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
Cognitive Systems Analysis of Alzheimer's Disease Genetic and Phenotypic Data (U01 Clinical Trial Not Allowed)
Activity Code
U01 Research Project – Cooperative Agreements
Announcement Type

New

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-19-269
Companion Funding Opportunity

PAR-17-214, 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 that propose Artificial Intelligence (AI), Machine Learning (ML), and/or Deep Learning (DL) approaches, collectively referred to here as "cognitive systems," that lead to the identification of gene mutations/variants that cause or contribute to the risk of or protection against the development of Alzheimer’s disease (AD) and Alzheimer's disease related dementias (ADRD) via analysis of a variety of genetic, genomic, and biomarker data that are currently available to the research community.

Key Dates

Posted Date

May 6, 2019

Open Date (Earliest Submission Date)
September 05, 2019
Letter of Intent Due Date(s)

30 days before the application due date

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. The first standard due date for this FOA is October 5, 2019.

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 08, 2022
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions

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.

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. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

This Funding Opportunity Announcement (FOA) is issued in response to National Alzheimer's Project Act (NAPA) milestones for the genetics of Alzheimer's disease (AD) to support the Alzheimer's Disease Sequencing Project (ADSP). The overarching goals of the ADSP and of this FOA 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/.

Current technologies are producing massive amounts of data. These data cannot reasonably be investigated via current methods; automated, computer-based technologies are needed for such data analysis. The essential need at this time is to develop fast and efficient cognitive systems approaches to identify changes in AD genetic architecture that increase risk of and protection against the disease. NIA seeks approaches to automate genetic data analysis operations to the greatest extent possible. For the purpose of this announcement, the phrase “cognitive systems” will be used as a global term that includes artificial intelligence (AI), machine learning (ML), and deep learning/neural networks (DL) approaches to analysis of AD genetic and related data.

Cognitive systems approach to analysis of AD genetic data

Cognitive systems approaches have been used successfully in the study of other complex diseases for clinical event prediction; clinical decision support tools to better manage patient- and disease-related data; data mining for risk prediction and prevention of disease comorbidities; and development of platforms to support research on data sets for benchmarking. Success stories in the analysis of neurological data using cognitive systems approaches include identification of gene variants in schizophrenia; genetic variant analysis; prediction of disease status from Alzheimer’s Disease Neuroimaging Initiative (ADNI) neuroimaging data; and prediction of cognitive decline in AD. To date, the majority of cognitive systems studies in AD have involved imaging or imaging combined with genome-wide association study (GWAS) (non-sequence)/non-genetic features.

Alternative approaches to the analysis of the available information will be required in order to fully define the genetic architecture underlying the etiology of AD. The amount of genetic data now being generated far exceeds the capacity of the ADSP to perform analysis to meet timelines set in place by the National Project Act (NAPA) and Public Law 111-375. For example, the number of AD subjects with GWAS presently exceeds 94,000. The ADSP expects more than 27,000 whole genomes to be available for analysis in 2019. By 2023, the total number of expected ADSP subjects from ethnically diverse populations with whole genomes available for analysis may approach 50,000--far more than the ADSP can analyze on its own in a timely fashion without the support of alternative approaches to data analysis.

In April of 2018, NIA held a focus group meeting to discuss the feasibility of using cognitive systems tools to analyze AD genetic, phenotypic, and other related data to advance identification of therapeutic targets for the disease. The meeting was comprised of cognitive systems industry experts, academicians, and AD geneticists and epidemiologists. The group was convened to determine whether the data presently available are appropriate and sufficient to conduct an analysis of AD genetic and related data with the ultimate goals of identification of appropriate therapeutic approaches for this disease. There was concurrence that there are now sufficient genetic and related data available in existing databases to enable the AD genetics community to embark on cognitive systems approaches to genetic data analysis. The group also agreed that data related to the study should be centralized in order to optimize analyses and increase efficiencies.

To be successful, cognitive systems analysis needs large, high-quality datasets, including genetic data, polygenic risk scores, raw genetic data (e.g. GWAS, imputation, whole genome, whole exome), endophenotypic data, clinical data, RNA sequencing, molecular panels, functional annotation data to accompany sequence data, and longitudinal epidemiology data to provide informative features for classification, prediction, and pattern discovery. Also needed are measures of other biological factors with large amounts of data that are already accessible in existing databases; these data can be analyzed in conjunction with genetic data. A compilation of the types of data that are available for this analysis by cognitive systems approaches can be found at: NIAGADS https://www.niagads.org/. 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 responsive to this FOA:

