Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
National Institutes of Health (NIH)
National Institute on Aging (NIA)
U01 Research Project Cooperative Agreements
This Funding Opportunity Announcement (FOA) invites applications specific to sample acquisition, genome wide association studies, whole genome sequencing, quality control checking, variant calling, data calling, data sharing, data harmonization, and analysis that will support the generation of data from multi-ethnic cohorts for the Alzheimer's Disease Sequencing Project Follow-Up Study 2.0: The Diverse Population Initiative (ADSP FUS 2.0).
30 days before the application due date.
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| June 05, 2021 * | July 05, 2021 * | Not Applicable | November 2021 | January 2022 | April 2022 |
| October 05, 2021 * | November 05, 2021 * | Not Applicable | March 2022 | May 2022 | July 2022 |
| February 05, 2022 * | March 05, 2022 * | Not Applicable | July 2022 | October 2022 | December 2022 |
| June 05, 2022 * | July 05, 2022 * | Not Applicable | November 2022 | January 2023 | April 2023 |
| October 05, 2022 * | November 05, 2022 * | Not Applicable | March 2023 | May 2023 | July 2023 |
| February 05, 2023 * | March 05, 2023 * | Not Applicable | July 2023 | October 2023 | December 2023 |
| June 05, 2023 * | July 05, 2023 * | Not Applicable | November 2023 | January 2024 | April 2024 |
| October 05, 2023 * | November 05, 2023 * | Not Applicable | March 2024 | May 2024 | July 2024 |
| February 05, 2024 * | March 05, 2024 * | Not Applicable | July 2024 | October 2024 | December 2024 |
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
Not Applicable
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.
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) and AD-related dementias (ADRD) in order to support the ongoing Alzheimer's Disease Sequencing Project (ADSP). The overarching goals of the ADSP are to: 1) identify new genes involved in AD/ADRD; 2) identify gene alleles contributing to increased risk for, or protection against, the disease; 3) provide insight as to why individuals with known risk factor genes escape from developing AD/ADRD; 4) identify potential avenues for therapeutic approaches and prevention of the disease; and 5) fully reveal the genetic architecture of AD/ADRD in multiple race and ethnicity categories. The samples for the ADSP were selected from well-characterized, diverse study cohorts of individuals both with and without an AD diagnosis as well as with and without known risk-factor genes. This study of human genetic variation and its relationship to health and disease involves a large number of study participants and aims to capture not only common single nucleotide variations, but also rare copy number and other structural variants that are increasingly thought to play an important role in complex diseases.
This FOA uses the Office of Management and Budget (OMB) official categories of race and ethnicity. For the purposes of this FOA, ethnic categories (i.e., Hispanic/Latino) and racial categories (i.e., American Indian/Alaska Native; Asian; and Black/African American) will be referred to as diverse populations . Cohorts of participants from individual ethnic or race categories will be referred to as diversity cohorts . Individuals in diversity cohorts will be referred to as diversity participants .
The ADSP has identified a large number of variations in the genomes of individuals affected with AD. The study population for these analyses was predominantly White. Lack of diversity in the sample set limits the possible clinical utility of emerging tools and methodological approaches for identifying potential therapeutics for a large proportion of the population. This, in turn, underscores the urgency to ensure appropriate representation of diverse populations to prevent potential gaps in the translation of research efforts to these populations. To this end, the initial ADSP findings will be pursued in diverse populations in the next phase of the study, called the ADSP Follow-Up Study (FUS) 2.0: The Diverse Population Initiative and referred to here as ADSP FUS 2.0. The long-term goals of the ADSP FUS 2.0 are to: 1) move the field closer to enabling prediction of who will develop AD; 2) fully characterize AD subtypes by studying endophenotypes in diverse populations; 3) better understand the differences in the genetic underpinnings of AD pathogenesis among diverse populations; and 4) identify specific therapeutic targets based upon diverse population.
Important instances of unique AD/ADRD genetic variation have already been identified in epidemiological cohorts with Hispanic/Latino and Black/African American participants. Variants for AD are rare and can only be identified with a larger number of study participants. Variants occur at different frequencies in different populations, and certain risk variants may be much easier to detect in some populations. US diversity groups are not represented in ADSP data in sufficient numbers to enable meaningful study, so the genetics of these populations remain largely unstudied. Hispanics/Latinos, Blacks/African Americans, and Asians are the largest and fastest-growing minority groups in the US, and AD/ADRD imposes a high economic and social burden upon the US population. US Asian population ADSP genetic data are completely absent.
Numbers of Hispanic/Latino and Black/African American participants in the US remain insufficient to provide statistical significance for identification of rare or very rare variants. Variants in the Alzheimer’s genome are largely rare or very rare in the population. It is estimated that for 80% certainty for single variant testing for rare variants, ~16,100 cases and ~16,100 controls are needed for a variant with a minor allele frequency of 0.5% in the population; single variant testing for rare variants indicate that for 90% certainty, ~18,500 cases and ~18,500 controls are needed for each population for a variant with a minor allele frequency of 1% in the population. To ensure that there are sufficient numbers of study participants to achieve statistical power for analysis of rare or vary rare variants in the three largest diversity cohorts AD/ADRD genome given the available funding, the primary focus of the ADSP FUS 2.0 will be on Hispanic/Latino, Black/African American, and Asian populations. Consortia should take advantage of cohorts already recruited or in planning for recruitment to obtain sufficient numbers; sharing diversity data across consortia is essential to the success of this effort. Investigators with cohorts representing other racial/ethnic categories, such as American Indians/Alaskan Natives, are encouraged to apply for funding separately under other NIA-supported FOAs. Sequencing of participants from founder populations such as those from Africa and Asia is allowed under this FOA in order to understand population substructure and ancestry-informative markers. A small amount of sequencing of Whites to bring significance to the 90% certainty of significance level will be allowed for rare or very rare variants for the US population; however, it is expected that the vast majority of sequencing in the ADSP FUS 2.0 will be done in Hispanics/Latinos, Blacks/African Americans, and Asians.
