National Institute on Aging (NIA)
Reissue of PAR-16-406
This Funding Opportunity Announcement (FOA) invites applications specific to sample acquisition, genome wide association studies, whole genome sequencing, quality control checking, variant calling, and data calling that will support the generation of data for the Alzheimer's Disease Sequencing Project Follow-Up Study.
April 2, 2019
30 days prior to the application due date
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.
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.
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 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 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/.
The ADSP Discovery Phase and the ADSP Discovery Extension Phase
The initial phase of the ADSP research plan is called the ADSP Discovery Phase. Samples were selected from well-characterized study cohorts of individuals with or without and AD diagnosis and the presence or absence of known risk factor genes. The Discovery Phase generated three sets of genome sequence data for these samples: (1) WGS for 584 samples from 113 multiplex families (two or more affected per family), (2) Whole Exome Sequence (WES) for 5,096 AD cases and 4,965 controls, and (3) WES of an enriched sample set comprised of 853 AD cases from multiply affected families and 171 Hispanic controls. The Case-Control and Enriched Case Study spans 24 cohorts provided by the Alzheimer’s Disease Genetics Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
To assess the genomes in diversity sample sets (African American and Caribbean Hispanics) and from well phenotyped subjects with autopsy material, an additional 3,000 subjects were whole genome sequenced. This portion of the study is called the Discovery Extension Phase. These data have been harmonized with Discovery Phase data and called on Hg Build 38. They are available through application to NIAGADS.
As part of the Discovery Phase and Discover Extension Phase, the NIA ADSP genetics investigators funded under PAR-12-183 and the NHGRI-funded Large Scale Sequencing and Analysis Centers (LSACs) conducted analysis of sequence data, including quality assessments and variant calling. Analysis of the Discovery Phase and Discovery Extension Phase sequence data has identified many new variations in the genome that may be implicated as new genetic risk or protective factors in older adults at risk for AD. These findings are being pursued in the next phase of the study called the ADSP Follow-Up Study (FUS).
The ADSP Follow-Up Study (FUS)?
In February 2016, ADSP consultants recommended that subsequent sequencing and analysis be done on whole genomes in lieu of whole exome or targeted sequencing. Funding was provided for the sequencing and analysis of up to 10,000 whole genomes. Due to the increase in efficiencies and the decrease in cost of sequencing, additional funding for ADSP whole genome sequencing is provided here.
This FOA is intended to provide funding for NIA-funded AD genetics investigators participating in the ADSP. It is designed to create an avenue to increase statistical power, particularly for diversity sample sets, as variants for the disease are rare and can only be identified with a larger number of subjects in the study. Major goals for this FOA are:
Funds for analysis of these data are not a component of the present FOA. Investigators are encouraged to submit separate applications for ADSP data analysis.
Under the present FOA the ADSP will improve the likelihood of obtaining sequence data on enough different examples of events that can change the known genetic architecture of AD. These data, when analyzed with existing 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. 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.
One or more ADSP investigators will work with one or more sequencing centers, leveraging existing infrastructure. Collection, storage, sample processing, and handling of new samples and data will be funded under this initiative, as will acquisition of documentation essential to meet standards to adhere to NIH policy. Collaboration with the National Cell Repository for Alzheimer’s Disease (NCRAD); The American Genome Center at the Uniformed Services University for the Health Sciences (TAGC at USUHS)-or another NIA approved sequencing center (with pre-approval from NIA), the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania; and the Genome Center for Alzheimer's Disease (GCAD) at the University of Pennsylvania is considered essential for the successful application. ADSP genetics investigators will recruit cohorts of subjects affected with AD, identify and select subjects for study, acquire and process DNA, generate whole genome sequence (WGS) data, and perform the preliminary quality control (QC) analysis on sequence data from well phenotyped AD cases and controls, and make these data available for analysis. Investigators from foreign institutions are expected to confer with the NIA program officer before the submission of an application if an alternative sequencing center is chosen due to local policy or country laws.
