measures, MRI, other neurologic phenotypes, demography, and risk factor data. The initial harmonization effort's preliminary outcomes will inform future harmonization processes. The process devised will allow future, more intensive application of different harmonization algorithms, as well as the addition of cohorts or variables. Consideration will be given to convenience approaches to the effort, such as harmonizing all Alzheimer’s Disease Centers (ADC) cognitive data or imaging data together. The ADSP-HC, in consultation with NIA, will determine what new methods or new types of data are being generated and decide whether/how to compare/harmonize with existing data.

Recommended Core Set of Variables

While the list of variables may be extended or modified, the initial core set of variables may include the following: demographics; medical history and risk factors assessments; cognitive function; cognitive domains such as memory, language, executive function, attention, visuospatial, and global cognition; structural MRI; PET scans (FDG, amyloid, tau); cerebrospinal fluid biomarkers; blood-based biomarkers; and risk factor data.

Methods to Facilitate Comparisons Across Studies

The ADSP-HC will determine which studies already have harmonized data and will devise work plans that leverage existing harmonization expertise, approaches, and outcomes. ADSP-HC domain-specific teams will draw upon existing expertise for related efforts. Examples are NIA-funded investigators with studies in progress using established data harmonization methods, NACC efforts to harmonize cognitive measures for ADC data, ENIGMA, and the Gateway to Global Aging. Teams will select domains to be harmonized; determine which studies will/will not be included; identify and address potential heterogeneity in the various measures; select leads and domain experts who have direct knowledge of the phenotype in question; understand the caveats of the data; engage Principal Investigators (PIs) who collected and understand the original data; and consider how much variation to retain/remove.

Methods to Maximize the Quality and Comparability of Extracted Data

The ADSP-HC will agree upon a harmonization protocol, definitions (e.g. MCI, vascular dementia), selection criteria, and how data will be handled for a pilot study. It is recommended that the team test the protocol in a pilot study. Attention should be given as to how to leverage studies that use more than one protocol (e.g. digit symbol vs. letter symbol). Co-calibration, using psychometric strategies, should be used to permit scores to be on the same metric across data sets.

Prevention of Data Loss

The overarching goal of this effort is to optimize the value of individual participant data. The successful application will present a cost-effective method to store and share harmonized data and harmonized summary data through sub-contracts to appropriate sites, engaging existing NIA-funded infrastructure wherever possible. The successful application will include mechanisms to ensure funding through subcontracts for those who provide cohort data from original studies, those who distribute data, those who aggregate data, and the central data distribution analysis site. Applicants are expected to contact the Program Officer for this FOA, the PIs of the Genome Center for Alzheimer’s Disease (GCAD), and the PIs of NIAGADS before preparing budgets involving subcontracts to avoid redundancy of effort.

The Role of NIAGADS in the Initiative

As recommended by the National Advisory Council on Aging (NACA), NIAGADS will coordinate the phenotype harmonization effort for data flow and sharing. NIAGADS is the data hub for the ADSP, functional genomics, and artificial intelligence/machine learning/deep learning (AI/ML/DL) effort and will require mission-appropriate augmentation; it provides computational infrastructure to support processing on a large number of features, including harmonized phenotypic data. The ADSP-HC should be capable of working in a cloud environment through NIAGADS.

The computational infrastructure that supports processing on a large number of features will be available to the ADSP-HC at NIAGADS. Teams of ADSP-HC domain experts will collaborate with NIAGADS as the data hub for the initiative to provide harmonized data to the research community. NIAGADS will retain the aggregate of genetic and phenotypic data for this effort. This will provide a single path for data flow from cohort teams, to the ADSP-HC team, to the research community. NIAGADS will provide harmonized data to investigators involved in AI/ML/DL and other NIA-funded efforts. NIAGADS will retain and make available documentation for each of the various cohorts and types of data. NIAGADS will ensure compliance with human subjects data sharing, data transfer agreements, and related documents needed for qualified access before data are distributed to the research community. NIAGADS will track data harmonization efforts, work with domain experts, share workflows, and provide outcome data to the ADSP-HC and the research community,

Summary

NIA intends to fund a single group of ADSP-HC collaborators who have a deep understanding of ADSP genetic and phenotypic data to facilitate and support the harmonization and analysis of large-scale phenotypic data for the next phase of the ADSP activities. The ADSP-HC will serve as a focal point for the next phase of ADSP data analysis and data sharing. The ADPS-HC will act as an interface between study leads contributing cohorts and studies, the ADSP investigators, NIAGADS, and the AD research community, including researchers involved in the AI/ML/DL efforts. The effort will serve as a means to better understand endophenotypes of AD/ADRD that may accelerate the discovery of therapeutic targets for AD/ADRD.