Accelerated identification of AD/ADRD genes, gene clusters, and endophenotypes driven by genetic and ethnic/racial characteristics will move the field toward selection of participants with similar endophenotypes to improve outcomes of clinical trials. The community is now able to layer different types of data to identify these endophenotypes. Analytic approaches are being developed for analysis of structural and rare variants, endophenotypes, and cross-phenotype genetic analyses to modify and/or apply analytic methods to data that are increasingly complex. In order to identify optimal drug targets, the full landscape of genetic variants must be identified and characterized.
Much work remains to develop analytic methods and resources to understand the functional significance of variants, particularly noncoding variants, in diverse populations. Under this funding opportunity announcement, studies that perform analysis of sequence data may include analysis of the functional genomic studies of regions of interest. Diversity datasets will need to be integrated and harmonized to fully annotate the AD genome. This may mean assembling annotation data such as that provided by ENCODE and similar approaches to help understand whether clusters of genes in the same network or with common function may be a component of the disease etiology that varies by ethnic and racial category. Applicants are encouraged to devise analysis plans to include data from genome wide association studies (GWAS) for AD; imputation analysis; ADSP whole exome and exome chip data, and whole genome AD sequencing efforts; related genetic data such as in deep (long read) sequencing analyses generated on AD subjects; and functional genomics data.
Research Objectives
NIA intends to support studies most likely to meet a major goal of this FOA: to identify and confirm a full set of rare variants contributing to AD/ADRD endophenotypes in diversity cohorts to enhance the probability of identifying potential therapeutic approaches for risk and prevention. Both sequencing and data analysis will be supported under this FOA. Applicants to this FOA for the ADSP FUS 2.0 should propose to: 1) sequence particular diverse study cohorts; 2) analyze either the entire dataset (cases and controls) or components of the dataset; or 3) both sequence and analyze these data. Justification for the choice of the approach must be provided. Applicants proposing to analyze only a component of the total cohort (i.e., selected cohorts or diverse subpopulations) should propose power calculations that support the likelihood of gene discovery. Applicants should design plans that clearly define which ADSP FUS 2.0 datasets, diverse subpopulations, and/or endophenotypes will be analyzed. Along with analysis of data funded under the present FOA, analysis plans for the ADSP FUS 2.0 should include data from diversity cohorts in the ADSP FUS funded under PAR-17-214, PAR-18-890, and PAR-19-234 where possible. The design and use of large-scale storage capacity with appropriate security and backup measures to support analytical capabilities should be considered.
Successful applications are anticipated to involve research conducted by multidisciplinary teams of investigators and should describe a comprehensive plan to develop leading-edge, innovative approaches for the analysis of whole genome sequence (WGS) and related genetic data. Analysis should encompass the criteria set out by the ADSP FUS funded under PAR-17-214, "Analysis of Data from NIA's Alzheimer's Disease Sequencing Project Follow-Up Study (U01)." In particular, these criteria include ethnic/racial diversity; autopsy-confirmed cases/controls, especially for non-European ancestry; availability of longitudinal data; no age limit for cases; cases unrelated to each other; and availability of comparable controls.
It is expected that the scientific environment in which the work will be done will contribute to the probability of success of the project and of the ADSP as a whole. Institutional support, equipment and other physical resources available to the investigators should be adequate for the project proposed, leveraging existing NIA-funded resources. Both the project itself and the ADSP should benefit from unique features of the scientific environment, subject populations, or collaborative arrangements. For applicants performing data analysis, it is expected that they will have the capacity to analyze whole-genome sequence data from sufficient numbers of affected and unaffected individuals to achieve statistical significance for rare or very rare variants in diverse groups.
The successful milestone-driven ADSP FUS 2.0 application would consist of a group of researchers with expertise in the genetics of complex neurological diseases, including AD, and the field of whole genome sequencing, as well as statisticians and other experts who will participate in study design and analysis. Successful applicant(s) may be expected to collaborate not only within their own study, but also with other PD(s)/PI(s) funded under this and related FOAs. Engagement of existing NIA-supported infrastructure is considered essential to the success of the project, so applicants should plan to financially support the National Central Cell Repository for Alzheimer’s Disease (NCRAD); The American Genome Center (TAGC) at the Uniformed Services University for the Health Sciences (USUHS) or another NIA-approved, large-scale sequencing center; the Genome Center for Alzheimer's Disease (GCAD); and the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) for their efforts in the ADSP.
Applicants should develop key quantitative milestones with a timeline for accomplishment. Quality control (QC) and data harmonization will be performed by GCAD. The order and process for data transfer, quality control checking, and data harmonization will be agreed upon by the ADSP as a whole and will follow closely the existing paradigm.