Program Directors/Principal Investigators (PDs/PIs) are expected to engage in the study of existing cohorts where possible. Investigators will recruit, cognitively test, and adjudicate subjects. New cohorts should encompass the richest possible ethnic diversity. ADSP investigators should identify the cohorts with the largest possible representation of well characterized sample sets. Where ethnic cohorts are selected for the ADSP FUS, an appropriate number of unaffected individuals, as determined by power calculations, from the same population should be included in the study in order to enable assessment of population substructure and other factors related to the cohort. Investigators will ensure appropriate informed consent has been obtained from study participants.
For this competition ADSP investigators will submit applications that include the following groups as subcontracts to the study:
NIA-funded ADSP genetics investigators and the TAGC sequencing center at USUHS (or another NIA pre-approved sequencing center) will collaborate and provide DNA and sequence data for the ADSP FUS. All data included in the ADSP FUS will be variant called and QC'd on the ADSP pipeline (Hg 38) by GCAD and shared with the ADSP and the research community at large. Data will be shared through the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and/or another NIA approved data storage site. 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. Funds for GWAS studies should also be included.
Funds will be provided:
These efforts will increase statistical power to detect risk and protective genes for the ethnic subpopulations studied in the ADSP FUS.
NIA expects that this component of the ADSP will need to be highly collaborative among AD geneticists funded under: (1) PAR-12-183, RFA-AG-16-001, RFA AG-16-002, PAR 16-406 and under other individual NIA grants and cooperative agreements; (2) NCRAD investigators funded under PAR-15-316; (3) the National Alzheimer’s Coordinating Center (NACC) funded under PAR-11-213; (4) Investigators funded by the NHGRI under RFA-HG-15-001; (5) NIAGADS funded under PAR-16-047; and (6) The NIA Genome Center for Alzheimer's Disease (GCAD) funded under PAR-AG- 16-001. 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.
Sample Sets and Power Calculations
For WGS data analysis, large sample sets are needed to attain sufficient statistical power to identify rarer variants of lower effect. Current analyses suggest that as many as 25,000 cases and 25,000 controls could be required for a particular disease study focused on analysis of protein-coding regions. Analysis of noncoding sequence variants could require even larger sample numbers because they are expected to be more difficult to interpret (e.g., smaller effect size; less clear assignment to gene function).
Given finite availability of funding and time constraints for the ADSP FUS, NIA will support the acquisition and handling of DNA, archiving DNA, distribution of DNA, GWAS, whole genome sequencing (WGS), QC analysis, and data sharing on AD cases and controls with an emphasis on diversity sample sets, consistent with achieving the goals of the program. In order to meet time constraints, financial considerations, and the milestones provided under the National Alzheimer’s Project Act (NAPA), sequence data from unaffected subjects may be drawn from existing WGS data from sequencing projects performed in large, well characterized age-matched cohorts with documented appropriate cognitive function testing. Samples from AD subjects should be from existing cohorts and sample sets where possible. Samples may come from all types of epidemiology study designs, existing case/control, family based, and other sample sets where AD is the underlying form of dementia.
An important goal of this project is to achieve ethnic diversity in the sequencing project. Risk raising and protective variants occur at different frequencies in different populations. Furthermore, it is important to understand AD in different populations, as some risk or protective variants may be much easier to detect in some populations. NIA recognizes the need to recruit subjects in the case of certain populations such as Asian, African, Africa American, Hispanic (including Central and South America) and other diverse populations. Analysis of samples from different ethnic groups, especially those of non-European ancestry that are under-represented in the current study are a significant element of this FOA. A discussion of the rationale for sample selection is essential in order to be responsive to this announcement. This includes consideration of power and sample number; phenotypes and endophenotypes; disease sub-groups and extremes; power calculations for gene discovery of risk and protective factors; polygenic risk scores; and justification of inclusion of unaffected individuals in ethnic cohorts that includes power calculations.