This milestone-driven effort will generate harmonized, ethnically diverse data sets that will need continual curation and updating as new cohorts or types of phenotypic data are added to the ADSP. Failure to meet milestones will result in restriction or termination of the award. This effort will generate data harmonization protocols and tools that will be made available to the larger research community. This U24 FOA will support a major research project contributing to improvement of the capability of resources provided by NIA to serve biomedical research. These rich data sets will become a central resource for numerous types of analysis in the field of AD/ADRD research. To avoid redundancy in existing infrastructure, access to these harmonized data will be provided through NIAGADS, which will act as a central hub for the effort. Investigators will coordinate efforts through NIAGADS to generate data that are consistent in presentation to the research community, and to integrate at NIAGADS ADSP harmonized cohort study data and related data files necessary for their research. Retention of harmonized data in a single repository/federated repository for ready access by investigators will be a significant step toward the feasibility of advanced data analysis approaches.

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

Section II. Award Information

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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.

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.
• 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.

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, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Fax: 301-494-1494
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

PD(s)/PI(s) must be thoroughly familiar with ADSP genetic and phenotypic data; their roles must be well suited to the goals of the ADSP-HC. It is expected that PD(s)/PI(s) have experience handling AD genetics, genomics, and phenotype data and have experience and training appropriate to the ADSP-HC. PD(s)/PI(s) must have demonstrated experience and an ongoing record of accomplishments in effectively managing large amounts of diverse types of data in order to discover risk and protective genetic factors for complex diseases. Investigators should demonstrate significant experience with coordinating collaborative (basic or clinical) research. The team of investigators should have complementary and integrated expertise and skills; the leadership approach, governance, plans for conflict resolution, and organizational structure should be appropriate for the ADSP-HC. PD(s)/PI(s) must have experience overseeing selection and management of sub-awards, if needed. PD(s)/PI(s) and other personnel should have appropriate experience and training for management of large-scale data with expertise in archiving, processing, and distributing phenotypic/endophenotypic data for AD. PD(s)/PI(s) should be facile in the curation of large data sets, including multiple layers of complex phenotypic/endophenotypic data relevant to genetic analysis, such as clinical and neuropathology data elements and related data. The PD(s)/PI(s) should be skilled in understanding and management of clinical measures that may be found across many studies, such as diagnosis, cognitive testing measures, and selected biomarker and imaging measures. The PD(s)/PI(s) should have a deep understanding of and ability to manage neuroimaging outcome data, including both structural and functional MRI as well as PET. The PD(s)/PI(s) should have a solid understanding of quantitative neuropathology data and comorbid conditions, including measures of various proteinopathies and vascular infarcts, and must have data management skills appropriate to such data. For multi-PD/PI applications, investigators must have complementary and integrated expertise and skills in order to provide appropriate leadership approach, governance, plans for conflict resolution, and organizational structure to the AD genetics and genomics data and data management infrastructure.

R&R Budget

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

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

Significance

Delineate why the ADSP-HC is needed to achieve the goals of the AD research programs it proposes to serve. Explain how the applicants will meet evolving needs in the AD research community, including ongoing collaborations and existing interactions with stakeholders. Define efforts to ensure that this research resource becomes a long-lived legacy data set that will be perpetually curated. Explain how the ADSP-HC will provide a means to better understand endophenotypes of AD/ADRD that may accelerate the discovery of therapeutic targets for AD/ADRD. Explain how receipt and distribution of genetic and genomic data facilitate or expedite AD research that would be delayed or infeasible if conducted as independent projects. Explain what advantages the ADSP-HC will bring to the AD research programs it services. Explain how the ADSP-HC will serve as an interface between the ADSP, the AD research community, and the NIA Coordinating Center for the Genetics and Genomics of Alzheimer's Disease.

Investigators

Investigators must demonstrate deep understanding of the ADSP genetic and phenotypic data and how well suited they are for their roles in the ADSP-HC. PD(s)/PI(s) should explain their level of experience and training in handling AD genetics, genomics, and phenotype data without duplicating information in the biosketches. PD(s)/PI(s) should define levels of experience in effectively managing large amounts of diverse types of data in order to discover risk and protective genetic factors for complex diseases and in coordinating collaborative (basic or clinical) research. Applicants should define their level of experience and training for management of large-scale data and their level of expertise in archiving, processing, and distributing phenotypic/endophenotypic data for AD. Investigators should delineate their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the ADSP-HC. For multi-PD/PI applications, explain complementary and integrated expertise and skills in order to provide appropriate leadership approach, governance, plans for conflict resolution, and organizational structure to the AD genetics and genomics data and data management infrastructure.