Under the present FOA, the ADSP will improve the likelihood of analyzing sequence data on enough different examples of events that change the genetic architecture of AD such that these data, when analyzed with existing ADSP datasets, will enhance the ability to better understand the genetic underpinnings of AD and to obtain a better understanding of rare risk and protective variants. The availability of high-quality, extensive phenotypic information on study participants is a critical consideration. Study design should include analysis of data from study participants with quantitative trait measures to more clearly define endophenotypes. Similarly, participants whose data will be used as controls should be well characterized.
Applications considered for funding must effectively leverage NIA and NIH investments in infrastructure to support studies related to the genetics of Alzheimer’s disease. The investigators funded under this FOA may utilize information from existing NIA- and NIH-funded research resources or other federal websites such as:
The Role of NIAGADS
NIAGADS was funded as a cooperative agreement in 2012 to establish a one-stop portal for the AD research community to access NIA-funded AD genetic data and findings. NIAGADS was launched simultaneously with the ADSP and coordinates ADSP phenotype/GWAS data collection, sequence data collection and delivery, and public data release. NIAGADS provides study registration and requirements for community access; manages data in a secure cloud environment (FISMA moderate) for all ADSP analysis and support workgroups; and develops resources facilitating community access to ADSP data and findings. NIAGADS is the designated data storage site for AD and related dementias genetic and genomic data. This FOA is intended to support their role in data acquisition, processing, curation, archiving, management, and data sharing, and these activities should be reflected in the budget.
PDs/PIs are expected to optimize accessibility and usefulness of the information generated by the study and to provide data to the AD research community through NIAGADS. NIA has issued a sharing policy specific to the genetics and genomics of Alzheimer's disease to which investigators must adhere; outcome data from the study will be deposited into NIAGADS or another NIA-approved data storage site for access by the AD research community.
Both the sequencing data and the outcome data derived from analyses will be stored at NIAGADS. Under certain limited circumstances, particular types of data may be stored at another NIA-approved repository. Study data should be released to the research community as soon as quality control checking and data harmonization are complete. PIs funded through this FOA will obtain from the NIA-approved data repository: 1) cleaned, quality control checked sequencing data; 2) information on the composition of the study cohorts (e.g., case-control, family based, and epidemiology cohorts); 3) descriptions of the study cohorts included in the analysis; 4) accompanying phenotypic information such as age at disease onset, gender, diagnostic status, and cognitive measures; and 5) epidemiological information such as educational level and certain environmental data available on the study participants genotyped.
Research Strategy and Scope
Recruitment and Retention
Robust efforts to leverage existing NIA-supported infrastructure for recruitment and retention of study participants in new ADSP cohorts should be made; diversity cohorts recruited under other NIA-funded mechanisms will be an important source of study participants. Plans to enhance diverse participant recruitment and retention of cohorts not supported under existing efforts should have a cohesive approach that proactively designs strategies to engage, collaborate with, recruit, and retain persons who are from the communities to be represented in the ADSP FUS 2.0 (ethnic category Hispanic/Latino and/or Racial Categories Black/African American, and Asian ). Investigators should be familiar with the culture and social construct of the diversity cohorts being selected and relevant ascertainment methods. Recruitment strategies should include community outreach using approaches that encourage working flexibly with individuals and families and that commit time and energy to ensure that recruitment is an interactive and trusted process. The research plan should include reportable milestones for recruitment that indicate the number of study participants that are expected to be recruited and timelines for recruitment.
ADSP Follow-Up Study (FUS) 2.0 Sequencing
An essential goal for the ADSP FUS 2.0 is to sequence data on a collective total, including all awards funded under this FOA, of diversity study participants in order to achieve sufficient power to identify rare and very rare variants in each of the major ethnic/racial categories. Case-control, family-based, and epidemiology cohorts are considered appropriate for this study. Quality control checking, phenotypic and genetic data harmonization, and analysis of sequence data should be done in each of the years of award. Variant calling should be in accord with existing ADSP pipelines. A proportion of study participants from each of the three key US ethnic/racial categories should be sequenced in each of the first four years of funding to allow for continuous data analysis.
ADSP investigators will submit applications that include: NCRAD for any needed sample handling; GCAD for quality control (QC) checking and genetic data harmonization; and NIAGADS for data sharing with the research community at large, and as subcontracts to the study. ADSP investigators will also include sequencing centers, as appropriate. Applicants should contact the Program Officer for this FOA regarding choice of large-scale sequencing center. NIA-funded ADSP genetics investigators and sequencing centers will collaborate and provide DNA and sequence data for the ADSP FUS 2.0. All data included in the ADSP FUS 2.0 will be called for genetic variants and quality control checked (QC'd) on the ADSP pipeline. Phenotypic data accrued by the ADSP FUS 2.0 investigators will be harmonized with existing ADSP phenotype data; these phenotypic data harmonization efforts are funded under PAR-20-099. Data generated under the present FOA may be analyzed as part of the ADSP effort using machine learning/artificial intelligence/deep learning approaches.
Under this FOA, when the application includes sequencing, investigators must include a funding stream (subcontract) for the four entities that are considered essential NIA infrastructure for the ADSP, as they are not otherwise supported for their efforts in this initiative. These are: 1) NCRAD; 2) TAGC or another NIA-approved sequencing center; 3) GCAD; and 4) NIAGADS.