Samples from subjects with quantitative trait measures may be included in order to more clearly define endophenotypes. The availability of high quality and extensive phenotypic information on each study subject is a critical practical and scientific consideration. Where relevant, environmental characterization of the persons from whom samples are drawn should be available. Preexisting or newly obtained participant consent and Institutional Review Board (IRB) clearances should allow for these investigations. The ability to carry out long-term follow up with study participants is desirable. For these reasons 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 phenotypes/endophenotyes regardless of the study design under which samples were collected.
NCRAD is a state-of-the-art sample repository for DNA, cell lines, plasma, serum, RNA, brain tissue, cerebrospinal fluid and peripheral blood mononuclear cells or fibroblasts.
To be appropriate for this FOA, samples from sample sets defined above will be provided by PD/PIs to NCRAD using standard operating procedures and documentation processing protocols to ensure compliance with NIH policy. For this component of the study, NCRAD will coordinate ADSP sample allocation by the following established procedures: request and obtain the WGS allocation for each of the sequencing centers; allocate samples from each of the contributing studies/sites in accordance with allocations in the ADSP discovery phase as well as the sequencing center target allocations; coordinate the complete material transfer agreement (MTA) with each of the contributing studies/sites with NCRAD; ensure that plates and/or materials are provided to each of the contributing studies/sites for sample shipment; identify and request replacement samples as needed.
The Role of the Sequencing Centers
Estimated costs for WGS have steadily declined since the technology was first developed. Because the sample sets that will be the subject of this initiative will be large, and the funding, though substantial, will be limited compared to the task, it is critical that the applicant sequencing center(s) recognize that significant cost reductions over time will provide a high confidence of attaining cost effectiveness, leveraging existing resources.
This FOA aims to fund a collaborative large-scale genome sequencing effort to identify risk and protective variants contributing to AD with the ultimate goal of doing this as comprehensively as possible within the evolving state-of-the-art. The sequencing center(s) will provide whole genome sequence and related data to GCAD. In some cases the sequencing center(s) may also perform GWAS. In addition to sequence data production, the sequencing center(s) will be involved in the QC and variant calling. The sequencing center(s) should have a demonstrated recent record of having generated large volumes of whole genome sequence data that are of high quality, have a record of collaboration or a strong indication that such interaction with NIA funded AD investigators will occur, have a strong working knowledge of the activities of the ADSP, and have a record of participation in analysis of complex diseases.
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 was designated as the Data Coordinating Center for the Project. . NIAGADS coordinates ADSP phenotype/genome wide association study (GWAS) data collection, sequence data production 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.
The Role of the Genome Center for Alzheimer’s Disease (GCAD)
The Genome Center for Alzheimer's Disease (GCAD) is funded under RFA-AG-16-001. The Center serves as a national resource for the specific purpose of identifying genetic and genomic factors that may lead to potential avenues for therapeutic approaches and prevention of Alzheimer's disease. The spectrum of the Center's activities comprises a multidisciplinary attack on AD in keeping with NIA's programmatic needs. GCAD was funded to assemble, quality control check, harmonize, and jointly analyze all of the genetic and phenotypic data associated with the ADSP. Data are provided to the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) for immediate sharing with the research community.
This FOA is intended to support their role in data receipt, processing, quality control measures, and variant calling. Specifically GCAD will: Receive and process sequence data from sequencing centers; provide QC and variant called sequence data to NIAGADS for data sharing; jointly analyze harmonized ADSP sequence data; coordinate and track the progress of the sequencing; deposit phenotypes for subjects participating in the study in NIAGADS; provide administrative support including reviewing documentation; receive data files and deposit them into NIAGADS; review dataset integrity; ensure that data are properly formatted for deposition at NIAGADS; ensure data documentation is accurate and complete; host information related to the project; maintain and provide genotype data as needed; maintain and develop the ADSP portal; assist in management of datasets deposited at NIAGADS; capture ADSP FUS sequence data, genotype data, and analysis data from the sequencing center(s); perform QC checking and variant calling in collaboration with the sequencing center(s) using the existing ADSP pipeline and established procedures employing existing ADSP Work Groups; and collaborate with investigators using alternative analytical tools such as artificial intelligence, machine learning, and deep learning approaches and novel bioinformatics and statistical approaches.