  • Genetic and genomic data: 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 together 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.
  • Epidemiology cohorts with genetic/genomic data: 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, orTOPMed); 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); 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, or AMP-AD); Rush Memory and Aging Project (MAP) (AMP-AD); and the Washington Heights-Inwood Community Aging Project (WHICAP).
  • Biobanks with genetic data for complex diseases, such as the UK Biobank, TOPMed, and All of Us.
  • Biomarker: See the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (adni.loni.usc.edu/).
  • Functional genomics: Genotype-Tissue Expression (GTEx) with tissue-specific gene expression; induced pluripotent stem cell (iPSC); Roadmap epigenomics; FANTOM 5 (enhancers); ENCODE; PsychENCODE; DASHR (noncoding RNAs).
  • Neuroimaging: Magnetic resonance imaging (MRI), positron-emission tomography (PET), and other nuclear medicine functional imaging methods used to observe metabolic processes in the brain as an aid to the diagnosis of AD; seeADNI and the NIA funded Alzheimer’s Disease Centers (ADCs).
  • Clinical data: Longitudinal clinical data from ADCs, the National Alzheimer’s Coordinating Center (NACC), and ADNI.
  • Single cell: See the Single Cell Analysis Program -- Transcriptome Project (SCAP-T), the Human Cell Atlas (https://www.humancellatlas.org/areas-of-impact; https://www.humancellatlas.org/), and the BRAIN Initiative.

Some aspects of the work may best be done manually, especially when the task size is manageable, the required analytic accuracy is high, and the manual work will not impede the scalability of a deployed system. NIA is primarily focused on developing automated technologies for genetic analysis that lead to therapeutic target discovery.

Research Objectives

This FOA will support the development of fast and efficient cognitive systems approaches to identify changes in AD genetic architecture that increase risk of and protection against the disease. The analytical approach chosen by applicants to this announcement will depend upon the type of data available, how much data there are, and where the data are stored. NIA recognizes that in some instances, small pilot projects may be needed to demonstrate the value of a particular approach and to build algorithms that may be further developed and refined. NIA also recognizes that human curation, at points in the data processing that would not impede scalability, could enable achievement of a substantially more capable data analytic approach. For this FOA, teams of geneticists, epidemiologists, bioinformaticians, statisticians, clinicians, cognitive systems specialists, and other academicians should work in concert on a common goal.

The emphasis is on the development and sharing of transformative, cognitive systems-based systems, emerging tools, and modern technologies for the analysis of genetic data. Both large and small projects using either supervised or unsupervised methodologies are of interest. NIA expects to receive applications with a variety of analytic approaches that leverage AD genetic and related data and outcomes, including creating models based on genetic data that can predict disease onset and progression; analyzing complex patterns and images; natural language processing to understand the underlying etiology of the disease; early-stage development of software, tools, and reusable neural networks; data reduction and “de-noising” in the harmonization of complex phenotypic data; and facilitation of interoperability among databases.

A key goal of this FOA is to establish an open, standards-based, multi-source “plug-and-play” architecture that abrogates the need for physical device reconfiguration or user intervention to resolve system-related conflicts. This includes the ability to easily add, remove, substitute, and modify software and hardware components. This will facilitate rapid innovation by providing a base for future users or developers of program technologies and other desired outcomes.

This announcement supports the creation and leveraging of open-source technology and architecture. Therefore, it is desired that all noncommercial software (including source code), software documentation, hardware designs and documentation, and technical data generated under this FOA be provided to the research community in such a way as to prevent researcher users’ rights from being adversely affected by costs of components or processes. Intellectual property rights asserted by applicants to the FOA should be aligned with open-source regimes.

NIA seeks applications that establish the validity and reliability of cognitive systems approaches and show whether they can provide added value beyond human-based analyses. Essential elements for the study design include description of approaches for validation testing, provision of clearly defined metrics for success or failure, and explanation of how the research community can apply the research tool or process.

The questions below express how that reliability and validity may be addressed, and ways in which added value might be achieved. NIA welcomes additional approaches to establishing validity and reliability and testing whether added value can be achieved. Applicants may explore more than one research question. Applicants who wish to explore areas outside of the enumerated topics should contact the NIA Program Officer listed in this announcement before submitting an application.