Funds will be provided:
These efforts will increase statistical power to detect risk and protective genes for the diverse subpopulations studied in the ADSP FUS 2.0.
ADSP Follow-Up Study (FUS) 2.0 Data Analysis
Given finite availability of funding and time constraints for the ADSP FUS 2.0, NIA will support the analysis of GWAS and sequence data for the whole genomes of AD cases and AD controls from diverse populations, in numbers providing sufficient statistical power to identify rare and very rare variants under this FOA.
Applications that include genetic data analysis should describe the capabilities for sequence data storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms; a timeline for accomplishing the stated goals; and the costs related to the analysis. In the description of the data analyses, the investigator should consider ethnic/racial categories, endophenotypes, disease-related covariates, co-morbidities, and significance of association with the disease for common, rare, and unique sequences. The investigator should also describe how structural rearrangements, insertions, deletions, and haplotypes as genomic changes will be analyzed and correlated with disease status. Knowledge of rearrangements may reveal new biological mechanisms in understanding and diagnosing the disease.
Examples of the expected types of analytical assessments to be accomplished in order to provide a complete evaluation of the genomic contributions to risk and protection for AD in ethnically diverse sample sets include, but are not limited to: gene discovery, association analysis, read mappings, variant frequencies, quality control information, coding sites, non-coding sites, and splice sites for affected genes. Where analysis of sequencing data is to be done, the application should fully describe: 1) the analytical approaches to identify genetic risk and protective factors (a variety of approaches may be employed); 2) the qualities and characteristics of the genomic sequence information to be produced by the investigator; and 3) the projected funding requirements. Applicants will be allowed to re-sequence limited amounts of DNA, for example, to validate findings.
Much more work is needed on developing analysis methods and resources to understand the functional significance of variants, particularly noncoding variants. Investigators should design analysis plans to inform the underlying molecular networks of AD. Approaches to this analysis should begin to deconstruct the interactions among genes, understand the driving or causal genes in a single network, and identify the interactions of genes among networks that may result in dysregulation of gene function. Sequence variants that implicate sets of genes underlying an associated phenotype provide some insight into the biology of disease, but this is inconclusive without further experimental functional validation. As resources that catalog gene and genome function grow over time, the ability to make functional inferences based on variant association data will improve. There is likely to be value in encouraging connections between variant discovery and improvement of functional validation. Analysis of functional inferences is a key component of this FOA to gain a systems-level understanding of the gene, protein, and metabolic networks within which these novel targets operate. Funds for computer software and hardware, for bioinformatics and statistical analysis, and for the personnel needed to conduct the analyses will be provided.
The capability to bring to bear other technologies that are used in genomic analysis, and which could be directly relevant to disease variant analyses, may also be included. These could include, for example: 1) genotyping, or production and integration of other data modalities that can readily be generated with genome sequencing platforms (e.g., transcriptomes and epigenomes) and that are directly relevant to understanding the role of variation in common disease; 2) functional genomics analysis of specific loci/genes identified during data analysis; and/or; 3) machine learning/artificial intelligence approaches to data analysis to confirm identified genetic regions of interest.
It is expected that functional genomics data that are generated under the present FOA will be shared with investigators performing ongoing ADSP functional genomics studies as soon as possible in order to expedite the discovery of therapeutic targets for AD. Joint or meta-analysis of ADSP FUS 2.0 data with data from existing comparable cohorts is encouraged. Variants occur at different frequencies in different populations, and certain risk variants may be much easier to detect in some populations.
Collaborative Efforts for Studies Involving Sequencing, Data Analysis, or both Sequencing and Analysis
NIA anticipates that this project will require a high degree of collaboration with other researchers with an interest in AD in order to identify appropriate sample sets and to provide expertise for QC and variant calling. Data will be widely disseminated as a research resource, and the broad use of the data will be ensured. NIA expects that this component of the ADSP FUS 2.0 will be highly collaborative among:
Investigators should work closely with researchers funded under PAR-20-099 (ADSP phenotypic data harmonization), RFA-AG-21-006 (ADSP functional genomics), and PAR-19-269 (machine learning analysis of ADSP genetic data). The development of novel computational sequence analysis methods for the purposes of improved, more efficient analysis of the data towards the goals of this initiative and the potential to collaborate with other investigators to pursue more functional follow-up studies to enhance analysis and/or validate findings may be considered in the application. The ADSP FUS 2.0 will work synergistically with investigators for these three new initiatives to learn how population diversity impacts AD genetic endophenotypes and resultantly clinical trial outcomes.
Collaborations with investigators with large cohorts with cognitive data and longitudinal follow-up, such as All of Us, Centers for Medicare and Medicaid, and the Million Veteran Program are encouraged in order to augment statistical power for the three ethnic/racial categories that are the focus of this FOA.
The formidable combination of ADSP collaborations; access to deep, longitudinal phenotypic data; the development of novel analytic tools; and the generation of robust outcome data will enhance the ability to better understand the genetic underpinnings of AD in diversity populations in unique ways that have not been possible before.