Approach

PD(s)/PI(s) should define approaches to curation of large data sets, including multiple layers of complex phenotypic/endophenotypic data relevant to genetic analysis, such as clinical and neuropathology data elements and related data. Applicants should delineate how they understand and will manage clinical measures that may be found across many studies (e.g. diagnosis, cognitive testing measures, and selected biomarker and imaging measures); neuroimaging outcomes, including both structural and functional MRI as well as PET; and quantitative neuropathology data and comorbid conditions, including measures of various proteinopathies and vascular infarcts

Innovation

Define any novel organizational concepts in the field of AD phenotypic data management strategies or in instrumentation in coordinating the AD research projects that the ADSP-HC will serve. Delineate concepts, approaches, methodologies, instrumentation, or interventions that are novel to the field of AD genetics or genomics research and to AD research in general. Define concepts, strategies, or instrumentation that are novel to AD genetics or genomics research or applicable in a broad sense.

Environment

Explain how the institutional environment(s) in which the ADSP-HC will operate can contribute to the probability of success in facilitating the AD research program it serves. Define the characteristics of the institutional support, equipment, and other physical resources that will be available to the investigators; in particular, define resources available within the scientific environment to support large-scale electronic information handling.

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.

The following modifications also apply:

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

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) 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 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.

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). 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.

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

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

See more tips for avoiding common errors.

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

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

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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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?

Is the proposed ADSP-HC needed to achieve the goals of the AD research programs it proposes to serve? How responsive and flexible is the proposed ADSP-HC likely to be in order to meet evolving needs in the AD research community, including its ongoing collaborations and existing interactions with stakeholders? How likely is this research resource to become a long-lived legacy data set that will be perpetually curated? How likely is the ADSP-HC to provide a means to better understand endophenotypes of AD/ADRD that may accelerate the discovery of therapeutic targets for AD/ADRD?What advantages will the ADSP-HC bring to the AD research programs it services? How responsive is the proposed ADSP-HC to the need to serve as an interface between the ADSP, the AD research community, and the NIA Coordinating Center for the Genetics and Genomics of Alzheimer's Disease?

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?

How familiar are the PD(s)/PI(s) with ADSP genetic and phenotypic data, and do they have experience handling AD genetics, genomics, and phenotypic data and effectively managing large amounts of diverse types of data in order to discover risk and protective genetic factors for complex diseases? Are the PD(s)/PI(s) and other personnel well suited to their roles in the ADSP-HC? How appropriate are their experience and training to the ADSP-HC? Do the investigators demonstrate significant experience with coordinating collaborative (basic or clinical) research? Are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the ADSP-HC? Do the PD(s)/PI(s) have experience overseeing selection and management of sub-awards, if needed? Do the PD(s)/PI(s) and other personnel have appropriate experience and training for management of large-scale data with expertise in archiving, processing, and distributing phenotypic/endophenotypic data for AD? How facile are the PD(s)/PI(s) in curation of large data sets, including multiple layers of complex phenotypic/endophenotypic data relevant to genetic analysis, such as clinical and neuropathology data elements and related data? How facile are the PD(s)/PI(s) in understanding and management of clinical measures that may be found across many studies, such as diagnosis, cognitive testing measures, and selected biomarker and imaging measures? How facile are the PD(s)/PI(s) in understanding and management of neuroimaging outcomes, including both structural and functional MRI as well as PET? How facile are the PD(s)/PI(s) in understanding and management of quantitative neuropathology data and comorbid conditions, including measures of various proteinopathies and vascular infarcts?

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

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

Are the operational plan and organizational structure well-reasoned and appropriate to accomplish the goals of the projects that the ADSP-HC will serve? Are potential problems, alternative strategies, and benchmarks for success presented that may impact AD research as a whole? How well coordinated are receipt and distribution of genetic and genomic data, and do they facilitate or expedite AD research that would be delayed or infeasible if conducted as independent projects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy 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?

Protections for Human Subjects

For research that involves human subjects but does not involve one of thecategories 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 project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of 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.

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

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

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.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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.

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.

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.htmlhttps://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.htmlor 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.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

The PD(s)/PI(s) will have primary authority and responsibility to define objectives, approaches, and harmonization/analysis protocols; data management; data interpretation; follow-up analysis; and quality control. The PD(s)/PI(s) will work directly with study leads and consortium members who manage cohorts whose phenotypic data will be harmonized through this effort. The PD(s)/PI(s) will work with the ADSP Discovery Phase studies funded under PAR-12-183; the ADSP Follow-Up Study funded under PAR-18-890, PAR-17-214. and companion FOAs; the NIA Genome Center for Alzheimer’s Disease (GCAD) (U54) funded under RFA-AG-16-001; and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) funded under PAR-16-047. The PD(s)/PI(s) will work with NIA program staff, program officers at other NIH Institutes and Centers, and study cohort leads who manage the cohorts whose data will be used in the data harmonization effort.