  • Diagnosis: Can cognitive systems approaches differentiate cases from controls using existing genetic, genomic and related data? Can cognitive systems approaches outperform conventional methods to differentiate cases from controls?
  • Polygenic risk scores (PRS), gene clusters, pathway analysis: Using cognitive systems approaches, can PRS be used to predict vulnerability to disease, age at onset, or rate of cognitive decline? Can biological hubs and cellular pathways be identified using existing genetic data? Are there differences in the composition of biological hubs when comparing across ethnic groups? Can a cognitive systems approach to identification and analysis of gene clusters or pathways bring the field closer to finding therapeutic targets for AD?
  • Endophenotypes: Can cognitive systems approaches be used to determine the endophenotypes associated with specific clusters of genes, delineate factors that can identify genetic and neuroanatomical signatures of AD, or discern differences across ethnicities?
  • Genetic variation: Can cognitive systems approaches be used to detect patterns of variants observed in the genetic architecture of AD or to detect variations in patterns across ethnic groups?
  • Disease progression: Can cognitive systems approaches use genetic and related data to assess symptomatic progression of subjects based on clinical scores from multiple timepoints?
  • Disease heterogeneity: Can cognitive systems approaches explain the heterogeneity of the disease, including age at onset, diversity of endophenotypes, and differences across ethnic groups?
  • Risk prediction: Can cognitive systems approaches identify subjects at highest risk for AD in order to bring them to clinical trials as early as possible?
  • Protective factors: Can cognitive systems approaches be used in the identification of protective genetic factors? Can cognitive systems approaches identify potential therapeutic targets based on the genetics (risk for or protection against) of the disease?
  • Genetic architecture: Can cognitive systems approaches successfully analyze copy number variation (CNVs) or structural variants (SVs) in AD whole genome sequence data?
  • Ethnicity and diversity sample sets: Can cognitive systems approaches be used to define the variation observed in the risk for and protection against AD? Can cognitive systems approaches, based on genetic and related data, identify therapeutic targets that vary based on unique genetic risk scores in specific populations?
  • Hypotheses: Does having etiological hypotheses for AD aid gene discovery leading to identification of therapeutic targets? Can cognitive systems approaches determine, among existing hypotheses, which is the most likely etiology of AD? Based on genetic data, can cognitive systems approaches predict the reason for failure of clinical trials in the past and aid in selection of trial design approaches going forward?

A deeper understanding of the genes, genetic pathways, genetic hubs, and functional genomics of AD is essential to the identification of potential therapeutic approaches to the disease. This FOA supports the design and development of intelligent and innovative algorithms, software, methods, and computational tools to enhance the analysis of AD genetic and genomic data. Genetic data can be analyzed in combination with a variety of other types of complex data such as biomarker, imaging, “omic,” epigenetic, and phenotypic data. Relevant technological approaches include those that will facilitate the organization, representation, retrieval, harmonization, analysis, recognition, and classification of biological, genetic, and clinical data that will lead to successful identification of therapeutic targets for AD. The level of funding for individual awards made under this FOA will depend upon the size of the project, the quality of the application, and the availability of funds. Applications should be framed as being advantageous to the over-arching goals of the ADSP and the NIA Genetics of Alzheimer’s Disease program.

Genetic Data Generated by the Alzheimer’s Disease Sequencing Project (ADSP)

The ADSP has identified a number of variations in the genomes of individuals affected with AD; it is anticipated that many more variants will be found. Briefly, there are three phases to the project: Discovery, Discovery Extension, and Follow-Up Study. The ADSP was launched in 2012 in response to NAPA milestones for the genetics of AD. 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 the presence or absence of known risk factor genes. Details about samples are available from NIAGADS at https://www.niagads.org/adsp.

The ADSP Discovery Phase generated the following three sets of genome sequence data for these samples as part of the Discovery Phase: (1) WGS for 584 samples from 113 multiplex families (two or more affected per family); (2) 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.

The ADSP Discovery Extension Phase is assessing the genomes in diversity sample sets (African Americans and Caribbean Hispanics) and from well-phenotyped subjects with autopsy material. An additional 3,000 subjects were whole genome sequenced. These data have been harmonized with Discovery Phase data, called on Hg Build 38, and made available by application to NIAGADS.

The ADSP Follow-Up Study (FUS) encompasses sequencing and analyzing the whole genomes of at least 20,000 subjects from well-characterized, ethnically-diverse cohorts. Sequencing on African American and Hispanic cohorts is ongoing. Recruitment and analyses of Asian and other ethnic groups are in progress. These data, when analyzed with existing datasets, will enhance the ability to understand the genetic underpinnings of AD and to obtain a better understanding of rare risk and protective variants. This effort will pursue rare variants as comprehensively as possible, including consideration of statistical power and exploration of a range of different populations containing those that are currently under-represented in sequencing studies.

NIA-Funded Infrastructure Supporting Alzheimer’s Disease Genomic Data Analysis

It is expected that applicants will engage existing NIA-funded infrastructure in the development of their research plans. The Genome Center for Alzheimer's Disease (GCAD) and NIAGADS are two components of NIA-funded infrastructure that support the ADSP and are considered to be integral components of the genetic data analysis to be funded under this FOA. It is expected that a letter of support from relevant NIA funded infrastructure components will be included in the application.