Summary
In summary, sequence and analysis data will be generated under this FOA for the examination and comparison of the genomes of affected and unaffected individuals in Hispanic/Latino, Black/African American, and Asian populations to identify rare and very rare variants in AD/ADRD. The proposed study should describe a comprehensive plan for the analysis of WGS and other genetic data generated by investigators to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Both fundamental scientific discovery and leading-edge analytical approaches will likely be needed to achieve the research goals. The study is anticipated to involve research conducted by multidisciplinary teams of investigators including sequencing centers, geneticists, and statisticians. The analyses of these data under the present FOA to be done by the successful applicant(s) will identify new genes contributing to increased risk of developing the disease or protection against developing AD with the goal of identifying potential avenues for therapeutic approaches and prevention of the disease in diversity cohorts. Data resulting from this study will become available to qualified investigators to enable rapid identification of therapeutic targets.
See Section VIII. Other Information for award authorities and regulations.
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.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
Not Allowed: Only accepting applications that do not propose clinical trials.
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NIH intends to fund an estimate of two to three awards, corresponding to a total of $9,900,000, for fiscal year 2022. Future year amounts will depend on annual appropriations.
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.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
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.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
Only PD/PIs, key personnel, and collaborators supported under ADSP-related PAR-16-406, PAR-17-214, PAR-19-234, PAR-18-890, and PAR-19-234 may be PDs/PIs of applications for this Limited Competition FOA.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Number of Applications
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Michael Bennani-Baiti, Ph.D.
Division of Neuroscience (DN)
National Institute on Aging (NIA)
Email: [email protected]
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing (DMS) Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
For sample and data acquisition, the PD(s)/PI(s) should have a deep understanding of the genetics of AD/ADRD. The PD(s)/PI(s) should have demonstrated accomplishment in effectively interacting with study participants from diverse populations both inside and outside the United States and have expertise in the genetics of complex diseases, population genetics, and statistics in order to discover risk and protective genetics factors for AD.
It is expected that key personnel will have appropriate clinical experience and training for acquisition and management of biological samples and data related to existing epidemiological, case/control, family based, and other sample sets from a variety of ethnic/racial categories where AD is the underlying form of dementia. If recruiting cohorts to the study, key personnel should have expertise in recruitment and retention of study participants. Key personnel should have expertise in the generation of GWAS and WGS data and the handling and analysis of genetic, clinical, population substructure, and endophenotypic data related to AD. Key personnel should have expertise in archiving, processing and distributing phenotypic data and samples used for genetic analysis. Key personnel should be facile in curation of large datasets, including genetic/genomic, and phenotypic data relevant to genetic analysis such as clinical and neuropathology data elements, and related data provided by NIA-funded investigators.
For applications that involve whole genome sequencing: For sample handling, key personnel should demonstrate significant experience with coordinating collaborative (basic or clinical) research. The key personnel should have expertise in managing a large sample repository that can store DNA and other biological materials for genetic and biomarker analysis. Key personnel should have expertise in coordinating the deposition of samples to an NIA-approved repository, phenotypes from newly recruited individuals, and any related genotype data to an NIA-approved database. The key personnel should have expertise in managing a large-scale sequencing project including appropriate QC measures. Personnel from sequencing centers must have a proven record of sequence data production and QC and variant calling.
For applications that involve analysis of sequence data: It is expected that key personnel will have appropriate clinical experience and training for analysis and management of whole-genome, GWAS, and clinical data related to existing epidemiological, case/control, family-based, and other sample sets from a variety of ethnic/racial categories where AD is the underlying form of dementia. Key personnel should also have expertise in the following areas:
If the application is multi-PD/PI, investigators should have complementary and integrated expertise and skills in order to provide an appropriate leadership approach, governance, plans for conflict resolution, and organizational structure applicable to the data. The applicant(s) should have experience overseeing selection and management of sub-awards, if needed.
R&R or Modular Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
For applications that involve whole genome sequencing
Funds to perform the following tasks should be included in the budget:
Subcontracts to one or more sequencing centers, NCRAD, TAGC at USUHS, NIAGADS, and GCAD must be provided as funded under this PAS. The budget may include support for the formation of groups of investigators at several institutions to assemble a team with the appropriate balance, breadth, and experience.
For applications that involve analysis of sequence data:
Budgets should include funds to provide necessary recruitment and retention of study participants from ethnic Hispanic/Latino and racial Asian and Black/African American categories and funds for longitudinal follow-up of recruited participants.
Funds to perform the following operations for coordination of ADSP data analysis should be an aspect of the budget:
Subcontracts to NIAGADS, and GCAD must be provided. The budget may include support for the formation of groups of investigators at several institutions to assemble a team with the appropriate balance, breadth, and experience.
All instructions in the SF424 (R&R) Application Guide must be followed.
For applications that involve whole genome sequencing:
Funds to perform the following operations for coordination of ADSP sample allocation should be an aspect of the budget:
Subcontracts for NCRAD, NIAGADS, CGAD, and one or more sequencing centers must be provided.
For applications that involve analysis of sequence data:
Coordinate the complete MTA with each of the relevant studies/sites. The budget may include support for the formation of groups of investigators at several institutions to assemble a team with the appropriate balance, breadth, and experience.
All instructions in the SF424 (R&R) Application Guide must be followed.