Institutions providing data will retain custody of, and primary rights to, the site-specific data developed under their individual awards, in keeping with Institutional Review Board approval, and subject to Government rights of access, consistent with current HHS, PHS, and NIH policies.

The PD(s)/PI(s), in consultation with the NIA Project Scientist, will establish a board of external consultants to provide guidance on harmonization/analytical methods and advances in methodology appropriate for use in this context. Consultants will be selected as individuals who are not involved in AD genetics research but who could advise the awardees with an emphasis on data harmonization and analytical methods.

The PD(s)/PI(s) and key ADSP-HC personnel, in consultation with the NIA Project Scientist, will form an Executive Committee. The Executive Committee will hold meetings and conference calls as needed to facilitate development and implementation of common measures and practices. The Executive Committee will define the rules regarding access to, and publication of, findings from harmonization/analyses of common data. NIA-funded ADSP-HC sites will transfer phenotypic data to NIAGADS as soon as harmonization and quality control checking is complete.

NIH policy will be considered at all stages of the effort, as will any legal or data sharing restrictions such as the European General Data Protection Regulation (EU GDPR). The PD(s)/PI(s) will make every effort to be in compliance with the Health Insurance Portability and Accountability Act (HIPAA), NIA/NIH human subjects and genetic data sharing policies, data transfer agreements, and related qualified access agreements. The PD(s)/PI(s) will ensure appropriate data sharing is approved by local IRBs.

The PD(s)/PI(s) will work collaboratively with other investigators to develop the study design, collect appropriate data, and perform analyses/harmonization for the AD genetics community, as approved by the Executive Committee in consultation with the NIA Project Scientist.

The PD(s)/PI(s) will be involved in collaborations with the Alzheimer's Disease Genetics Consortium (ADGC), the Consortium for Alzheimer's Sequence Analysis (CASA), the Alzheimer's Disease Centers (ADC), the National Cell Repository on Alzheimer's Disease (NCRAD), the National Alzheimer's Coordinating Center (NACC), the Genome Center for Alzheimer's Disease (GCAD), and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) during all phases of the award. The PD(s)/PI(s) will administer the establishment, operation, and quality control of harmonized phenotypic data, including the development of procedures for assuring data quality control and procedures for transfer of data generated by NIH-funded investigators into the database. The PD(s)/PI(s) are responsible for working cooperatively with study sites and sponsoring organizations and for overseeing the implementation of, and adherence to, common protocols, as well as assuring quality control of the data collected. In addition to organizing and attending regular meetings, the PD(s)/PI(s) will be expected to maintain close communications with the NIA Project Scientist and, where appropriate, the Program Directors of the ADSP, NIAGADS, and GCAD.

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 scientific involvement during conduct of this activity through technical assistance, advice, and coordination, assisting in those aspects of the award as described below. The NIA Project Scientist will monitor the deposition of phenotypic data into NIAGADS to ensure that NIA-funded investigators have appropriately deposited data and have properly acknowledged the use of the cohorts and related phenotypic data in thepublication of their work. The NIA Project Scientist will review protocols for work flow and data sharing before they can be implemented. The NIA Project Scientist will be a non-voting "ex officio" member of the Executive Committee and all key subcommittees.

Additionally, the NIA Program Official will be responsible for normal program stewardship, including assessing the progress toward the accomplishment of specified milestones, and for recommending release of additional funds to the project, and will be named in the award notice.

Areas of Joint Responsibility include:

For areas of joint responsibility, an Executive Committee including Program Director(s) of the ADSP-HC; selected Program Director(s) from the ADSP, GCAD, and NIAGADS; and the NIA Project Scientist should be formed. The Executive Committee will serve as the main decision-making body for the shared aspects of the study and will devise common protocols related to data harmonization and sharing among collaborators, stakeholders, and the AD research community. Appropriate data storage site staff may attend the Executive Committee meetings as needed. Members of the Executive Committee for the data storage site will contribute to the effort by accessing and assessing appropriate phenotype data and providing expertise in the harmonization of phenotypic data from specific AD cohorts. The Executive Committee will meet as needed.

The external board of consultants will advise the PD(s)/PI(s) on analytical approaches; phases of the award will proceed only after review of the common protocols and approval by the Executive Committee and acceptance by NIA.

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

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 agreementsare 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. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission 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:[email protected](preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:[email protected]

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

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9666
Email: [email protected]

Jillian Morris
National Institute on Aging (NIA)
Telephone: 301-496-8986
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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.