The Genome Center for Alzheimer's Disease (GCAD) is funded under an NIA cooperative agreement/specialized center award to identify genetic variants that cause, influence risk, or protect against this disorder and to identify the underlying genes affected by these variants. The role of GCAD is to coordinate the integration and meta-analysis of all available AD-relevant genetic data, with the goal of identifying AD risk/causative/protective genetic variants and eventual therapeutic targets. GCAD performs the following for the ADSP:

  • Harmonizes all AD-relevant genetic and phenotype data to be compatible for use in subsequent analysis. This includes sequence data generated by the ADSP, as well as data from other sources.
  • Analyzes the ADSP Follow-Up Phase data for AD risk/causative/ protective genetic variants in ethnically diverse cohorts.
  • Provides a combined analysis of the ADSP Discovery and Follow-Up data for AD risk/causative/protective genetic variants.
  • Extends replication analyses by meta-analyzing ADSP and non-ADSP genetics data for AD risk/causative/protective genetic variants.

NIAGADS is a national genomics data repository that serves as the Data Coordinating Center for the ADSP. It was established to facilitate access by qualified repository investigators to genotypic and associated phenotypic data for secondary analysis as part of the study of the genomics of AD. ADSP phenotype and genetic data are made available to the research community at large via cloud-based services immediately after quality control checks and variant calls are completed, in accordance with the NIH Genomics Data Sharing Policy (https://osp.od.nih.gov/scientific-sharing/genomic-data-sharing/) and the NIA Genomics of Alzheimer’s Disease Data Sharing Policy. Data are shared in a manner consistent with the research participants’ informed consent, protecting confidentiality of the data and the privacy of participants. NIAGADS has FISMA moderate security clearance. Access to human genomic data is provided to research investigators who, along with their institutions, have certified their agreement with the expectations and terms of access outlined by NIA at https://dss.niagads.org/ , https://www.nia.nih.gov/research/dn/alzheimers-disease-genomics-sharing-plan, and https://www.niagads.org/sites/all/public_files/NIAGADS-DDA.pdf. It is the intent of the NIA that approved users of datasets recognize any restrictions on data use established by the submitting institution through the Institutional Certification, as stated on the NIAGADS website (https://www.niagads.org/).

NIAGADS is the designated database for data harmonization, analysis, and sharing for this initiative. Applicants proposing the use of alternative databases for final data harmonization/data sharing will not be accepted. Any number of platforms may be used in the study, provided that existing NIA-funded infrastructure components can support them. Applicants should discuss plans for use of specific platforms with the Program Officer listed in this FOA before submission of applications.

Data integration and cloud-based analysis

Subsets of data that have already been harmonized by geneticists and epidemiologists are available to the research community. Large amounts of relevant harmonized data are available both at NIAGADS and in other repositories. These include clinical data from subjects who have been whole genome sequenced at NACC; ADNI imaging and clinical data stored at the University of Southern California's Laboratory of Neuro Imaging (LONI); and Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD) data stored at Sage Bionetworks. To avoid redundancy in existing infrastructure, for this FOA, arrangements for access to these harmonized data will be provided through NIAGADS, which will act as a central hub for the effort. Working with NIAGADS, investigators will coordinate efforts to generate data that are consistent in presentation to the research community.

Though much genetic and genomic data has already been harmonized and stored at NIAGADS, it is unlikely that all epidemiological data needed for some cognitive systems analyses are currently harmonized and available through NIAGADS. Therefore, this FOA allows for harmonization of the epidemiological data needed for particular cognitive systems analyses. Where existing datasets have not yet been harmonized, applicants will collaborate with investigators from existing projects to determine which variables can be harmonized and how best to undertake this effort. For epidemiologic datasets where certain types of data have not yet been harmonized, collaborative groups will work in partnership with NIAGADS to provide data that are presented consistently across cohorts. Lists of resources and harmonized genetic, genomic, and phenotypic data will be provided through NIAGADS. Where newly harmonized data are generated, these data will be made available through NIAGADS which will ensure consistency in data presentation for the effort.

Supported under other mechanisms, NIAGADS will provide access to space for analysis of data that have been harmonized and will assist in the development of approaches for use of cognitive science tools and algorithms that can be brought to the NIAGADS workspace. Configuration of the NIAGADS repository space will be done in consultation with NIH staff at other NIH institutes to ensure that systems and platforms are interoperable. In the long term, data generated by awardees of the FOA will continue to be made available through NIAGADS to ensure they will be accessible after the studies funded under the FOA are complete.

Retention of harmonized data related to the cognitive systems analysis of AD genetic data in NIAGADS will be a significant advantage for rapid and efficient data analysis. The cloud-based environment and cross-cloud support capability will allow cognitive systems approaches to be efficiently applied to large data sets. NIAGADS works in partnership with major web-based services engaged in data management. Existing “off-the-shelf” solutions for data management of such large data are already commercially available. A cloud environment for computation with elastic resources will reduce infrastructure burden.