Applications considered for funding must effectively leverage NIA and NIH investment in infrastructure to support studies related to the genetics of AD. The ADSP FUS may utilize information from existing NIA-and NIH-funded research resources, including, but not limited to, the following:
In summary, ADSP investigators will generate a large amount of sequence and related data for the examination and comparison of the genomes of individuals affected with AD during the ADSP FUS. One or more ADSP investigators will work with one or more sequencing centers. PD/PIs will identify well characterized ethnically diverse sample sets that will comprise AD cases with related clinical/phenotypic and GWAS data. DNA from these subjects will be provided to NCRAD for processing, quality control checking, and assignment to sequencing centers. Sequencing centers will generate whole genome sequence data on affected individuals and controls from ethnically diverse populations and participate in the initial quality control and variant calling. These data will in turn be provided to NIAGADS for data management. Sequence data will be made available to CGAD for QC checking and variant calling. Studies funded under separate auspices will analyze the sequence data to identify new genes/regions/loci contributing to increased risk of developing the disease or protection against developing AD with the goal of identifying potential avenues for therapeutic approaches and prevention of the disease. Data resulting from the present study are expected to become available to qualified investigators through NIAGADS immediately upon completion of quality control checks to enable rapid identification of therapeutic targets.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
The scope of the proposed project should determine the project period, with the maximum project period being five years.
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
Non-domestic (non-U.S.) Entities (Foreign Institutions)
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.
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.
Applicants must have access to a sequencing center either through a subcontract or as part of the application. Applications from Non-domestic (non-U.S.) Entities (Foreign Institutions, Non-domestic (non-U.S.) components of U.S. Organizations, or Foreign components, as defined in the NIH Grants Policy Statement must have an established collaboration with a member or members of the ADSP.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
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.
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:
Marilyn Miller, Ph.D
National Institute on Aging (NIA)
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. Both the project itself and the ADSP should benefit from unique features of the scientific environment, subject populations, or collaborative arrangements. The research environment should have appropriate resources at the applicant Institution(s) to accomplish the research objectives of the project. It is expected that applicants will have the capacity to provide whole genome sequence data from affected individuals for identification and follow-up of genetic variants for the ADSP. The use of the research environment should appropriately leverage existing resources at the applicant's Institution(s) to accomplish the research objectives of the project.
Sequencing centers should have a demonstrated record of having generated large, high-quality volumes of WGS data, 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.
For sample and data acquisition, the PD(s)/PI(s) should have a deep understanding of the genetics of AD. The PD(s)/PI(s) should have demonstrated accomplishment in effectively interacting with subjects 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 groups where AD is the underlying form of dementia. 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 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.
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 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 sample allocation should be an aspect of the budget:
Subcontracts for NCRAD, NIAGADS, CGAD, and one or more sequencing centers must be provided.
Specific Aims: 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 planning and 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 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 and especially the ADSP and other major AD genetics projects. The applicant(s) should provide a rationale for selection of study subjects, and the approach and rationale for selection of sequencing methodology to be done 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 diagrams, and show how the research will serve particular communities of researchers studying Alzheimer's disease. Describe the strategy for effectively carrying out each specific aim. Explain how this component of the ADSP FUS will interface with the existing units of the ADSP. 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 this component of 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 Follow-Up Study 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.