Other Plan(s):
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy: Provide a succinct description of how the proposed work will continue to meet the overall scientific goals, the expected outcomes, and the impact of the ADSP. Describe the organization and operational procedures of the collaborative research, including the use of established infrastructure and how the expertise of the members will be integrated and applied to complete the analysis of WGS data derived from diverse affected and unaffected study participants in sufficient numbers to achieve statistical significance for rare/very rare variants. Where possible, studies should leverage other existing cohorts for this effort. Describe the processes, analytical approaches, and resources that will be used to identify and validate rare variations in the genomes of participants to be studied over the course of the award. Delineate any novel concepts, approaches, and methodologies or interventions that will be employed to augment the outcomes of the ADSP FUS 2.0. Define any novel organizational concepts, management strategies, or analytical approaches used to address the goals of the ADSP FUS 2.0. Describe novel concepts, strategies, and approaches that will augment the genetics of AD or the field of the genetics of complex diseases as a whole.
For applications that involve whole genome sequencing:
The applicant(s) should provide a rationale for selection of study participants, and the approach and rationale for selection of sequencing methodology to be done in the study. Explain how the augmentation of the number of samples in the various ethnic/racial categories affects power calculations for detecting rare and very rare risk and protective variants for AD. Show how the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic material and related clinical data, GWAS data, WGS data, and QC'd and variant called data will facilitate the ADSP as a whole for gene discovery.
For applications that involve analysis of sequence data:
Present an integrated plan for analysis of GWAS and WGS data for participants affected with AD and unaffected individuals for each of the selected ethnic/racial categories under study. If proposing to analyze only a component of the total data, provide justification and power calculations that support the likelihood of gene discovery. Provide a rationale for selection of analytical, statistical, and bioinformatic approaches. Include documentation of plans for key procedures, work flow, and relevant timelines. Specify the contributions of individual key personnel. Describe the strategy for effectively carrying out each specific aim. Define the type of advisory committee that will be engaged. Show how the plan to arrange, coordinate receipt of, store, back up, secure, process, and distribute genetic data and related clinical data will facilitate the ADSP as a whole and other research in AD that is supported in independent projects. Provide a clear data flow plan that assures QC'd and variant-called data using the established ADSP pipeline are analyzed and shared widely with the research community through NIAGADS. Explain how the proposed approach is appropriate and consistent with achieving the goals of the program.
Fully describe: 1) the analytical approaches to identify genetic risk and protective factors for AD in diversity cohorts (a variety of approaches may be employed); and 2) the qualities and characteristics of the genomic sequence analysis information to be produced by the investigator. Include a timeline for accomplishing the stated goals. Limited amounts of DNA may be re-sequenced, for example, to validate findings. Examples of the expected types of analytical assessments to be accomplished include: gene discovery, association analysis, read mappings, variant frequencies, quality control information, coding sites, non-coding sites, functional annotation, and splice sites for affected genes. Provide a rationale for determination of the potential function of selected genomic regions of interest.
Describe analysis methods for associating variants with specific endophenotypes to determine whether genetic subgroups can be identified that will point toward specific therapeutic approaches for the disease. Include consideration of power and sample number; phenotypes and endophenotypes; disease sub-groups and extremes; ethnic/racial categories; power calculations for gene discovery of risk and protective factors; and justification for inclusion of unaffected individuals in diversity cohorts. Describe the capabilities for sequence data storage, data analysis, and annotation accuracy to distinguish between sequencing errors and real polymorphisms. In the description of the data analyses, address disease-related covariates, population substructure, and significance of association with the disease for common, rare, and unique sequences. Describe how structural rearrangements, insertions, deletions, and haplotypes as genomic changes will be analyzed and correlated with changes in gene function and disease status.
If other large collaborative studies are proposed, such as meta or joint data analysis with All of Us or the Million Veteran Program, explain how data will be called on the ADSP pipeline and how harmonization of genetic and phenotypic data will be done. Analysis plans should include existing ADSP genetic and phenotypic data.
Include an explanation or diagram of how the existing components of the ADSP will be engaged in the ADSP FUS 2.0 Diversity Initiative, including:
1) the integration of the structure of the existing ADSP components including any new projects or subprojects
2. the ADSP Executive Committee comprised of signatories of the ADSP Memorandum of Understanding (MOU)
3) the Analysis Coordination Group and Analysis Work Group comprised of key members of ADSP Work Groups to oversee the normal operations of the consortium, and ADSP policy and trouble shooting.
4) the individual Work Groups responsible for various components of data analysis
5) cross collaboration with awardees of ADSP-related studies:
Elaborate key quantitative milestones with a timeline for accomplishment. Data should be QC'd/harmonized using the infrastructure, platform, pipeline(s), and HG build that the ADSP employs at the time of award. Explain how investigators of the ADSP FUS 2.0 will interface with advisors.
Innovation
Explain how the concepts, augmented sample number accrued under this FOA, approaches or methodologies, or interventions used in the ADSP FUS 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 in coordinating the research projects that the ADSP FUS 2.0 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 sample and data acquisition, WGS, QC or variant calling, and data handling for QC'd datasets. Explain how the ADSP FUS 2.0 will advance and augment the development of novel therapeutics for AD.
Approach
The application should describe how the proposed study will ensure the collection, storage, and sharing of data and augment the existing ADSP analyses as appropriate and consistent with achieving the goals of the program. Explain how the ADSP FUS 2.0 will facilitate the mission of the ADSP, and how the ADSP FUS 2.0 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, consistent with achieving the goals of this program. Explain why the proposed approach is feasible, how particularly risky aspects will be managed, and how the ADSP FUS 2.0 will advance and augment the development of novel therapeutics for AD. Explain how potential problems, alternative strategies, and benchmarks for success will be carried out. Define milestones and a timeline for key events for the project.