Applicants should work with lead NIAGADS investigators where relevant data have been generated for selected datasets to determine the content of the dataset, the number of subjects/samples in the dataset, and any other information that will be essential for harmonization of data across studies. Applicants should request that lead investigators for selected datasets/cohorts provide a letter of collaboration for NIAGADS’s effort. PDs/ PIs are expected to include funds for data harmonization in their application. If the data harmonization capabilities of GCAD are planned, then lead investigators should provide a letter of collaboration for their effort in the study. The types of data, types of analyses, and analytical approaches should be explained; the type of data that will be generated should be defined, as should expected outcomes.

Before submission of applications, applicants are expected to notify the program contact listed on this FOA to define the data sets and specific types of data and data analysis that will be proposed for harmonization and analysis. Program officials may request additional information from applicants either before or after an award is made. Data sets that are not discussed with the program official in advance of the application may not be included in the study. Proposed budgets should encompass and augment existing ADSP-supported infrastructure. Research plans should be milestone-driven.

Applications for funding under this FOA will have Genomic Data Sharing documents, appropriate Institutional Review Board (IRB) approvals, sharing plans, data deposition and data transfer agreements in place before awards are made. Data will be provided to applicants based on IRB consent category. Additional information on the process can be found at https://dss.niagads.org/about-dss/.

Summary

Under this FOA, a large amount of existing GWAS, whole genome, whole exome, genomic, endophenotypic, clinical, and epidemiological data from ethnically diverse affected and unaffected individuals will be harmonized and analyzed using cognitive systems analytical approaches. Analysis of these data will identify new genes and genetics pathways that will identify risk and protective factors for AD and guide the field toward novel therapeutic approaches to the disease. Applications will engage cognitive systems specialists, AD geneticists, and other field experts and leverage existing NIA infrastructure to answer selected questions posed by NIA. Both small exploratory projects and large analytic efforts are eligible. Harmonized data, final outcome data, and other data resulting from this study will be shared with the research community through NIAGADS. Open source technology, including all noncommercial software (including source code), software documentation, hardware designs and documentation, and technical data generated under this FOA will be provided to the research community in a transparent fashion. Intellectual property rights asserted by applicants will be aligned with open source management. Investigators will submit applications that may include ADSP investigators, geneticists and other experts with expertise in complex neurological diseases, private industry partners, and academicians with expertise in cognitive systems approaches.

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 2-6 awards, corresponding to a total of $4 million, 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:

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

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

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

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

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) – 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.
  • 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.

NIA welcomes engagement from all responsible sources capable of satisfying the needs of this funding opportunity announcement. Applicants must have expertise in the domain areas of one or more of the following: artificial intelligence, machine learning, deep learning, neural nets and related areas, bioinformatics, computational biology, supervised and unsupervised learning, and related topics. PDs/PIs and collaborators supported under ADSP-related PAR-12-183, PAR-14-070, RFA-AG-16-001, RFA-16-406, and PAR-17-214 may be PDs/PIs or collaborators on applications for this FOA. At least one geneticist and one epidemiologist with expertise in AD genetics must be included on the application.

2. Cost Sharing

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

3. Additional Information on Eligibility

 

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

 

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

Entities performing cognitive systems analysis should have a demonstrated record of having analyzed large volumes of complex data and generated analysis data that are of high quality using cognitive systems approaches; have in place a collaboration with NIA-funded ADSP investigators; have a strong working knowledge of the activities of the ADSP; and have established collaborations with a record of participation in analysis of complex diseases.

SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.

It is expected that key personnel will have appropriate experience and training for the acquisition, management, and cognitive systems analysis of data related to complex diseases. This includes existing epidemiological, case/control, family-based, and other data sets from a variety of ethnic groups. Key personnel should have expertise in the analysis of complex types of data and the handling and analysis of complex data sets such as genetic, clinical, population substructure, and endophenotypic data related to complex diseases. Key personnel with clinical, genetic, and epidemiologic expertise in the field of AD and previous collaboration with ADSP investigators is essential. Key personnel should have expertise in archiving, retrieving, processing, and distributing phenotypic data used for genetic analysis or a related field associated with human disease. Key personnel should be facile in curation of large data sets such as genetic, genomic, epidemiological, biobank, clinical, biomarker, functional genomics, neuroimaging, neuropathology, clinical, and single-cell data relevant to genetic analysis.  Key personnel must be familiar with clinical and neuropathology data elements and related data that will be provided by NIA-funded investigators. Key personnel should have expertise in managing a large data repository that can store, manage, share, and harmonize multiple types of data for genetic analysis. Key personnel should have expertise in coordinating the deposition of data into an NIA-approved repository. Key personnel should have expertise in managing a large-scale project.  

If the application is multi-PD/PI, investigators should have complementary and integrated expertise and skills in order to provide an appropriate approach to leadership, governance, plans for conflict resolution, and organizational structure applicable to the database. The applicant(s) should have experience overseeing selection and management of sub awards, if needed.