Approach: The proposed study should describe a comprehensive plan to address the vital 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. Provide a rationale for selection of new cohorts of subjects affected with AD, in particular minority cohorts. 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. Provide the rationale and power calculations for inclusion of controls where ethnically diverse cohorts are to be engaged. The application should describe the processes, methods, and resources that will be used to identify and evaluate subjects, manage sample acquisition, and manage data handling and sharing. Explain the approach and rationale for selection of genotyping and sequencing methodology to be used in the study. Delineate plans 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 Alzheimer's disease. 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 this component of the ADSP FUS study will facilitate the mission of the ADSP, and how the ADSP FUS applicants will work cooperatively with the ADSP as a whole. Explain how the research plan will enable the ADSP to extend previous discoveries. Explain why the proposed approach is feasible, how risky aspects will be managed, and how this component of the ADSP FUS 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.
The following modifications also apply:
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 with the following additional instructions:
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.
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.
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.
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.
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.
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.
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 well suited are the PD(s)/PI(s) and other personnel to their roles in the ADSP FUS? 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? How appropriate are the experience and training of the key personnel for acquisition of ethnically diverse cohorts? How appropriate is their record of accomplishments in effectively managing large sample sets like the ADSP FUS? 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 sample and phenotypic and related data acquisition?? If the application is multi-PD/PI, do investigators have complementary and integrated expertise and skills in order to provide an appropriate leadership approach, governance, plans for conflict resolution, and organizational structure to the ADSP FUS? Does the sequencing center have a demonstrated record of having generated large volumes of WGS data that are of high quality; 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? Are sequencing center key personnel appropriate for the study design?
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 the ADSP FUS to the field of AD 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 or that are applicable in a broad sense? How innovative are approaches for sample and data acquisition, WGS, QC or variant calling, and data handling for QC'd datasets?
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 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 well reasoned and appropriate to accomplishing the specific aims of the project are the overall strategy, methodology, and analysis approaches? 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 investigators for this component of the project interface with the existing components and goals of the program?
How likely to be successful are the overall scientific goals and the expected outcomes? 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 likely is it that the selection of study subjects, especially including samples from diverse populations, and the approach and rationale for selection of sequencing methodology will reveal new AD risk and protective genetic factors? How appropriate and statistically well powered is the plan to study controls in the case of diversity population sample sets? How appropriate is the plan to obtain informed consent and perform cognitive testing on newly identified subjects? How appropriate are the proposed approach and rationale for selection of genotyping and sequencing methodology to be used in the study?
How responsive is the proposed study likely to be to 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 goals of the ADSP? How appropriate are benchmarks for success? How well does the proposed strategy establish feasibility and manage the risks associated with the activities of the projects as related to the AD research community? How appropriate are the proposed plans for work-flow and timelines? How well will the proposed ADSP FUS assist the research community and NIA in achieving the goals of the Alzheimer's disease research programs it proposes to serve? 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 diverse cohorts?
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 much will the institutional environment(s) in which the ADSP FUS operate(s) contribute to the probability of success in facilitating the AD research program it serves? How adequate are the institutional support, equipment and other physical resources available to the investigators? How adequate are resources available within the scientific environment to support electronic information handling?
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.
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, populations, or environmental conditions that exist in other countries and 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.
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.
Information regarding the disposition of applications is available 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.
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.
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 awardees 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 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 external consultants will provide membership to the ADSP FUS. 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 the NIA.
The PD/PI(s) of the cooperative agreement will be involved in collaborations with the ADSP, NIAGADS, The Genome Center for Alzheimer's Disease at USUHS and other NIA-approved sequencing centers, tthe National Cell Repository on Alzheimer's Disease (NCRAD; http://ncrad.iu.edu/), the NIA Genome Center for Alzheimer's Disease (GCAD), and other relevant NIA-funded entities during all phases of the award. 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. 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.
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, lead ADSP FUS 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. 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 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 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.
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.
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Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
National Institute on Aging (NIA)
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