Provide the rationale and power calculations for inclusion of controls where ethnically diverse cohorts are to be engaged. 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, ascertainment, sample collection, WGS, QC, variant calling, and data sharing for individuals affected with AD, consistent with achieving the goals of this program.
For studies that include sequencing of participants from Hispanic/Latino, Asian, and/or Black/African American categories:
The applicant(s) should provide a rationale for selection of new diversity cohorts of participants affected with AD. For newly organized cohorts, provide the rationale for the selection of the sample set, define methods for cognitive testing and adjudication, and provide power calculations to confirm the feasibility of inclusion of the cohort. The application should describe the processes and resources that will be used to identify and evaluate participants to be studied over the course of the award, as well as the methods used for sample acquisition and handling and WGS, QC, variant calling, and data sharing. Explain the plan to obtain informed consent for newly identified participants. Explain the approach and rationale for selection of genotyping and sequencing methodology to be used in the study. 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, QC, variant calling, and data sharing consistent with achieving the goals of this program. Applicants should describe the methods used for sample acquisition and handling and WGS, QC, variant calling, and data sharing.
For studies that include analysis of genetic data:
For the diversity cohorts, provide the approach for data analysis that can integrate outcomes of cognitive testing and adjudication into existing data. Explain how the augmentation in sample number will increase the likelihood of identifying rare and very rare variants that may be found uniquely by ethnic/racial categories. Provide power calculations to confirm the feasibility of inclusion of the selected cohorts in the analysis plan. Explain how the inclusion of diversity populations will help define endophenotypes of the disease.
Explain how the study will coordinate activities with other ongoing analysis projects funded under PAR-17-214 (the existing analysis study). State plans to participate actively in data exchange and to collaborate with other investigators in the ADSP, other awardees of this FOA, and with awardee(s) of other NIA grants and cooperative agreements in order to enhance the likelihood of identifying therapeutic targets for AD.
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:
When involving human subjects research, clinical research, and/or NIH-defined 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.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
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.
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.
This initiative is not subject to intergovernmental review.
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.
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 not complete will not be reviewed.
In order to expedite review, applicants are requested to notify the NIA Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Requests of $500,000 or more for direct costs in any year
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.
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.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Will the proposed work identify genetic risk to AD in diverse ethnic populations through comprehensive analyses of existing genetic and genomic data sets? Are the plans sufficiently bold to constitute a substantial advance in the ability to analyze whole-genome sequencing, genotypic and phenotypic data? Does the proposed work have the potential to define and refine AD endophenotypes in ethnic/racial categories? Does the proposed work use an approach that will aid the discovery of changes in gene function that may impact the expression of endophenotypes in diverse populations? For studies performing data analysis, does the proposed work have a strong likelihood of revealing the structure of the genome of subjects with AD in diverse populations? For the overall application, does the organization integrate the activities and add value to the individual parts?
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 appropriate is the record of accomplishments of the PD(s)/PI(s) and other personnel in effectively managing large sample sets like the ADSP FUS 2.0? Do the PD(s)/PI(s) have enough experience overseeing selection and management of sub-awards; have a record of collaboration with NIA-funded AD investigators; have a strong working knowledge of the activities of the ADSP; and have a record of participation in analysis of complex diseases? Do the PD(s)/PI(s) and staff have sufficient experience and training for management of largescale genetic and phenotypic data acquisition with expertise in curation and distribution of large data sets including: pedigrees; genetic, genomic, and phenotypic data relevant to genetic analysis; clinical and neuropathology data elements; sequence data and related data in diversity populations?
For applications proposing sequencing:
How appropriate are the experience and training of the key personnel for recruitment and retention of participants for this study? How familiar are investigators with management of data from diversity cohorts? Does the sequencing center have a demonstrated record of having generated large volumes of WGS data that are of high quality? How experienced are the key personnel in handling AD genetic samples, study-related samples (e.g. samples for biomarkers, autopsy material), and curation of study related genetic data and phenotype data? Do the PD(s)/PI(s) and staff have sufficient appropriate experience and training for management of large-scale sample, phenotypic, genetic and related data acquisition and processing?
For applications proposing analysis:
Does the applicant(s) have a demonstrated record of analyzing large volumes of WGS data?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
For the overall project, will new statistical approaches or other analytical methods be developed that can be applied to the genetics of complex disease? Are novel approaches to integrating the analysis of GWAS data and WGS data employed? How novel are organizational concepts and management strategies?
For applications proposing sequencing:
How innovative are approaches for sample and data acquisition, WGS, QC or variant calling, and data handling for QC'd datasets?
For applications proposing analysis:
Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions related to ethnic/racial categories proposed? Will novel approaches to analyzing intergenic regions of the genome be developed? Will functional genomics be applied to the data in such a way as to reveal how genes and gene sets interact? Are there innovative strategies for analysis of existing genomic data sets that will lead to the development of new paradigms for analyzing genotype-phenotype relationship in AD research? Does the proposed work lead to the development of innovative bioinformatics approaches or novel computational tools to analyze and interpret multiple high-throughput genomic data sets?
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?
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?