 

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

Funds to perform the following operations for coordination of ADSP data analysis should be an aspect of the budget: request and obtain the genetic data and related information from various research resources such as UK Biobank; coordinate the complete material transfer agreements (MTA) with each of the contributing studies/sites with GCAD and NIAGADS; and ensure that data and/or materials are provided to each of the contributing studies/sites for transfer in keeping with data transfer agreements. Subcontracts for NIAGADS and CGAD may be provided for unique data management procedures.

R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Provide a succinct description of how the proposed work will meet the overall scientific goals, the expected outcomes, and the impact on the ADSP. Describe the organization and operational procedures of the collaborative research, including how established infrastructure will be used and how the expertise of the members will be integrated and applied to complete planning, preliminary evaluation, ascertainment, and sample collection for a number of large, ethnically diverse population sample sets. Describe the processes and resources that will be used to identify and evaluate data from subjects to be studied over the course of the award. Please refer to the Funding Opportunity Description in Section I when formulating Specific Aims.

Research Strategy: The applicant(s) should present an integrated plan that will be responsive and flexible regarding the evolving needs of the scientific community, especially the ADSP and other major AD genetics and genomics projects. The applicant(s) should provide a rationale for selection of study data and the approach and rationale for selection of analysis methodology to be used in the study. Plans for documentation of key procedures and work flow should be included. The contributions of individual key personnel should be specified. Provide an overall description of the proposed organizational structure and project management plan, including any relevant flow charts, and show how the research will serve particular communities of researchers studying AD. Describe the strategy for effectively carrying out each specific aim. Explain how the study will interface with the existing units of the ADSP, what collaborative interactions will be established, and the type of advisory committee that will be engaged. Provide a plan to arrange coordinated receipt, storage, harmonization, analysis, and distribution of genetic and related clinical data. Explain how cognitive systems approaches to the analysis of GWAS, WES, WGS, and variant called data will facilitate the ADSP as a whole and other independent projects researching AD. Please refer to the funding Opportunity Description in Section I when developing the Research Strategy.

Innovation: Explain how the concepts, approaches or methodologies, or interventions used in the cognitive systems analysis of ADSP and related data are novel to the field of AD research. Explain how refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed are novel to the field of AD research. Explain any novel organizational concepts, management strategies, or analytical approaches to coordinating the research projects that the cognitive systems analysis will serve. Describe any concepts, strategies, or approaches that are novel to the genetics and genomics of AD research or that are applicable in a broad sense. Explain any refinement, improvement, or new application of organizational concepts, management strategies, or instrumentation that will be employed in the research. Explain any innovative approaches for data acquisition and data handling.

Approach: The proposed study should describe a comprehensive plan to address the vital need for well-coordinated acquisition and handling of genetic and related clinical data, including GWAS, WES, and WGS data, from a large number of affected individuals from existing sample sets from ethnically diverse populations. The applicant(s) should provide a rationale for selection of cohorts of subjects affected with AD, particularly minority cohorts. Provide preliminary data, along with power and related calculations, to confirm the feasibility of the study approach. The application should describe the organization and operational procedures of the collaborative research infrastructure and how the expertise of the members will be integrated and applied to complete planning, evaluation, data collection, and data sharing for up to 30,000 individuals affected with AD, consistent with achieving the goals of the ADSP. The application should describe the processes and resources that will be used to identify and evaluate data to be studied over the course of the award. Explain the approach and rationale for selection of methodology to be used in the study. Plans for documentation of key procedures should be included. State plans to participate actively in data exchange and to collaborate with other investigators in the ADSP and with awardee(s) of other NIA grants and cooperative agreements in order to enhance the likelihood of identifying therapeutic targets for AD. The contributions of individual key personnel should be specified. Provide an overall description of the proposed organizational structure and project management plan, including any relevant flow charts, and show how the research will serve particular communities of researchers studying AD. Describe how the proposed study will ensure the collection, storage, and sharing of data is done in a manner that is appropriate and consistent with achieving the goals of the program and augments the existing ADSP analyses. Describe the strategy for effectively carrying out each specific aim. Explain how the study will facilitate the mission of the ADSP, and how the applicants will work cooperatively with the ADSP as a whole. Explain how the research plan will enable the ADSP to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Explain why the proposed approach is feasible, how particularly risky aspects will be managed, and how the study will advance and augment the development of novel therapeutics for AD. Explain how potential problems will be addressed, alternative strategies carried out, and benchmarks for success achieved. Define project milestones and a time line for key events. Please refer to the funding Opportunity Description in Section I when developing the Approach.

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 that is consistent with the NIA Genomics of Alzheimer's Disease Sharing Policy and the goals of the NIA Genetics of Alzheimer's Disease program. It is the policy of NIA that all Genomic Data derived from NIA-funded studies for the genomics of late-onset Alzheimer’s disease, including secondary analysis data, be deposited at NIAGADS or another NIA approved site, or both whenever possible. More information can be found at: https://www.nia.nih.gov/research/dn/alzheimers-disease-genomics-sharing-plan.

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information
When involving NIH-defined human subjects research, clinical research, and/or clinical 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.

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.
 

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

3. 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 {IC} Referral Office by email atramesh.vemuri@nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

 

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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

 

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 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 experienced are the key personnel in handling complex data types (e.g. study-related epidemiologic, endophenotypic, biomarker, and necropsy data), study-related genetic data, and phenotype data? How appropriate are the experience and training of the key personnel for acquisition of data from ethnically diverse cohorts? How appropriate is their record of accomplishments in effectively managing large data sets like those of the ADSP? How experienced is/are the applicant(s) in handling datasets for complex diseases? How appropriate is their experience in coordinating collaborative research? How appropriate are the approaches to leadership, governance, and organizational structure for the ADSP? How appropriate are plans for conflict resolution? Do the PD(s)/PI(s) have enough experience overseeing selection and management of sub-awards? Do the PD(s)/PI(s) and staff have sufficient appropriate experience and training for management of large-scale data acquisition? Do PD(s)/PI(s) and staff have expertise in curation and distribution of large sample sets, including pedigree, genetic, genomic, and phenotypic data relevant to genetic analysis; clinical and neuropathology data elements; sequence data; and related data? How likely to succeed is the plan to form an effective advisory committee to oversee the work? If the application is multi-PD/PI, do investigators have complementary and integrated expertise and skills in order to provide an appropriate approach to leadership, governance, conflict resolution, and organizational structure for the ADSP FUS? Does the sequencing center have a demonstrated record of generating large volumes of WGS data that are of high quality; a record of collaboration with NIA-funded AD investigators; a strong working knowledge of the activities of the ADSP; and a record of participation in analysis of complex diseases?

 

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?

Does the application propose novel management strategies? How novel are the concepts, approaches or methodologies, or interventions used in the augmentation of ADSP data to the field of AD research? How well does the application explain any refinements, improvements, or new applications of organizational concepts, management strategies, or instrumentation that will be employed in the research? How novel are organizational concepts, management strategies, or analytical approaches? How novel are concepts, strategies, or approaches to the genetics and genomics of AD research? How innovative are approaches to data acquisition?

 

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?

How well will expertise of the members be integrated and applied to complete planning and execution of the study? How well do the PD(s)/PI(s) describe the processes and resources that will be used to identify and evaluate subjects to be studied? How likely to succeed are the processes and resources that will be used to identify and evaluate subjects? How likely is it that the selection of study subjects, especially those from diverse populations, will lead to gene discovery? How well-reasoned and appropriate to accomplishing the specific aims of the project are the overall strategy, methodology, and analytic approaches? How likely is it that the approach and rationale for selection of analysis methodology will reveal new AD risk and protective genetic factors? How appropriate are the proposed work flows and timelines? How well-organized are operational procedures for collaborative research? How well do the PD(s)/PI(s) describe their plans for documentation of the project’s key procedures? How well-reasoned are the operational plans and organizational structure? How appropriate are benchmarks for success? How appropriate and consistent are project goals with achieving the goals of the AD genetics program? How likely is the program to meet overall scientific goals and generate expected outcomes? How well does the proposed strategy establish feasibility and manage the risks associated with the activities of the project? How well will the proposed strategy maintain the continuity of the existing study? How well will the investigators interface with the existing components and collaborations of the ADSP? How likely to succeed are collaborations with ADSP investigators and with awardee(s) of other NIA grants and cooperative agreements? How responsive is the proposed study likely to be to the need to serve as an interface between the ADSP; related infrastructure, such as NIAGADS and GCAD; and the AD research community at large? How well-developed are plans to ensure appropriate data and sample sharing? How comprehensive is the plan to address the need for well-coordinated acquisition and handling of clinical, epidemiological, neuropathological, genetic, and genomic data number of affected individuals from existing ethnically diverse sample sets? How likely to succeed is the plan to arrange coordinated receipt, storage, and distribution of study data? How efficiently will the project provide a large sample of genetic and related phenotypic data for broad use by the research community?

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?

 

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

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

 

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.

 

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.

 

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.

 

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.

 

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.

 

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

 

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
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.

 

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 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).

 

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).

 

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.

 

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 the National Institute on Aging, 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 National Advisory Council on Aging. The following will be considered in making funding decisions:

  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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.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.

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 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 analysis protocols, as well as methods for sample and data acquisition and distribution. The PD(s)/PI(s) will work directly with members of the ADGC, the Consortium for Alzheimer's Sequence Analysis (CASA), the Collaboration on Alzheimer’s Disease REsearch (CADRE), the CHARGE Consortium, the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease (U54) -https://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-001.html#sthash.CkRnSTCU.dpuf, all phases of the ADSP, PIs of NIA-supported infrastructure, and other NIA-funded investigators.