How likely is the proposed study likely to effectively address the need to serve as an interface between the ADSP, the AD research community, and related infrastructure such as NCRAD, NACC, NIAGADS, and CGAD? How well will the proposed strategy maintain the continuity of the existing study? How appropriate is the plan to accomplish the ADSP's goals related to race and ethnicity? How appropriate are the proposed plans for work-flow and timelines? How well will the proposed ADSP FUS 2.0 assist the research community and NIA in achieving the goals of the Alzheimer's disease research programs it proposes to serve?
For applications proposing sequencing:
How appropriate is the plan to obtain informed consent and perform cognitive testing on newly identified participants? How well reasoned is the recruitment and retention plan for ethnically diversity cohorts? How appropriate are the proposed approach and rationale for selection of genotyping and sequencing methodology to be used in the study? How comprehensive is the plan to address the need for well-coordinated acquisition and handling of DNA and related clinical data, GWAS data, and WGS data from a large number of affected individuals from existing sample sets? How likely to be successful is the plan to arrange coordinated receipt, storage, genotyping, and distribution of genetic material and related clinical data, GWAS data, WGS data, QC'd data, and variant called data and data sharing? How well is the expertise of the members integrated and applied to complete planning, ascertainment, evaluation, and sample collection for a large number of samples from affected individuals from ethnically diversity cohorts?
For applications proposing analysis:
How statistically well powered is the plan to study diversity cohorts? How likely is it that the selection of study subjects from diverse populations will reveal new AD risk and protective genetic factors and/or will reveal endophenotypes in diversity populations? How well organized are operational procedures for collaborative research? How well will expertise of the members be integrated and applied to complete planning and execution of the study? How well will the ADSP FUS 2.0 investigators for this component of the project interface with the existing components and goals of the program?
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?
How adequate are resources available within the scientific environment to support electronic information handling?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
Inclusion of Women, Minorities, and Individuals Across the Lifespan
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Renewals
For Renewals, the committee will consider the progress made in the last funding period.
Revisions
For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Applications from Foreign Organizations
Not Applicable.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
Authentication of Key Biological and/or Chemical Resources:
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIA, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications will receive a written critique.
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.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
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 recipient's business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
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, Recipients, 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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
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.
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.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 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 recipient for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
For Revision Applications:
Each revision made under this FOA will be subject to the same terms and conditions specified for the original U01 award. Applicants should consult the Notice of Award for their current U01 for the specifics of those terms and conditions.
For New and Renewal Applications:
The PD(s)/PI(s) will have primary responsibility for:
The PD/PI(s) will have primary authorities and responsibilities to define objectives, approaches, and analysis protocols; sample and data acquisition and distribution.
The ADSP FUS 2.0 Program Director(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 existing ADSP FUS external consultants will provide membership to the ADSP FUS 2.0. Consultants will be selected as individuals who are not involved in AD genetics research but who could advise the awardees with an emphasis on sequencing and genotyping approaches, population diversity, sample banking, and biomarkers for AD. The external consultants will advise the Program Director(s) on methodological approaches; phases of the award will proceed only after review of the common protocols and approval by the Executive Committee and acceptance by NIA.
The PD/PI(s) of the cooperative agreement will be involved in collaborations with the ADSP, NCRAD, TAGC at USUHS and other NIA-approved sequencing centers, GCAD, NIAGADS and other relevant NIA-funded entities during all phases of the award as well as will other investigators funding under this and related FOAS. The PD/PI(s) of the cooperative agreement will administer the establishment, operation, and quality control of genotypic and phenotypic data, including the development of procedures for assuring data quality control and procedures for transfer of data as appropriate. The Program Director(s) of the cooperative agreement is/are responsible for working cooperatively with study sites and sponsoring organizations and for overseeing the implementation of, and adherence to, common protocols, as well as assuring quality control of the samples collected. In addition to organizing and attending regular meetings, the Program Director(s) of the cooperative agreement 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 Program Director(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 below. Awardees will work in accord with the mutually agreed upon ADSP_MOU.
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 the progress toward the accomplishment of specified milestones, and for 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, assisting in those aspects of the award as described below. The NIA Project Scientist will monitor the deposition of samples into NCRAD to ensure that NIA-funded investigators have appropriately deposited data and have properly acknowledged the use of the ADSP FUS in the publication of their work. The NIA Project Scientist will ensure that quality-control-checked, harmonized data are released in a timely fashion through NIAGADS or other NIA-approved data sharing sites. The NIA Project Scientist will review protocols for work flow and data sharing before they can be implemented. The NIA Project Scientist will be a non-voting "ex officio" member of the Executive Committee and all key subcommittees.
Areas of Joint Responsibility include:
For areas of joint responsibility, a subset of lead ADSP FUS 2.0 Program Director(s), in consultation with the NIA Project Scientist, will be members of an Executive Committee for internal decision making. Insofar as is possible, the existing ADSP Discovery Phase Executive Committee will provide membership to the ADSP FUS 2.0. 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 ADSP FUS 2.0 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 2.0 staff may attend the Executive Committee Meetings as needed. As needed, 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. 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. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
Data Management and Sharing
Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.
Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.
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.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that 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)
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Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]
Michael Bennani-Baiti, Ph.D.
Division of Neuroscience (DN)
National Institute on Aging (NIA)
Email: [email protected]
Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9666
Email: [email protected]
Robin Laney
National Institute on Aging (NIA)
Telephone: 301-496-1473
Email: [email protected]
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.