The PD(s)/PI(s), in consultation with the NIA Project Scientist, will establish a board of external consultants to provide guidance on sample acquisition and advances in methodology appropriate for use in this context. Insofar as is possible, the board will include existing ADSP external consultants. Selected consultants will be individuals who are not involved in AD genetics research but who could advise the awardees with an emphasis on advanced bioinformatics and cognitive sciences methodology, population diversity, and AD data banking. Phases of the award will proceed only after review and approval of the common protocols by the Executive Committee and acceptance by NIA.

The PD(s)/PI(s) will be involved in collaborations with the investigators associated with all phases of the ADSP, as well as investigators associated with NIAGADS, GCAD, and the ADGC. The PD(s)/PI(s) will administer the establishment, operation, and quality control of cognitive sciences analysis of project-related data, as well as ensuring implementation of and adherence to common protocols. This includes the development of procedures for assuring data quality control, transfer of data, and data harmonization.

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 Director(s) of the ADSP and the NIA Coordinating Center for Genetics and Genomics of Alzheimer's Disease. The PD(s)/PI(s) will ensure that ADSP data are made available immediately upon deposition into the data storage site. The NIA Project Scientist will have substantial scientific involvement that is above and beyond the normal stewardship role in awards, as described in the next section.

The PD(s)/PI(s) will ensure that the project creates and leverages open source technology and architecture and that all noncommercial software (including source code), software documentation, hardware designs and documentation, and technical data generated under this FOA are provided to the research community in a transparent fashion immediately upon completion of the project. The PD(s)/PI(s) will ensure that intellectual property rights asserted by the FOA applicant(s) are aligned with open source regimes.

The PD(s)/PI(s) will ensure that data are shared in a manner consistent with the research participants’ informed consent, and the confidentiality of the data and the privacy of participants is protected. The PD(s)/PI(s) will implement and use cloud-based services for data exchange using, at minimum, FISMA moderate security clearance. The PD(s)/PI(s) will certify their agreement with the expectations and terms of access outlined by NIA at https://dss.niagads.org/, https://www.nia.nih.gov/research/dn/alzheimers-disease-genomics-sharing-plan, and https://www.niagads.org/sites/all/public_files/NIAGADS-DDA.pdf. The PD(s)/PI(s) will recognize any restrictions on data use established by the Institutional Certification stated on the NIAGADS website (https://www.niagads.org/).

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

The NIA Program Official will be responsible for normal program stewardship, including assessing progress toward the accomplishment of specified milestones and recommending release of additional funds to the project. The designated NIA Project Scientist will have scientific involvement during conduct of this activity, through technical assistance, advice, and coordination. The NIA Project Scientist will monitor the deposition of data into NIAGADS to ensure that NIA-funded investigators have appropriate access to deposited data and have properly acknowledged the use of the ADSP data in the publication of their work. The NIA Project Scientist will ensure that data are shared in a manner consistent with the research participants’ informed consent, and that the confidentiality of the data and the privacy of participants are protected. The NIA Project Scientist will ensure that PD(s)/PI(s) implement and use cloud-based services for data exchange using, at minimum, FISMA moderate security clearance. The Project Scientist will ensure that PD(s)/PI(s) recognize any restrictions on data use established by the Institutional Certification stated on the NIAGADS website (https://www.niagads.org/). The NIA Project Scientist will review protocols for work flow and data sharing before their implementation. The NIA Project Scientist will be a non-voting, "ex officio" member of the Executive Committee and all key subcommittees.

Areas of Joint Responsibility include:

For areas of joint responsibility, lead ADSP FUS PD(s), in consultation with the NIA Project Scientist, will be members of the Executive Committee. Insofar as is possible, the existing ADSP Discovery Phase Executive Committee will provide membership to the ADSP FUS. The Executive Committee will hold meetings and conference calls to facilitate development and implementation of common measures, policies, and practices. The ADSP Executive Committee will define the rules regarding access to, and publication of, findings from analyses of NIA Late Onset of Alzheimer’s Disease Family-Based Study (LOAD FBS) samples and related data. 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 sharing among collaborators, stakeholders, and the AD research community. Appropriate ADSP FUS staff may attend the Executive Committee meetings on an as-needed basis. Similarly, members of the Executive Committee for NIAGADS may contribute to the effort by accessing and assessing appropriate genetic and phenotype data and providing expertise in the analysis of genetics data from specific AD cohorts, as needed. The Executive Committee will meet bi-monthly, or as needed.

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, including 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 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: 301-496-9666
Email: ramesh.vemuri@nih.gov

Financial/Grants Management Contact(s)

Traci Lafferty
National Institute on Aging (NIA)
301-496-8987
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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